Beruflich Dokumente
Kultur Dokumente
edited by
Jaap Verweij
Department of Medical Oncology
Erasmus University Medical Center
Rotterdam, The Netherlands
and
Herbert M. Pinedo
Department of Medical Oncology
Free University Medical Center
Amsterdam, The Netherlands
No part of this eBook may be reproduced or transmitted in any form or by any means, electronic,
mechanical, recording, or otherwise, without written consent from the Publisher
Index 181
This page intentionally left blank
Preface
Jaap Verweij
Herbert M. Pinedo
Editors
This page intentionally left blank
Chapter 1
Correspondence to:
Caroline Seynaeve, MD, PhD
Dept. of Medical Oncology,
Erasmus University Medical Centre-Daniel den Hoed Cancer Centre,
Groene Hilledijk 301
3075 EA Rotterdam, the Netherlands
2
1 INTRODUCTION
Although over the last decades several known and new compounds have
been tested for activity in STS, only doxorubicin and ifosfamide have
meaningful activity. For both drugs a dose-response curve in STS has been
identified, with higher response rates for doxorubicin administered at a cycle
dose of and ifosfamide at a cycle dose of or more.
Reported single agent response rates vary between 16-36%. Dacarbazine, while
yielding some activity, has only shown short lasting responses of limited value
(Seynaeve/Verweij, 1999; OSullivan et al, 2002). The value of these drugs has
been studied in neo-adjuvant, adjuvant and metastatic setting.
survival (Gortzak et al, 2001), the question remains actual since other groups
have suggested impressive response rates using more dose-intensive regimens
(Patel et al, 1998; Patel, 2002). The discussion has recently been stirred up by the
results of the study by Delaney et al. reporting on the activity of MAID (mesna,
adriamycin, ifosfamide and dacarbazine) interdigitated with radiotherapy and
followed by surgery and postoperative chemotherapy in a subset of STS at very
high risk of distant metastasis (Delaney et al, 2003, OSullivan/Bell, 2003). In
comparison with a cohort of historical controls, the MAID regimen resulted in a
dramatic improvement of distant disease free, disease-free and overall survival
being 75% and 44%, 70 and 42%, and 87% and 58% respectively, all being
statistically significant. As appealing these data may seem however, they have to
be interpreted with great caution since all results come from non-randomised
studies, while this approach should be investigated in randomised studies to
avoid for bias in the comparative groups before it can be incorporated as
standard of care.
A similar discussion is ongoing with respect to the role of adjuvant
therapy in STS (Verweij/Seynaeve, 1999). The most powerful evaluation of the
value of chemotherapy (doxorubicin-based, standard doses versus control)
originated from the Sarcoma Meta-Analysis Collaboration (SMAC) and showed
a statistically significant improvement in local relapse-free survival (6%), distant
metastasis-free (10%) and disease-free survival (10%) for treated patients, but
only a trend toward an increased overall survival (4%) after a median follow-up
of 9.4 years (SMAC, 1997). In 2001, the Italian Sarcoma Group reported that an
intensified chemotherapy regimen consisting of epirubicin/ifosfamide
in comparison with a control group, resulted in a significant
increase of disease-free (48 versus 16 months, p=.04) and overall survival (75
versus 46 months, p=.03) in high-risk STS after a follow up of 59 months.
Although this study was prematurely closed because of the interim results in
favour of the chemotherapy group, it has to be noticed that where fewer
metastatic events were seen at 2 years in the chemotherapy group (28% vs.
45%), identical metastatic rates were observed at the 4-year time point (Frustaci
et al, 2001). Long term follow-up data from this study are therefore crucial,
especially, where two other small studies using intensive
anthracycline/ifosfamide regimens failed to confirm a benefit (OSulllivan/Bell,
2003). Further, the data of the ongoing EORTC study investigating the value of
doxorubicin versus controls will hopefully add
relevant information on this issue
Over the last decades of clinical research it has been recognised that
many of the STS subtypes are associated with distinctive clinical and prognostic
features. Therefore, it has already longer been questioned whether the one-size-
fits-all-approach with respect to chemotherapy as has been applied till now is
still appropriate. An analysis of the Soft Tissue and Bone Sarcoma Group Study
(STBSG) of the EORTC into prognostic factors for the outcome of
chemotherapy in advanced STS reported in univariate analysis an increased
overall survival (OS) in lipo- and synovial sarcoma (SS), a decreased survival
time in malignant fibrous histiocytoma (MFH), a lower response rate in
leiomyosarcoma (LMS), and a higher response rate in liposarcoma (p<0.05, for
all log-rank and X2 tests). In multivariate analysis, the subtype dropped out of
the logistic model as independent prognostic factor (van Glabbeke et al, 1999).
Comments that should be considered hereby are: in the multivariate analysis
liver involvement, irrespective of the subtype, was included as covariate, being
the more important with respect to the subtypes as for example synovial sarcoma
where this metastatic pattern is only infrequently observed; the EORTC database
has been set up at a moment that the histologic entity of gastrointestinal stromal
tumours (GIST) had not yet been identified, and therefore a number of so-called
leiomyosarcomas probably were GISTs which at this moment are known to be
chemotherapy-insensitive. In a more recent publication of the EORTC,
progression-free rates (PFR) at 6 months (as an alternative for response rate) in
non-pre-treated patients differed between subtypes, showing a PFR > 50% in
synovial and liposarcoma, and in LMS and MFH (see figure 1) (van
Glabbeke et al, 2002). This is in accordance with the clinical observation that SS
is more chemo-sensitive. Whether this chemosensitivity indeed especially
6
concerns high-dose ifosfamide as has been reported in small series (Rosen et al,
1994, Spillane et al, 2000), remains to be proven in larger studies. However, the
above mentioned may partly explain why some investigators report impressive
results of a certain agent in a specific STS subtype, albeit that this was never
observed in properly designed studies allowing inclusion of a variety of
subtypes.
6 CONCLUSION
7 REFERENCES
1. Balcerzak SB, Benedetti J, Weiss GR et al. (1995) A phase II trial of paclitaxel in patients with
advanced soft tissue sarcomas. Cancer 76, 2248-2252
2. Blay J-Y, van Glabbeke M, Verweij J, et al. (2003) Advanced soft tissue sarcoma: a disease that
is potentially curable for a subset of patients treated with chemotherapy. Eur J Cancer 39: 64-69
3. Borden EC, Baker LH, Bell RS et al. (2003) Soft tissue sarcomas of adults: state of the
translational science. Clin Cancer Research 9: 1941-56
4. Brain EGC (2002) Safety and efficacy of ET-743: the French experience. Anti-cancer Drugs 13
(suppl 1): 11-14
5. Bramwell V, Anderson HC, Charette ML et al. (2000) Doxorubicin-based chemotherapy for
the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma: a
meta-analysis and clinical practice guidelines. Sarcoma, 4: 103-112
6. Casper ES, Waltzman RJ, Schwartz GK et al. (1998) Phase II trial f paclitaxel i patients with
soft tissue sarcoma. Cancer Invest 16: 442-446
7. Delaloge S, Yovine A, Taamma A et al. (2001) Ecteinasidin-743: a marine derived compound
in advanced, pretreated sarcoma patients preliminary evidence of activity. J Clin Oncol 19: 1248-
1255
8. Delaney TF, Spiro IJ, Suit HD et al. (2003) Neoadjuvant chemotherapy and radiotherapy for
large extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys, 56: 1117-1127
9. Demetri GD (2002) ET-743: the US experience in sarcomas of soft tissues. Anti-cancer Drugs
13 (Suppl 1): 7-9
10. Dent S, Zee B, Dancey J et al. (2001) Application of a new multinomial phase II stopping rule
using response and early progression. J Clin Oncol 19: 785-791
11. Fata F, OReilly E, Ilson D et al. (1999) Paclitaxel in the treatment of patients with
angiosarcoma of the scalp or face. Cancer 86: 2034-2037
12. Frustaci S, Gherlinzoni F, de Paoli A, et al. (2001) Adjuvant chemotherapy for adult soft tissue
sarcomas of the extremities and girdles : results of the Italian randomized cooperative trial. J Clin
Oncol, 19: 1238-1247
13. Gortzak E, Azarelli A, Buesa J et al. (2001) A randomised phase II study on neo-adjuvant
chemotherapy for high-riskadult soft tissue sarcoma. Eur J Cancer 37: 1096-1103
14. Hensley ML, Maki R, Venkatraman E et al. (2002) Gemcitabine and docetaxel with
unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 20: 2824-2831
15. Korn EL, Arbuck SG, Pluda JM et al. (2001) Clinical trial designs for cytostatic agents: are
new approaches needed? J Clin Oncol 19: 265-272
16. Labropoulos SV, Papadopoulos S, Hadjiyiassemi L et al. (2003) Response of metastatic
dermatofibrosarcoma protuberans to imatinib mesylate. Proceedings ASCO 2003, J Clin Oncol 22:
830 (#3334)
17. Le Cesne A. (2002) Improving efficacy in soft tissue sarcoma. Satellite symposium ESMO
2002, 18 October, Nice, France.
18. Lee Y-F, John M, Edwards S et al. (2003) Molecular classification of synovial sarcomas,
leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. Brit J Cancer
88: 510-515
14
19. Leyvraz S, Jundt G, Lissoni A et al. (2001) High-dose Ifosfamide and doxorubicin for the
treatment of gynaecological sarcomas. Proceedings ASCO 2001, J Clin Oncol 20 (part 1): 362a
(#1443)
20. Nielsen TO, West RE, Linn SC et al. (2002) Molecular expression of soft tissue tumours: a
gene expression study. Lancet 359: 1301-1307
21. Okuno S, Edmonson J, Mahoney M et al. (2002) Phase II trial of gemcitabine in advanced
sarcoma. Cancer 94: 3225-3229
22. Okuno S, Ryan LM, Edmonson J et al. (2003) Phase II trial of gemcitabine in patients with
advanced sarcomas. Cancer 97: 1969-1973
23. OSullivan B, Bell RS, Bramwell V (2002) Sarcoma of the soft tissue. In: Souhami R,
Tannock I, Hohenberger P, and Horiot JC (eds): Oxford Textbook of Oncology. Oxford
University Press, Oxford, UK, 2002, 2495-2523
24.OSullivan B, Bell RS (2003) Has MAID made it in the management of high-risk soft tissue
sarcoma? Int J Radiat Oncol Biol Phys, 56: 915-916
25. Pautier P, Genestie C, Fizazi K et al. (2002) Cisplatin-based chemotherapy regimen (DECAV)
for uterine sarcomas. Int J Gynaecol Cancer 12: 749-754
26. Patel SR, Linke KA, Burgess MA et al. (1997) Phase II study of paclitaxel in patients with soft
tissue sarcomas. Sarcoma 1, 95-97
27. Patel SR, Vadhan-Rai S, Burgess MA, et al. (1998) Results of two consecutive trials of dose-
intensives chemotherapy with doxorubicin and ifosfamide in patients with sarcoma. Am J Clin
Oncol 21: 317-321
28. Patel SR, Gandhi V, Jenkins J et al. (2001) Phase II clinical investigation of gencitaine in
advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate
accumulation. J Clin Oncol 19: 3483-4389
29. Patel SR (2002) Systemic therapy for advanced soft tissue sarcoma. Curr Oncol Rep 4: 299-
304
30. Robertson JFR, Wilsher PC, Cheung KL et al. (1997) The clinical relevance of static disease
category for 6 months on endocrine therapy in patients with breast cancer. Eur J Cancer 33: 1774-
1779
31. Robertson JFR, Howell A, Buzdar A et al. (1999) Static disease on anastrozole provides
similar benefit as objective response in patients with advanced breast cancer. Breast Ca Res &
Treatm 58: 157-162
32. Rosen G, Forscher C, Lowenbraun S et al. (1994) Synovial sarcoma: uniform responsee of
metastases to high-dose ifosfamide. Cancer 73: 2506-2511
33. Sarcoma Meta-Analysis Collaboration (1997) Adjuvant chemotherapy for localised respectable
soft tissue sarcoma of adults: meta-analysis of individual data. Lancet 350: 1647-1654
34. Scappaticci FA, Marina N (2001) New molecular targets and biological therapies in sarcomas.
Ca Treatm Reviews 27: 317-326
35. Schuetze SM, Rubin BP, Eary JF et al. (2002) Molecular targeting of PDGF beta by imatinib
mesylate in dermatofibrosarcoma protuberans. Proceedings CTOS 2002, Sarcoma 6 (suppl 2): 71
(#25)
36. Seynaeve C, Verweij J (1999) High-dose chemotherapy in adult sarcomas: no standard yet.
Semin Oncol, 26: 119-133
37. Seynaeve C, Verweij J. (2002) High dose chemotherapy in sarcomas: science, fiction or
science fiction? In: Lorigan P, Vandenberghe E (eds): High dose chemotherapy, Principles and
Practice. Dunitz Publishers, London, UK, 2002, 167-179,
38. Spath-Schwalbe E, Genvresse I, Koschuth A et al. (2000) Phase II trial of gemcitabine in
patients with pretreated advanced soft tissue sarcoma. Anti-cancer drugs 11: 325-329
39. Spillane AJ, AHern R, Judson I et al. (2000) Synovial sarcoma: a clinicopathologic, staging,
and prognostic assessment. J Clin Oncol, 16: 1794-3803
40. Stojadinovic A, Leung DHY, Allen P et al. (2002) Primary adult soft tissue sarcoma: Time-
dependent influence of prognostic variables. J Clin Oncol 20: 4344-4352
15
41. Svancarova L, Blay J-Y, Judson I et al. (2002) Gemcitabine in advanced adult soft tissue
sarcomas. A phase II study of the EORTC soft tissue and bone sarcoma group. Eur J Cancer 38:
556-559
42. Therasse P, Arbuck GA, Eisenhauer EA et al. (2000) New guidelines to evaluate the response
to treatment in solid tumors. J Natl Cancer Inst 92: 205-216
43. Tuveson DA, Fletcher JA (2001) Signal transduction pathways in sarcoma as targets for
therapeutic intervention. Curr Opin Oncol 13: 249-255
44. Van Glabbeke M, van Oosterom AT, Oosterhuis JW et al. (1999) Prognostic factors for the
outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated
with anthracycline-containing first line regimens an EORTC soft tissue and bone sarcoma group
study. J Clin Oncol 17: 150-157
45. Van Glabbeke M, Verweij J, Judson I et al. (2002) Progression-free rate as the principal end-
point for phase II trials in soft-tissue sarcomas. Eur J Cancer 38: 543-549
46. Van Oosterom AT (1986) Phase II new drug trials in soft tissue sarcomas. In: Pinedo H and
Verweij J (eds): Clinical management of soft tissue sarcomas. Boston, MA, Martinus Nijhoff
Publishers, 131-138
47. Verweij J, Seynaeve C. (1999) The reason for confining the use of adjuvant chemotherapy in
soft tissue sarcoma to the investigational setting. Semin in Radiation Oncology, 9: 352-359
48. Verweij J, Lee SM, Ruka W et al. (2000) Randomized phase II study of docetaxel versus
doxorubicin in first- and second-line chemotherapy fr locally advanced or metastatic soft tissue
sarcoma in adults: a study of the EORTC soft tissue and bone sarcoma group. J Clin Oncol 18:
2081-2086
49. Verweij J, van Glabbeke M (2003) Translating targets into treatment: changes in trial
methodology and treatment approaches for soft tissue sarcomas. In: Educational book, ASCO
2003, 522-530
50. Weiss SW, Goldblum JR (2001) In: Weiss SW, Goldblum JR (eds): Enzinger and Weisss Soft
Tissue Tumors. Mosby Inc, St Louis, Missouri, 2001: 1-19
This page intentionally left blank
Chapter 2
Correspondence:
Brian OSullivan
Department of Radiation Oncology
Princess Margaret Hospital
University of Toronto
610 University Avenue
Toronto, Ontario
Canada, M5G 2M9
Tel: 416 946 2123
Fax: 416 946 6556
Email: brian.osullivan@rmp.uhn.on.ca
18
1 INTRODUCTION
ensure that the fascial planes are appropriately recognized and encompassed in
the radiation target volume. 2
and treatment planning and delivery systems could not tailor radiation dose to
irregularly shaped volumes. Consequently, for many years conventional
radiotherapy technique for limb STS essentially comprised two parallel opposed
rectangular fields.10
Over the last decade unprecedented improvements in treatment planning
and delivery have become available. Two new approaches, three-dimensional
conformal radiotherapy (3D CRT) and intensity-modulated radiation therapy
(IMRT), have been successfully applied to the treatment of other cancers, but
their application to the management of STS is very new. The introduction of 3D
CRT and IMRT is an important opportunity to reevaluate many aspects of the
current treatment paradigm, which had evolved under the technological
constraints of the past.
assessment of coverage of the target volume by a single beam and the potential
for collision of couch and gantry). Presentation of dose distributions in different
planes and in three dimensions allow assessment of RT dose perturbation within
and adjacent to the target volume, including hot spots and cold spots.
3D CRT procedures facilitate development of a plan which deposits
dose to the target volume with minimal dose to surrounding tissues. The degree
of conformality may be quantified by the conformity index (CI), which is the
ratio of volume enclosed by the prescription isodose surface to the planning
target volume (PTV). 14 This is somewhat helpful in comparing candidate plans
but in practice it is more useful to compare dose-volume histograms (DVHs) for
volumes of interest (figure 3), 15 as the CI does not fully reveal the effects on
critical structures.
The IMRT concept relies on the fact that multiple beams crossing a
target from different directions do so with great redundancy that can be
harnessed to provide substantial flexibility in distributing dose. Instead of
permitting the full intensity of a beam to traverse the target, the dose in part(s)
of the field aperture is reduced in a variable way (by programming the
configuration and timing of the MLC leaf positions), according to the
requirements. This can permit sparing of a structure on the one hand or delivery
of relatively enhanced dose to the target in another part of the field aperture
thereby causing deliberate perturbation of the RT dose distribution of a beam.
At the same time, the variable dose incurred in components of the aperture of a
given beam by this process can be compensated by enhancing or reducing the
dose in components of the apertures of other beams directed at the target from
other directions. In this way a beam directed from a given direction, can be
fashioned to comprise numerous (e.g. dozens to hundreds) of mini-beams
(termed beamlets) with variable shape and intensity of radiation exposure.
The ultimate result from the combination of numerous beams of
different direction, intensity patterns, and shape provides an unprecedented three
dimensional configuration to the composite dose distribution from all beams.
Ironically, it is now reasonably certain that the capability of placing dose and
avoiding tissues is significantly more precise than our knowledge of what issues
are indeed involved and the measures required to minimize geometric
uncertainty related to normal physiologic movements in the patient (eg.
breathing, adjustment related to hollow viscous filling and emptying, etc).
lung avoidance in different situations. This differs from the discussion of late
tissue toxicity (section 4.1), because the context here concerns whether
radiotherapy can be delivered at all with curative intent, out of concern for life
threatening complications to critical anatomy. This approach may be best
exemplified by retroperitoneal sarcomas and paraspinal tumours.
Retroperitoneal sarcoma frequently recurs locally, despite optimal
surgery, and radiotherapy is often used pre-, intra- or postoperatively to improve
control.25-28 Local recurrences are still the rule, however. The need to observe
the tolerance of bowel, liver, kidneys and other organs generally requires that
lower doses be prescribed than for sarcomas at other sites and target coverage is
often compromised. 3D CRT and MRT provide the opportunity to treat large
and complex retroperitoneal tumor volumes that were previously close to
impossible to treat. These modalities are especially well suited to pre-operative
radiotherapy because the target is in situ with less risk of intra-abdominal
contamination so that the region to be treated can be readily defined. In
addition, bowel is both mobile and displaced by the tumor and treatment is well
tolerated 28 in contrast to the post-operative setting 29 where the bowel is
frequently tethered in the surgical bed making safe delivery of substantive doses
of radiotherapy problematic. In addition, a problem that is especially difficult is
presented by the large right sided retroperitoneal sarcoma where tumor is in
direct proximity to the liver and frequently hooded by this stucture. Standard
radiotherapy cannot achieve safe coverage of the target while permitting the
liver to be spared. Even 3D CRT is problematic for these lesions and IMRT
presents many advantages (figure 5).
Paraspinal tumors also pose prodigious problems for the safe delivery of
radiotherapy. The real possibility exists for the spine to be severely injured by
the treatments themselves (radiotherapy and surgery are both severely
constrained by normal tissue tolerance) or by tumor. Target volumes partially
enveloping the spinal cord pose a challenge in dose delivery not previously
achievable with standard planning but that can be overcome with IMRT (see
figure 3 and 4, and table 2).
4.3 Retreatment
Reirradiation of limb soft tissue sarcoma after local recurrence has been
shown to contribute to limb conservation, although there is a risk of inducing
radionecrosis, chronic ulceration and fracture. 30, 31 Brachytherapy has been
advocated as the optimal radiation modality for this situation 31-34 but IMRT has
the potential advantages, through inverse planning, to tailor the dose to treat
sites inaccessible to brachytherapy. This approach has been used successfully to
retreat vertebral metastases, including sarcoma,35 and it is well suited to locally
recurrent STS.
31
32
7 OTHER MODALITIES
8 FUTURE PERSPECTIVES
9 CONCLUSION
10 REFERENCES
1. Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy, revisited. Members of the
Musculoskeletal Tumor Society [see comments]. J Bone Joint Surg Am 1996;78(5):656-63.
2. OSullivan B, Wunder J, Pisters PW. Target description for radiotherapy of soft tissue
sarcoma. In: Gregoire V, Scalliet P, Ang KK, editors. Clinical target volumes in conformal
radiotherapy and intensity modulated radiotherapy. Heidelberg: Springer; 2003. p. 205-227.
3. OSullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, Wunder J, Kandel R,
Goddard K, Sadura A, Pater J, Zee B. Preoperative versus postoperative radiotherapy in soft-
tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359(9325):2235-41.
4. Panicek DM, Schwartz LH. Soft tissue edema around muskuloskeletal sarcomas at
magnetic resonance imaging. Sarcoma 1997; 1:189-191.
39
5. ICRU Report 50. Prescribing, Recording, and Reporting Photon Beam Therapy. Bethesda:
International Commission on Radiation Units and Measurement; 1993.
6. ICRU Repor t62. Prescribing, Recording, and Reporting Photon Beam Therapy
(Supplement to ICRU Report 50). Bethesda: International Commission on Radiation Units
and Measurement; 1999.
7. Nielsen OS, Cummings B, OSullivan B, Catton C, Bell RS, Fornasier VL. Preoperative
and postoperative irradiation of soft tissue sarcomas: effect of radiation field size. Int J Radiat
Oncol Biol Phys 1991;21(6):1595-9.
8. Enneking WF, Spanier SS, Goodman MA. Current concepts review. The surgical staging
of musculoskeletal sarcoma. J Bone Joint Surg Am 1980;62(6):1027-30.
9. Simon MA, Enneking WF. The management of soft-tissue sarcomas of the extremities. J
Bone Joint Surg Am 1976;58(3):317-27.
10. Tepper J, Rosenberg SA, Glatstein E. Radiation therapy technique in soft tissue sarcomas
of the extremity--policies of treatment at the National Cancer Institute. Int J Radiat Oncol Biol
Phys 1982;8(2):263-73.
11. Lindberg RD, Martin RG, Romsdahl MM, Barkley HT, Jr. Conservative surgery and
postoperative radiotherapy in 300 adults with soft-tissue sarcomas. Cancer 1981;47(10):2391-
7.
12. Suit HD, Spiro I. Role of radiation in the management of adult patients with sarcoma of
soft tissue. Semin Surg Oncol 1994;10(5):347-56.
13. Emami B, Graham MV, Michalski JM, Perez CA. Three-Dimensional Conformal
Radiation Therapy: Clinical Aspects. In: Perez CA, Brady LW, editors. Principles and
Practice of Radiation Oncology. 3rd ed. Philadelphia: Lippincott-Raven; 1998. p. 371-386.
14. Knoos T, Kristensen I, Nilsson P. Volumetric and dosimetric evaluation of radiation
treatment plans: radiation conformity index. Int J Radiat Oncol Biol Phys 1998;42(5):1169-
76.
15. Mohan R, Brewster LJ, Barest GD. A technique for computing dose volume histograms
for structure combinations. Med Phys 1987;14(6):1048-52.
16. Ling CC, Humm J, Larson S, Amols H, Fuks Z, Leibel S, Koutcher JA. Towards
multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality.
Int J Radiat Oncol Biol Phys 2000;47(3):551-60.
17. IMRT. Intensity-modulated radiotherapy: current status and issues of interest. IMRT
Collaborative Working Group. Int J Radiat Oncol Biol Phys 2001;51(4):880-914.
18. Webb S. Advances in three-dimensional conformal radiation therapy physics with
intensity modulation. Lancet Oncol 2000;1(1):30-6.
19. Robinson MH, Spruce L, Eeles R, Fryatt I, Harmer CL, Thomas JM, Westbury G. Limb
function following conservation treatment of adult soft tissue sarcoma. Eur J Cancer
1991;27(12):1567-74.
20. Stinson SF, DeLaney TF, Greenberg J, Yang JC, Lampert MH, Hicks JE, Venzon D,
White DE, Rosenberg SA, Glatstein EJ. Acute and long-term effects on limb function of
combined modality limb sparing therapy for extremity soft tissue sarcoma. Int J Radiat Oncol
Biol Phys 1991;21(6):1493-9.
21. OSullivan B, Davis A. A Randomized phase III trial of pre-operative compared to post-
operative radiotherapy in extremity soft tissue sarcoma.[Abstract].Proc 43rd Annual Meeting,
American Society of Therapeutic Radiology and Oncology. Int J Radiation Oncology Biol
Phys 2001;51(3, supplement 1):151.
22. Millar BM, Bragg CM, Conway J, Robinson MH. Investigation of the use of intensity
modulated radiotherapy (IMRT) in comparison with conformal radiotherapy in the
management of soft tissue sarcoma.[Abstract]. Proc 43rd Annual Meeting, American Society
of Therapeutic Radiology and Oncology. International Journal of Radiation Oncology
Biology Physics 2001;51(3 (Supplement 1)):412.
23. Holt GE, Wunder JS, Griffin AM, Bell RS. Fractures following radiation therapy and
limb salvage surgery for soft tissue sarcomas: high versus low dose radiotherapy.[Abstract]
Proc Muskuloskeletal Tumor Society 2002:41.
40
24. Hong L, Alektiar K, Hunt M, Leibel S. Intensity Modulated Radiotherapy for Soft Tissue
Sarcoma of Thigh [Abstract]. Proc 44th Annual Meeting, American Society of Therapeutic
Radiology and Oncology. Int J Radiat Oncol Biol Phys 2002;54 (2S):140-1.
25. Gieschen HL, Spiro IJ, Suit HD, Ott MJ, Rattner DW, Ancukiewicz M, Willett CG.
Long-term results of intraoperative electron beam radiotherapy for primary and recurrent
retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys 2001;50(1):127-31.
26. Petersen IA, Haddock MG, Donohue JH, Nagorney DM, Grill JP, Sargent DJ, Gunderson
LL. Use of intraoperative electron beam radiotherapy in the management of retroperitoneal
soft tissue sarcomas. Int J Radiat Oncol Biol Phys 2002;52(2):469-75.
27. Stoeckle E, Coindre JM, Bonvalot S, Kantor G, Terrier P, Bonichon F, Nguyen Bui B.
Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165
patients of the French Cancer Center Federation Sarcoma Group. Cancer 2001;92(2):359-68.
28. Jones JJ, Catton CN, OSullivan B, Couture J, Heisler RL, Kandel RA, Swallow CJ.
Initial results of a trial of preoperative external-beam radiation therapy and postoperative
brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol 2002;9(4):346-54.
29. Gilbeau L, Kantor G, Stoeckle E, Lagarde P, Thomas L, Kind M, Richaud P, Coindre JM,
Bonichon F, Bui BN. Surgical resection and radiotherapy for primary retroperitoneal soft
tissue sarcoma. Radiother Oncol 2002;65(3):137-43.
30. Graham JD, Robinson MH, Harmer CL. Re-irradiation of soft-tissue sarcoma. Br J Radiol
1992;65(770):157-61.
31. Nori D, Schupak K, Shiu MH, Brennan MF, Shupak K. Role of brachytherapy in
recurrent extremity sarcoma in patients treated with prior surgery and irradiation. Int J Radiat
Oncol Biol Phys 1991;20(6):1229-33.
32. Catton C, Davis A, Bell R, OSullivan B, Fornasier V, Wunder J, McLean M. Soft tissue
sarcoma of the extremity. Limb salvage after failure of combined conservative therapy.
Radiother Oncol 1996;41(3):209-14.
33. Pearlstone D, Janjan NA, Feig B, Yasko A, Hunt K, Pollock R, Lawyer A, Horton J,
Pisters P. Re-resection with brachytherapy for locally recurrent soft tissue sarcoma arising in a
previously irradiated field. Cancer J Sc Am 1999;5(1):26-33.
34. Crownover RL, Marks KE. Adjuvant brachytherapy in the treatment of soft-tissue
sarcomas. Hematol Oncol Clin North Am 1999;13(3):595-607.
35. Milker-Zabel S, Zabel A, Thilmann C, Schlegel W, Wannenmacher M, Debus J. Clinical
results of retreatment of vertebral bone metastases by stereotactic conformal radiotherapy and
intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2003;55(1):162-7.
36. Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term
results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J
Clin Oncol 1996;14(3):859-68.
37. Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, DeLaney T,
Glatstein E, Steinberg SM, Merino MJ, Rosenberg SA. Randomized prospective study of the
benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity.
J Clin Oncol 1998;16(1):197-203.
38. OSullivan B, Bell R. Has MAID made it in the management of high-risk soft-tissue
sarcoma. International Journal of Radiation Oncology Biology Physics 2003;56(4):915-916.
39. Cormier JN, Patel SR, Herzog CE, Ballo MT, Burgess MA, Feig BW, Hunt KK, Raney
RB, Zagars GK, Benjamin RS, Pisters PW. Concurrent ifosfamide-based chemotherapy and
irradiation. Analysis of treatment-related toxicity in 43 patients with sarcoma. Cancer
2001;92(6):1550-5.
40. Sauer R, Schuchardt U, Hohenberger W, Wittekind C, Papadopoulos T, Grabenbauer GG,
Fietkau R. [Neoadjuvant radiochemotherapy in soft tissue sarcomas. Optimization of local
functional tumor control]. Strahlenther Onkol 1999;175(6):259-66.
41. DeLaney TF, Spiro IJ, Suit HD, Gebhardt MC, Hornicek FJ, Mankin HJ, Rosenberg AL,
Rosenthal DI, Miryousefi F, Ancukiewicz M, Harmon DC. Neoadjuvant Chemotherapy and
Radiotherapy for Large Extremity Soft Tissue Sarcomas. International Journal of Radiation
Oncology Biology Physics 2003;56(4): 1117-1127.
41
42. Coles CE, Twyman N, Earl HM, Burnet NG. Conformal radiotherapy facilitates the
delivery of concurrent chemotherapy and radiotherapy: a case of primitive neuroectodermal
tumour of the chest wall. Sarcoma 2000;4(3):129-133.
43. Haycocks T, Kelly V, Islam M, OSullivan B, Swallow CJ, Catton CN. High resolution,
intensity modulated radiation therapy (IMRT) for retroperitoneal soft tissue sarcoma (RPS)
[Abstract]. Proceedings of the 7th Annual Meeting of the Connective Tissue Oncology
Society. Sarcoma 2001;5(Supplement 1,):S24-S25.
44. OSullivan B, Wylie J, Catton C, Gutierrez E, Swallow CJ, Wunder J, Gullane P, Neligan
P, Bell R. The local management of soft tissue sarcoma. Semin Radiat Oncol 1999;9(4):328-
48.
45. Low DA. Quality assurance of intensity-modulated radiotherapy. Semin Radiat Oncol
2002;12(3):219-28.
46. Dixon P, OSullivan B. Radiotherapy quality assurance: time for everyone to take it
seriously. Eur J Cancer 2003;39(4):423-9.
47. Purdy JA. Dose-volume specification: New challenges with intensity-modulated radiation
therapy. Semin Radiat Oncol 2002;12(3):199-209.
48. Pirzkall A, Carol M, Lohr F, Hoss A, Wannenmacher M, Debus J. Comparison of
intensity-modulated radiotherapy with conventional conformal radiotherapy for complex-
shaped tumors. Int J Radiat Oncol Biol Phys 2000;48(5):1371-80.
49. Verellen D, Vanhavere F. Risk assessment of radiation-induced malignancies based on
whole-body equivalent dose estimates for IMRT treatment in the head and neck region.
Radiother Oncol 1999;53(3):199-203.
50. Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT.
Int J Radiat Oncol Biol Phys 2003;56(1):83-8.
51. Kovacs G, Hebbinghaus D, Dennert P, Kohr P, Wilhelm R, Kimmig B. Conformal
treatment planning for interstitial brachytherapy. Strahlenther Onkol 1996;172(9):469-74.
52. Catton CN, Swallow CJ, OSullivan B. Approaches to local salvage of soft tissue sarcoma
after primary site failure. Semin Radiat Oncol 1999;9(4):378-88.
53. Suit H. The Gray Lecture 2001: coming technical advances in radiation oncology. Int J
Radiat Oncol Biol Phys 2002;53(4):798-809.
54. Ma CM, Pawlicki T, Lee MC, Jiang SB, Li JS, Deng J, Yi B, Mok E, Boyer AL. Energy-
and intensity-modulated electron beams for radiotherapy. Phys Med Biol 2000;45(8):2293-
311.
55. Nishizawa K, Okunieff P, Elmaleh D, McKusick KA, Strauss HW, Suit HD. Blood flow
of human soft tissue sarcomas measured by thallium-201 scanning: prediction of tumor
response to radiation. Int J Radiat Oncol Biol Phys 1991;20(3):593-7.
56. Nelson SJ. Multivoxel magnetic resonance spectroscopy of brain tumors. Mol Cancer
Ther 2003;2(5):497-507.
57. Sijens PE. Phosphorus MR spectroscopy in the treatment of human extremity sarcomas.
NMR Biomed 1998;11(7):341-53.
58. Baudelet C, Gallez B. How does blood oxygen level-dependent (BOLD) contrast
correlate with oxygen partial pressure (pO2) inside tumors? Magn Reson Med
2002;48(6):980-6.
59. Jaffray DA, Siewerdsen JH, Wong JW, Martinez AA. Flat-panel cone-beam computed
tomography for image-guided radiation therapy. Int J Radiat Oncol Biol Phys
2002;53(5):1337-49.
60. Mackie TR, Kapatoes J, Ruchala K, Lu W, Wu C, Olivera G, Forrest L, Tome W, Welsh
J, Jeraj R, Harari P, Reckwerdt P, Paliwal B, Ritter M, Keller H, Fowler J, Mehta M. Image
guidance for precise conformal radiotherapy. Int J Radiat Oncol Biol Phys 2003;56(1):89-105.
42
61. Borden EC, Baker LH, Bell RS, Bramwell V, Demetri GD, Eisenberg BL, Fletcher CD,
Fletcher JA, Ladanyi M, Meltzer P, OSullivan B, Parkinson DR, Pisters PW, Saxman S,
Singer S, Sundaram M, Van Oosterom AT, Verweij J, Waalen J, Weiss SW, Brennan MF.
Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Res
2003;9(6):1941-56.
62. Partsch H, Stoberl C, Wruhs M, Wenzel-Hora BI. Indirect lymphography with iotrolan.
Fortschr Geb Rontgenstrahlen Nuklearmed Erganzungsbd 1989;128:178-81.
Chapter 3
Correspondence to:
Peter Pisters MD
The University of Texas M. D. Anderson Cancer Center,
1515 Holcombe Boulevard
Box 444
Houston, TX 77030-4009
USA
44
1 INTRODUCTION
2.2 Sarcomas
Sarcomas are among the group of solid tumors for which the benefits
of induction therapy have been difficult to establish. Survival benefits have
not been definitively demonstrated because of the paucity of adequately
powered randomized clinical trials. However, single-institution reports
suggest that preoperative therapy enables tumor downstaging and organ
sparing in some patients.
Several distinct groups of sarcomas are recognized: soft tissue
sarcomas, bone sarcomas (osteosarcomas and chondrosarcomas), Ewings
sarcomas, and peripheral primitive neuroectodermal tumors. Since the late
1980s, preoperative chemotherapy has been the standard treatment for
patients with osteosarcoma based on data from randomized controlled trials
demonstrating a significant survival advantage with systemic therapy (4,5).
The histologic subtypes rhabdomyosarcoma and Ewings sarcoma have been
demonstrated to have a higher propensity for systemic metastases, and for
these histologies, the addition of chemotherapy may have survival advantages
and is considered standard care (6,7).
The use of chemotherapy (preoperative or postoperative) for other
sarcomas remains controversial. Patients with large (> 5 cm), high-grade,
deep, extremity soft tissue sarcomas (American Joint Committee on Cancer
stage III) commonly develop distant recurrence and subsequently die of
sarcoma. Consequently, pre- or postoperative anthracycline-based
chemotherapy is often considered in these patients.
46
Based on the high rates of local control obtained with surgery plus
radiation therapy in patients with extremity and trunk sarcomas, there has
been interest in attempting such strategies for patients with retroperitoneal
sarcomas.
Administering preoperative radiation therapy to retroperitoneal soft
tissue sarcomas is complex. Large tumors in proximity to vital radiosensitive
anatomic structures frequently hinder safe delivery of treatment. However,
there are several advantages to administering radiation therapy preoperatively
for retroperitoneal sarcomas: the gross tumor volume is definable, which
allows accurate treatment planning; tumors often displace radiosensitive
viscera outside of the radiation field; and biologically effective radiation
doses may be lower in the preoperative setting (15).
Several groups have prospectively examined the effects of
preoperative and intraoperative radiation therapy administered to patients with
retroperitoneal sarcomas (16-19). These studies demonstrate that preoperative
radiation doses of 45 to 50.4 Gy can be delivered to the retroperitoneum with
acceptable treatment-related toxicity.
chemoradiation have demonstrated that these approaches are safe and feasible
for patients with retroperitoneal sarcomas.
The Radiation Therapy Oncology Group is conducting a multicenter
phase II trial of combined multimodality treatment for patients with
intermediate- or high-grade retroperitoneal sarcomas (RTOG S-0124,
www.rtog.org). Patients are given preoperative systemic therapy with
doxorubicin and ifosfamide (up to 4 cycles) followed by preoperative
external-beam radiation therapy (45 to 50 Gy) and then surgical resection with
an intraoperative or postoperative radiation boost. The objective of the trial is
to assess the feasibility, toxicity, and complications of this multimodality
treatment regimen.
chemotherapy and that if left untreated, these peripheral tumor cells are likely
to be responsible for tumor recurrence (53).
Chemotherapy-induced pathologic necrosis is a predictor of survival
in patients who receive preoperative chemotherapy for osteogenic and
Ewings sarcoma (54-57). However, the incidence of treatment-induced
pathologic necrosis and its correlation with clinical outcomes are not well
defined in patients with soft tissue sarcomas (2). Small studies have reported
rates of complete pathologic tumor necrosis following doxorubicin-based
induction chemotherapy of only 5% to 9% (58-60).
In a retrospective analysis of 496 patients with intermediate- and
high-grade extremity soft tissue sarcomas who were treated with preoperative
therapy (consisting primarily of doxorubicin-based chemotherapy and
radiation), complete pathologic responses were noted in 69
patients (14%). With a mean follow-up of 10 years, the 10-year local
recurrence rate for patients with complete pathologic necrosis was 11%,
compared to 23% for patients with less than 95% pathologic necrosis.
However, the 10-year survival rate for patients with complete pathologic
responses was 71%, compared to 55% for other patients (p = 0.0001)(2).
Based on these results, the authors concluded that pathologic assessment of
necrosis can be considered a surrogate endpoint for survival outcomes in
patients with soft tissue sarcomas and, as such, can be used as a valid and
timely endpoint by which novel agents and treatment protocols are evaluated
(2).
5 SURVIVAL
5.2 Chemotherapy
6 SURGICAL COMPLICATIONS
6.2 Chemotherapy
two treatment groups in both those with extremity sarcomas (34% versus
41%) and those with retroperitoneal/visceral sarcomas (29% versus 34%).
The most common complications in both groups were wound infections.
7 CONCLUSIONS
8 REFERENCES
9. Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF.
Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft
tissue sarcoma. J Clin Oncol 1996;14(3):859-68.
10. Suit HD, Mankin HJ, Wood WC, Proppe KH. Preoperative, intraoperative, and
postoperative radiation in the treatment of primary soft tissue sarcoma. Cancer
1985;55(11):2659-67.
11. Sadoski C, Suit HD, Rosenberg A, Mankin H, Efird J. Preoperative radiation,
surgical margins, and local control of extremity sarcomas of soft tissues. J Surg Oncol
1993;52(4):223-30.
12. Wilson AN, Davis A, Bell RS, et al. Local control of soft tissue sarcoma of the
extremity: the experience of a multidisciplinary sarcoma group with definitive surgery
and radiotherapy. Eur J Cancer 1994;30A(6):746-51.
13. Nielsen OS, Cummings B, OSullivan B, Catton C, Bell RS, Fornasier VL.
Preoperative and postoperative irradiation of soft tissue sarcomas: effect of radiation
field size. Int J Radiat Oncol Biol Phys 1991 ;21(6): 1595-9.
14. OSullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative
radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet
2002;359(9325):2235-41.
15. Pisters PW, OSullivan B. Retroperitoneal sarcomas: combined modality
treatment approaches. Curr Opin Oncol 2002;14(4):400-5.
16. Jones JJ, Catton CN, OSullivan B, et al. Initial results of a trial of preoperative
external-beam radiation therapy and postoperative brachytherapy for retroperitoneal
sarcoma. Ann Surg Oncol 2002;9(4):346-54.
17. Petersen IA, Haddock MG, Donohue JH, et al. Use of intraoperative electron
beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J
Radiat Oncol Biol Phys 2002;52(2):469-75.
18. Gieschen HL, Spiro IJ, Suit HD, et al. Long-term results of intraoperative
electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue
sarcoma. Int J Radiat Oncol Biol Phys 2001;50(1):127-31.
19. Pisters PWT, Ballo MT, Fenstermacher MJ, et al. Phase I trial of preoperative
concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative
electron-beam radiation therapy for patients with localized retroperitoneal sarcoma. J
Clin Oncol 2003 (In Press).
20. Seynaeva C, Verweij J. High-dose chemotherapy in adult sarcomas: no standard
yet. Semin Oncol 1999;26(1):119-133.
21. Antman KH. Chemotherapy of advanced sarcomas of bone and soft tissue. Semin
Oncol 1992;19(6 Suppl 12):13-20.
22. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus
doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a
randomized study of the European Organization for Research and Treatment of
Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995;13(7):1537-3.
59
23. Benjamin RS, Legha SS, Patel SR, Nicaise C. Single-agent ifosfamide studies in
sarcomas of soft tissue and bone: the M. D. Anderson experience. Cancer Chemother
Pharmacol 1993;31:S174-9.
24. Patel SR, Vadhan-Raj S, Papadopolous N, et al. High-dose ifosfamide in bone
and soft tissue sarcomas: results of phase II and pilot studies--dose-response and
schedule dependence. J Clin Oncol 1997;15(6):2378-84.
25. OBryan RM, Baker LH, Gottlieb JE, et al. Dose response evaluation of
Adriamycin in human neoplasia. Cancer 1977;39(5):1940-8.
26. Nielsen OS, Judson I, van Hoesel Q, et al. Effect of high-dose ifosfamide in
advanced soft tissue sarcomas. A multicentre phase II study of the EORTC Soft
Tissue and Bone Sarcoma Group. Eur J Cancer 2000;36(1):61-7.
27. Frustaci S, Buonadonna A, Romanini A, et al. Increasing dose of continuous
infusion ifosfamide and fixed dose of bolus epirubicin in soft tissue sarcomas. A
study of the Italian group on rare tumors. Tumori 1999;85(4):229-33.
28. Palumbo R, Palmeri S, Antimi M, et al. Phase II study of continuous-infusion
high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas.
Ann Oncol 1997;8(11):1159-62.
29. Buesa JM, Lopez-Pousa A, Martin J, et al. Phase II trial of first-line high-dose
ifosfamide in advanced soft tissue sarcomas of the adult: a study of the Spanish Group
for Research on Sarcomas (GEIS). Ann Oncol 1998;9(8):871-6.
30. Eilber FR, Giuliano AE, Huth JH, Mirra JJ, Rosen G, Morton DL. Neoadjuvant
chemotherapy, radiation, and limited surgery for high grade soft tissue sarcoma of the
extremity. In: Ryan JR, Baker LO, eds. Recent Concepts in Sarcoma Treatment.
Dordrecht, The Netherlands: Kluwer Academic Publishers, 1988: 115-22.
31. Pisters PW, Ballo MT, Patel SR. Preoperative chemoradiation treatment
strategies for localized sarcoma. Ann Surg Oncol 2002;9(6):535-42.
32. Goodnight JE, Jr., Bargar WL, Voegeli T, Blaisdell FW. Limb-sparing surgery
for extremity sarcomas after preoperative intraarterial doxorubicin and radiation
therapy. Am J Surg 1985;150(1):109-13.
33. Levine EA, Trippon M, Das Gupta TK. Preoperative multimodality treatment for
soft tissue sarcomas. Cancer 1993;71(11):3685-9.
34. Wanebo HJ, Temple WJ, Popp MB, Constable W, Aron B, Cunningham SL.
Preoperative regional therapy for extremity sarcoma. A tricenter update. Cancer
1995;75(9):2299-306.
35. Temple WJ, Temple CL, Arthur K, Schachar NS, Paterson AH, Crabtree TS.
Prospective cohort study of neoadjuvant treatment in conservative surgery of soft
tissue sarcomas. Ann Surg Oncol 1997;4(7):586-90.
36. Rhomberg W, Hassenstein EO, Gefeller D. Radiotherapy vs. radiotherapy and
razoxane in the treatment of soft tissue sarcomas: final results of a randomized study.
Int J Radiat Oncol Biol Phys 1996;36(5): 1077-84.
37. Goffman T, Tochner Z, Glatstein E. Primary treatment of large and massive adult
sarcomas with iododeoxyuridine and aggressive hyperfractionated irradiation. Cancer
1991;67(3):572-6.
60
38. Sondak VK, Robertson JM, Sussman JJ. Preopertive idoxuridine and radiation
for large soft tissue sarcomas: clinical results with five-year follow-up. Ann Surg
Oncol 1998;5:106-112.
39. Pisters PW. Chemoradiation treatment strategies for localized sarcoma:
conventional and investigational approaches. Semin Surg Oncol 1999;17(1):66-71.
40. Eilber FR, Giuliano AE, Huth JF, Weisenburger TH, Eckardt J. Intravenous (IV)
vs. intraarterial (IA) Adriamycin, 2800r radiation and surgical excision for extremity
soft tissue sarcomas: a randomized prospective trial [Abstract 309]. Proc Am Soc Clin
Oncol 1990.
41. Cormier JN, Patel SR, Herzog CE, et al. Concurrent ifosfamide-based
chemotherapy and irradiation. Analysis of treatment-related toxicity in 43 patients
with sarcoma. Cancer 2001;92(6):1550-5.
42. Toma S, Palumbo R, Vincente M. Concomitant doxorubicin (DOXO) by
continuous infusion (CI) and radiotherapy (RT) at low doses in locally advanced
and/or metastatic soft tissue sarcomas (STS): long-term results of a phase II study
[Abstract 520]. Proc Am Soc Clin Oncol 1995.
43. Kraybill WG, Spiro IJ, Harris J. Radiation Therapy Oncology Group (RTOG) 95-
14: a phase II study of neoadjuvant chemotherapy (CT) and radiation therapy (RT) in
high risk (HR), high grade, soft tissue sarcomas (STS) of the extremities and body
wall: a preliminary report [Abstract 348a]. Proc Am Soc Clin Oncol 2001.
44. Eilber F, Eckardt J, Rosen G, Forscher C, Selch M, Fu YS. Preoperative therapy
for soft tissue sarcoma. Hematol Oncol Clin North Am 1995;9(4):817-23.
45. Pisters PWT, Patel SR, Pollock RE. Phase I trial of preoperative doxorubicin-
based concurrent chemoradiation and electron-beam intraoperative radiation therapy
(IORT) for resectable retroperitoneal sarcomas [Abstract 103]. Cancer J Sci Am 1998.
46. Alektiar KM, Leung D, Zelefsky MJ, Brennan MF. Adjuvant radiation for stage
II-B soft tissue sarcoma of the extremity. J Clin Oncol 2002;20(6):1643-1650.
47. Fleming JB, Berman RS, Cheng SC, et al. Long-term outcome of patients with
American Joint Committee on Cancer stage IIB extremity soft tissue sarcomas. J Clin
Oncol 1999;17(9):2772-80.
48. Baldini EH, Goldberg J, Jenner C, et al. Long-term outcomes after function-
sparing surgery without radiotherapy for soft tissue sarcoma of the extremities and
trunk. J Clin Oncol 1999;17(10):3252-9.
49. Meric F, Hess KR, Varma DG, et al. Radiographic response to neoadjuvant
chemotherapy is a predictor of local control and survival in soft tissue sarcomas.
Cancer 2002;95(5):1120-6.
50. Davis AM, OSullivan B, Bell RS, et al. Function and health status outcomes in a
randomized trial comparing preoperative and postoperative radiotherapy in extremity
soft tissue sarcoma. J Clin Oncol 2002;20(22):4472-7.
51. Bell RS, OSullivan B, Davis A, Langer F, Cummings B, Fornasier VL.
Functional outcome in patients treated with surgery and irradiation for soft tissue
tumours. J Surg Oncol 1991;48(4):224-31.
61
52. Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS.
Preoperative vs. postoperative radiation therapy for soft tissue sarcoma: a
retrospective comparative evaluation of disease outcome. Int J Radiat Oncol Biol
Phys 2003;56(2):482-8.
53. Stephens FO. Induction chemotherapy: to downgrade aggressive cancers to
improve curability by surgery and/or radiotherapy. Eur J Surg Oncol 2001 ;27(7):672-
88.
54. Lindner NJ, Scarborough MT, Spanier SS, Enneking WF. Local host response in
osteosarcoma after chemotherapy referred to radiographs, CT, tumour necrosis and
patient survival. J Cancer Res Clin Oncol 1998;124(10):575-80.
55. Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for
osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the
response of the primary tumor to preoperative chemotherapy. Cancer
1982;49(6):1221-30.
56. Wunder JS, Paulian G, Huvos AG, Heller G, Meyers PA, Healey JH. The
histological response to chemotherapy as a predictor of the oncological outcome of
operative treatment of Ewing sarcoma. J Bone Joint Surg Am 1998;80(7):1020-33.
57. Picci P, Bohling T, Bacci G, et al. Chemotherapy-induced tumor necrosis as a
prognostic factor in localized Ewings sarcoma of the extremities. J Clin Oncol
1997;15(4):1553-9.
58. Ottaiano A, De Chiara A, Fazioli F, et al. Neoadjuvant chemotherapy for
intermediate/high-grade soft tissue sarcomas: five-year results with epirubicin and
ifosfamide. Anticancer Res 2002;22(6B):3555-9.
59. Henshaw RM, Priebat DA, Perry DJ, Shmookler BM, Malawer MM. Survival
after induction chemotherapy and surgical resection for high-grade soft tissue
sarcoma. Is radiation necessary? Ann Surg Oncol 2001;8(6):484-95.
60. Rahoty P, Konya A. Results of preoperative neoadjuvant chemotherapy and
surgery in the management of patients with soft tissue sarcoma. Eur J Surg Oncol
1993;19(6):641-5.
61. Brennan MF. More is less: systemic treatment for local control in soft tissue
sarcoma. Ann Surg Oncol 2001;8(6):480-1.
62. Brennan MF, Alektiar KM, Maki RG. Sarcomas of the soft tissue and bone. In:
DeVita V, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of
Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:1841.
63. Espat NJ, Lewis JJ. The biological significance of failure at the primary site on
ultimate survival in soft tissue sarcoma. Semin Radiat Oncol 1999;9(4):369-77.
64. Cheng EY, Dusenbery KE, Winters MR, Thompson RC. Soft tissue sarcomas:
preoperative versus postoperative radiotherapy. J Surg Oncol 1996;61:90-99.
65. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-
risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast
Cancer Cooperative Group DBCG 82c randomised trial. Lancet
1999;353(9165):1641-8.
62
80. Prosnitz LR, Maguire P, Anderson JM, et al. The treatment of high-grade soft
tissue sarcomas with preoperative thermoradiotherapy. Int J Radiat Oncol Biol Phys
1999;45(4):941-9.
81. Langstein HN, Robb GL. Reconstructive approaches in soft tissue sarcoma.
Semin Surg Oncol 1999;17(1):52-65.
82. Meric F, Milas M, Hunt KK, et al. Impact of neoadjuvant chemotherapy on
postoperative morbidity in soft tissue sarcomas. J Clin Oncol 2000;18(19):3378-383.
This page intentionally left blank
Chapter 4
Correspondence to:
Alexander M.M. Eggermont, MD, PhD
Professor Surgical Oncology, Head of Department
Department of Surgical Oncology
Erasmus University Medical Center - Daniel den Hoed Cancer Center
301 Groene Hilledijk
3075 EA Rotterdam
The Netherlands
Tel: 31-10-439 19 11
Fax: 31-10439 10 11
E-mail: a.m.m.eggermont@erasmusmc.nl
66
1 INTRODUCTION
approved and registered in Europe for the sarcoma-indication in 1998 (27). The
European TNF/ILP assessment group evaluated 246 patients with irresectable
STS enrolled in 10 years in 4 studies. All cases were reviewed by an
independent review committee and compared with conventionally treated
patients (often by amputation) of a population based Scandinavian STS
database. In short: there were 246 patients with locally very advanced disease:
Primary sarcomas in 55%, local recurrent sarcomas in 45%, multifocal
primary or multiple local recurrences in 22 %. Overt concurrent metastatic
disease in 15%. Tumors >10 cm in 46%. Grade III tumors in 66%. Previous
radiotherapy (13%), chemotherapy (15%). Patients underwent 1 ILP (222 pts)
or 2 ILPs (24 pts) of 90 minutes at 39-40 C with 2-4 mg TNF + melphalan (10-
13 mg/L limb volume). The first 56 pts also received A delayed marginal
resection of the tumor remnant was usually (76%) done 2-4 months after ILP.
Major responses were seen in 56.5 to 82.6 % of the patients after which usually
resection of the sarcoma became possible.
Limb salvage was achieved in 74%-87% in these 4 studies and in 71 %
of the 196 patients who had been classified by the independent review
committees as cases that normally could only have been managed by
amputation (87%) or by functionally debilitating resection + radiotherapy
(13%). Comparison with the survival curves based on a matched control study
with cases from the Scandinavian Soft Tissue Sarcoma Databank showed that
TNF had no negative effect on survival (p=0.96). It was concluded that the
application of TNF in combination with melphalan in the setting of isolated
limb perfusion represents a new and successful option in the management of
irresectable locally advanced extremity soft tissue sarcomas (27).
and radiotherapy, with the recurrent sarcoma in the irradiated field, we reported
on the Rotterdam experience in 24 patients. A response rate of 74% and a limb
salvage rate of 67% was reported in these patients otherwise destined for
amputation.
angiogenesis, also become necrotic after ILP with TNF+ melphalan, but not after
ILP with melphalan alone.
We have demonstrated a number of crucial elements in our rat tumor
models identifying the mechanisms for the strong synergy between TNF and
Cytostatic drugs in ILP and have identified the prerequisites for an effective ILP:
6.7 Hypoxia
6.8 Interferon-gamma
Various vasoactive drugs have been and are being studied in our
laboratory models. Nitric Oxide (NO) is an important molecule in the
maintenance of both vascular tone and the integrity of the vascular wall and is
highly produced in experimental and human tumors. We postulated that its
inhibition could lead to hypoxia and an enhancement of TNF early vascular
effects in the tumor. In our ILP BN 175 rat model we performed a response study
with TNF in combination with the Arginine analogues L-NAME and LNA,
which inhibit NO synthase. In rats treated with TNF combined with L-
NAME/LNA important and immediate antitumor effects were observed in all
rats and necrosis of the skin at the tumor site. These effects are normally only
observed when hypoxia or melphalan are added to TNF as described above.
Typical TNF tumor response was observed, when NO synthase was inhibited
during ILP (60).
Another vasoactive drug is histamine, which is currently being studied.
Also in this case we see a clear synergy with melphalan in our tumor models
(61) These findings show the importance of agents that can change the patho-
physiology of tumor vasculature, rheologic conditions en thereby can improve
drug uptake in tumors. These findings underline the importance of investigating
how to modulate tumor physiology and the potential that this approach has to
improve efficacy of various standard agents.
7 CONCLUSIONS
8 REFERENCES
1. Gaynor JJ, Tan CC, Casper ES, et al. Refinement of clincopathologic staging for localized soft
tissue sarcoma of the extremity: a study of 423 adults. J Clin Oncol 1992;10:1317-1327
2. Potter DA, Kinsella D, Gladstein E et al. High grade soft tissue sarcomas of the extremities.
Cancer 1986;59:190-205
3. Stotter AT, AHearn RP, Fisher C, Mott AF, Fallowfield ME, Westbury G. The influence of
local recurrence of extremity soft tissue sarcoma on metastasis and survival. Cancer
1990;65:1119-1129
4. Gustafson P, Rser B, Rydholm A. Is local recurrence of minor importance for metastases in
soft tissue sarcoma? Cancer 1991;67:2083-2086
5. Landis S, Murray T, Bolden S, Wingo P. Cancer Statistics, 1999. CA Cancer J Clin 1999;9:8-
26
6. Suit HD, Proppe KH, Mankin HJ, Wood WC. Preoperative radiation therapy for sarcoma of
soft tissue. Cancer 47:2269-2274, 1981
7. Eilber FR, Mirra JJ, Grant T, Weisenburger T, Morton DL. Is amputation necessary for
sarcoma: a 7-year experiment with limb salvage. Ann Surg 1980;192:431-437
8. Eilber FR, Morton DL, Eckhardt J, Grant T, Weisenburger T. Limb salvage for skeletal and
soft-tissue sarcomas: multidisciplinary preoperative therapy. Cancer 1984;53:2579-2584
9. Shiu MH, Hilaris BS, Harrison LB, Brennan MF. Brachytherapy and function-saving
resection of soft tissue sarcoma arising in the limb. Int J Radiat Oncol Biol Phys 1991;21:1485-
1492
10. Creech O, Krementz E, Ryan E, Winblad J. Chemotherapy of cancer: regional perfusion
utilising an extracorporeal circuit. Ann Surg 1958;148:616-632
11. Benckhuijsen C, Kroon BB, van Geel AN, et al: Regional perfusion treatment with melphalan
for melanoma in a limb: an evaluation of drug kinetics. Eur J Surg Oncol 1988;14:157-63
12. Thompson JF, Gianoutsos MP. Isolated limb perfusion for melanoma - effectiveness and
toxicity of cisplatin compared with that of melphalan and other drugs. World J Surg 1992;16:227-
233
76
13. Klaase JM, Kroon BBR, Van Geel AN, Eggermont AMM, Franklin HR. Systemic leakage
during isolated limb perfusion for melanoma. Br J Surg 1993;80:1124-1126
14. Wieberdink K, Benckhuijsen C, Braat RP, Van Slooten EA, Olthuis GAA. Dosimetry in
isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic
tissue reactions. Eur J Cancer Clin Oncol 1982; 18:905-910
15. Krementz ET, Carter RD, Sutherland CM, Hutton I. Chemotherapy of sarcomas of the limbs
by regional perfusion. Ann Surg 1977;185(5):555-564
16. Muchmore JH, Carter RD, Krementz ET. Regional perfusion for malignant melanoma and soft
tissue sarcoma: a review. Cancer Invest. 1985;3:129-143
17. Pommier RF, Moseley HS, Cohen J et al. Pharmacokinetics, Toxicity, and Short-term results
of cisplatin hyperthermic isolated limb perfusion for soft tissue sarcoma and melanoma of the
extremities. Am J Surg 155:667-671, 1988
18. Klaase JM, Kroon BBR, Benckhuysen C, Van Geel AN, Albus-Lutter ChE, Wieberdink J.
Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the
extremities. Cancer 64:616-621, 1989
19. Rossi CR, Vecchiato A, Foletto M, et al. Phase II study on neoadjuvant hyperthermic-
antiblastic perfusion with doxorubicin in patients with intermediate or high grade limb sarcomas.
Cancer 73:2140-2146, 1994
20. Lienard D, Ewalenko, Delmotte JJ, Renard N, Lejeune FJ. High-dose recombinant tumor
necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion
of the limbs for melanoma and sarcoma. J Clin Oncol 1992; 10:50-62
21. Eggermont AMM, Linard D, Schraffordt Koops H, Rosenkaimer F, Lejeune FJ. Treatment
of irresectable soft tissue sarcomas of the limbs by isolation perfusion with high dose TNF-a in
combination with gamma-Interferon and melphalan. Fiers W and Buurman WA (eds), In: Tumor
Necrosis Factor: Molecular and Cellular Biology and Clinical Relevance, Basel, Karger Verlag,
1993, pp 239-243
22. Hill S, Fawcett WJ, Sheldon J, Soni N, Williams T, Thomas JM. Low dose tumor necrosis
factor-alpha and melphalan in hyperthermic isolated limb perfusion. Br J Surg 1993; 80:995-997
23. Eggermont AMM, Schraffordt Koops H, Lienard D, et al: Isolated limb perfusion with high-
dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for
nonresectable extremity soft tissue sarcomas: a multicenter trial [see comments]. J Clin Oncol
14:2653-65, 1996a
24. Santinami M, Deraco M, Azzarelli A, Cascinelli F, Chiti A, Costagli V, Manzi R, Quagliolo V,
Rebuffoni G, Santoro N, Vaglini M. Treatment of recurrent sarcoma of the extremities by isolated
perfusion using tumor necrosis factor alpha and melphalan. Tumori 1996;82:579-84
25. Eggermont AMM, Schraffordt Koops H, Klausner JM, et al: Isolated limb perfusion with
tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft
tissue extremity sarcomas. The cumulative multicenter European experience. Ann Surg 224:756-
64; discussion 764-5, 1996b
26. Gutman M, Inbar M, Lev-Shlush D, Mozes M, Chaitchik S, Meller I, Klausner JM. High dose
tumor necrosis and melphalan administered via isolated limb perfusion for advanced limb
soft tissue sarcoma results in a > 90% response rate and limb preservation. Cancer 1997;79:1129-
37
27. Eggermont AMM, Schraffordt Koops H, Klausner JM, Schlag PM, Kroon BBR, Gustafson P,
Steinmann G, Lejeune FJ. Limb Salvage by Isolation Limb Perfusion with Tumor Necrosis Factor
Alpha and melphalan for locally advanced extremity soft tissue sarcomas: results of 270 perfusions
in 246 patients. Proceed ASCO 1999;11:497(abstract)
28. Rossi CR, Foletto M, Di Filippo F, Vaglini M, Anza M, Azzarelli A, Pilati P, Mocellin S,
Lise M. Soft tissue limb sarcomas: Italian clinical trials with hyperthermic antiblastic perfusion.
Cancer, 1999;86:1742-9
29. Lejeune FJ, Pujol N, Lienard D, Mosimann F, Raffoul W, Genton A, Guillou L, Landry M,
Chassot PG, Chiolero R, Bischof-Delaloye A, Leyvraz S, Mirimanoff RO, Bejkos D, Leyvraz
PF. Limb salvage by neoadjuvant isolated perfusion with TNFalpha and melphalan for non-
resectable soft tissue sarcoma of the extremities. Eur J Surg Oncol 2000, 26:669-78
77
necrosis factor-alpha and melphalan for unresectable bone sarcomas of the lower extremity [In
Process Citation]. Eur J Surg Oncol, 1999;25:509-14
46. Lev-Chelouche D, Abu-Abeid S, Nakache R, Issakov J, Kollander Y, Merimsky O, Meller
I, Klausner JM, Gutman M. Limb desmoid tumors: a possible role for isolated limb perfusion
with tumor necrosis factor-alpha and melphalan. Surgery 1999;126:963-967
47. Sijens PE, Eggermont AMM, Van Dijk P, Oudkerk M. magnetic resonance spectroscopy as
predictor for clinical response in human extremity sarcomas treated by single dose
melphalan isolated limb perfusion. NMR in Biomedicine 1995;18:215-224
48. Renard N, Linard D, Lespagnard L, Eggermont AMM, Heimann R, Lejeune FJ. Early
endothelium activation and polymorphonuclear cell invasion precede specific necrosis of human
melanoma and sarcoma treated by intravascular high-dose tumour necrosis factor alpha
Int J Cancer 1994;57:656-663
49. Nooijen PTGA, Eggermont AMM, Schalkwijk L, Henzen-Logmans S, DeWaal RMW, Ruiter
DJ. Complete response of melanoma in-transit metastasis after isolated limb perfusion with tumor
necrosis factor-alpha and melphalan without massive tumor necrosis: clinical and histopathological
study of the delayed-type reaction patterns. Cancer Res 1998;58:4880-4887
50. Manusama ER, Nooijen PTGA, Stavast J, Durante NMC, Marquet RL, Eggermont AMM.
Synergistic antitumour effect of recombinant human tumour necrosis factor with melphalan in
isolated limb perfusion in the rat. Br J Surg 1996;83:551-555
51. Manusama ER, Stavast J, Durante NMC, Marquet RL, Eggermont AMM. Isolated limb
perfusion in a rat osteosarcoma model: a new anti-tumour approach. Eur J Surg Oncol
1996;22:152-157
52. De Wilt JHW, ten Hagen TLM, de Boeck G, van Tiel ST, de Bruijn EA, Eggermont
AMM. Tumour Necrosis Factor alpha increases melphalan concentration in tumour tissue after
isolated limb perfusion. Br J Cancer 2000;82:1000-1003
53. Veen vd AH, Wilt de JHW, Eggermont AMM, van Tiel ST, ten Hagen TLM.
augments intratumoural concentration of doxorubicin in isolated limb perfusion
in rat sarcoma models and enhances antitumour effects. Br J Cancer,2000;82:973-980
54. B van Etten, M de Vries, M van IJken, T Lans, G Guetens, G Ambagtsheer, S van Tiel, G
de Boeck, E de Bruijn, AMM Eggermont AMM, TLM Ten Hagen. Degree of tumour
vascularity correlates with drug accumulation and tumour response upon TNF-based isolated
hepatic perfusion. Br J Cancer. 2003;87:314-9
55. Kristensen CA, Nozue M, Boucher Y and Jain RK. Reduction of interstitial fluid pressure
after TNF-alpha treatment of three human melanoma xenografts. Br J Cancer 1996;74:533-
536.
56. Manusama ER, Nooijen PTGA, Stavast J, de Wilt JHW, Marquet RL and Eggermont
AMM. Assessment of the role of neutrophils on the antitumor effect of in an in vivo
isolated limb perfusion model in sarcoma - bearing Brown Norway rats. J Surg Res
1998;78:169-175
57. DeWilt JHW, Manusama ER, van Tiel ST, van IJken MGA, ten Hagen TLM, Eggermont
AMM. Prerequisites for effective isolated limb perfusion using tumour necrosis factor-alpha and
melphalan in rats. Br J Cancer 1999;80:161 -166
58. Manusama ER, de Wilt JHW, ten Hagen TLM, Marquet RL, Eggermont AMM. Toxicity and
antitumor activity of interferon-gamma alone and in combinations with TNF and Melphalan in
isolated limb perfusion in the BN175 sarcoma tumor model in rats. Oncol Rep 1999;6:173-177
59. Seynhaeve ALB, de Wilt JHW, vanTiel SA, Eggermont AMM, ten Hagen TLM.
Combination of Actinomycin D with TNF-a in Isolated Limb Perfusion results in improved
tumour response in soft tissue sarcoma-bearing rats but is accompanied by severe dose limiting
local toxicity. . Br J Cancer 2002; 86:1174-1179.
60. DeWilt JHW, Manusama ER, van Etten B, van Tiel ST, Jorna AS, Seynhaeve ALB, ten
Hagen TLM, Eggermont AMM: Inhibition of Nitric Oxide Synthesis by L-NAME results in
synergistic antitumour activity with melpahlan and tumour necrosis factor-alpha- based isolated
limb. Br J Cancer, 2000:83: 1176-11
79
61. Brunstein F, Hoving S, van Tiel S, ten Hagen TLM, Eggermont AMM. Synergistic
antitumor activity of histamine in combination with chemotherapy in the regional treatment of
soft tissue sarcomas. Eur J Cancer 2003;39:in press
62. Ten Hagen TLM, FJ Lejeune, Eggermont AMM. TNF is here to stay Revisited, Trends in
Immunology (Formerly Immunology Today), 2001;22:127-129
This page intentionally left blank
Chapter 5
Correspondence to:
Pancras C.W.Hogendoorn
Dept. of Pathology,
Leiden University Medical Center,
PO Box 9600
2300 RC Leiden,
The Netherlands
82
1 INTRODUCTION
There has been a continuous debate over the past years whether core-
needle biopsies, or open biopsies should be used in the diagnostic process of
soft tissue tumors. Though a diagnostic accuracy has been documented as
high as 90% in bone tumors (2), this number is debated widely for soft tissue
tumors. Unfortunately due to increasing economic issues in health care and
patient expectations the work up of patients with soft tissue tumors focuses on
speed and patient friendliness instead of accuracy and a scientific basis for
treatment. As a result core needle biopsies become more and more popular
complicating accurate diagnosis and making grading virtually impossible.
This is especially worthwhile realizing the more and more popular use of pre-
operative chemotherapy and isolated limb perfusion, which if successful leave
virtual no tissue left for definite diagnosis, meaning that a substantial number
of patients will be treated with toxic therapies, while one honestly does not
know what kind and grade of tumor has been treated. Core needle biopsies are
however very useful for the differential diagnosis with metastatic carcinoma,
melanoma and to rule out lymphoma. In a specialized hospital setting it is
useful for the diagnosis of a number of tumors with consistent genetic
abnormalities which can be very accurately assessed by molecular techniques
83
Calcifying aponeurotic
fibroma
Angiomyofibroblastoma
Cellular angiofibroma
Nuchal type fibroma
Gardner fibroma
Calcifying fibrous tumor
Giant cell angiofibroma
SO CALLED FIBROHISTIOCYTIC TUMORS
Benign Intermediate (rarely Malignant
metastasizing)
Giant cell tumor of tendon Plexiform fibrohistiocytic Pleomorphic
sheath tumor MFH /
undifferentiated
pleomorphic
sarcoma
Diffuse type giant cell tumor Giant cell tumor of soft Giant cell MFH /
tissue undifferentiated
pleomorphic
sarcoma with
giant cells
Deep benign fibrous Inflammatory
histiocytoma MFH /
undifferentiated
pleomorphic
sarcoma with
prominent
inflammation
SMOOTH MUSCLE TUMORS
Benign Malignant
Angioleiomyoma Leiomyosarcoma (excl skin)
Deep leiomyoma
Genital leiomyoma
PERICYTIC (PERIVASCULAR) TUMORS
Glomus tumor (and variants), malignant glomus tumor
Myopericytoma
SKELETAL MUSCLE TUMORS
Benign Malignant
Rhabdomyoma (adult, fetal, Embryonal rhabdomyosarcoma (incl. spindle cell,
genital type) botryoid, anaplastic)
Pleomorphic rhabdomyosarcoma
Alveolar rhabdomyosarcoma (incl. solid,
anaplastic)
86
VASCULAR TUMORS
Benign Intermediate (locally Malignant
aggressive)
Haemangioma (incl.capillary, Kaposiform Epithelioid
cavernous, arteriovenous, haemangioendothelioma haemangioendo-
venous, intramuscular, thelioma
synovial, subcutis /
soft tissue)
Epithelioid haemangioma Intermediate (rarely Angiosarcoma of
metastasizing) soft tissue
Angiomatosis Retiform
haemangioendothelioma
Lymphangioma Papillary intralymphatic
angioendothelioma
Composite
haemangioendothelioma
Kaposi sarcoma
CHONDRO-OSSEOUS TUMORS
Benign Malignant
Soft tissue chondroma Mesenchymal chondrosarcoma
Extraskeletal osteosarcoma
TUMORS OF UNCERTAIN DIFFERENTIATION
Benign Intermediate (rarely Malignant
metastasizing)
Intramuscular myxoma Angiomatoid fibrous Synovial sarcoma
(incl. cellular variant) histiocytoma
Juxta-articular myxoma Ossifying fibromyxoid Epithelioid
tumor (incl. atypical / sarcoma
malignant)
Deep (aggressive) Mixed tumor / myoepi- Alveolar soft part
angiomyxoma thelioma / parachordoma sarcoma
Pleomorphic hyalinizing Clear cell sarcoma
angiectatic tumor of soft tissue
Ectopic hamartomatous Extraskeletal
thymoma myxoid
chondrosarcoma
PNET/
extraskeletal
Ewing tumor
Desmoplastic
small round
cell tumor
Extra-renal
rhabdoid tumor
Malignant
mesenchymoma
87
PEComa /
neoplasms with
perivascular
epithelioid cell
differentiation
Intimal sarcoma
TUMOURS OF PERIPHERAL NERVES (5)
Benign Malignant
Schwannoma (incl. cellular, plexiform, Malignant peripheral nerve sheath
Melanotic) tumor (MPNST)
(incl. epithelioid, with divergent
mesenchymal and / or
epithelial differentiation, melanotic,
melanotic psammomatous)
Neurofibroma (incl. plexiform)
Perineurioma (incl. intraneural, soft tissue)
not predictable on the basis of histology. Malignant soft tissue tumors, called
soft tissue sarcomas, have a significant risk of distant metastases, ranging
from 20-100% depending on histological type and grade (1). Some low grade
sarcomas have initially a lower metastatic risk but they may advance in grade
upon local recurrence, increasing the risk of distant spread. It is important to
note that the intermediate categories of biological potential as defined in the
WHO classification do not correspond to the histologically defined
intermediate grade of malignancy (see histological grading) (1).
3 HISTOPATHOLOGICAL GRADING
Table 2. FNCLCC grading system for (adult) soft tissue sarcoma (8;9)
HISTOLOGICAL GRADE
Grade 1 Total score 2,3
Grade 2 Total score 4,5
Grade 3 Total score 6,7,8
* HPF (high power field) defined as
89
histological typing was only 61% (10). When both grading systems are
compared using the same set of 410 tumors concordance rates are only around
65% (9). The FNCLCC system is favored because it correlates better with
overall and metastasis free survival, and it allocates less patients in the
intermediate grade category and is more reproducible than the NCI system
(9). The establishment of the tumor differentiation score in the FNCLCC
system can however be problematic. A listing of the differentiation scores for
the most common tumors has been reported (table 3)(9), but the rationale for
some of these scores is not clear (11).
TUMOR
HISTOLOGIC TYPE DIFFERENTIATION
SCORE
Well differentiated liposarcoma 1
Myxoid liposarcoma 2
Round cell liposarcoma 3
Pleomorphic liposarcoma 3
Dedifferentiated liposarcoma 3
Fibrosarcoma
Well differentiated 1
Conventional 2
Poorly differentiated 3
Malignant peripheral nerve sheath tumor (MPNST)
Well differentiated 1
Conventional 2
Poorly differentiated 3
Epithelioid 3
Malignant Triton tumor 3
Myxofibrosarcoma (myxoid MFH) 2
Pleomorphic sarcoma (pleomorphic MFH)
With storiform pattern 2
Patternless pleomorphic sarcoma 3
With giant cells (giant cell MFH) 3
With prominent inflammation (inflammatory MFH) 3
90
Leiomyosarcoma
Well differentiated 1
Conventional 2
Poorly differentiated / pleomorphic / epithelioid 3
Biphasic / monophasic synovial sarcoma 3
Embryonal / alveolar / pleomorphic rhabdomyosarcoma 3
Myxoid chondrosarcoma 2
Mesenchymal chondrosarcoma 3
Conventional angiosarcoma 2
Poorly differentiated / epithelioid angiosarcoma 3
Extraskeletal osteosarcoma 3
Ewing sarcoma / PNET 3
Alveolar soft part sarcoma 3
Epithelioid sarcoma 3
Malignant rhabdoid tumor 3
Clear cell sarcoma 3
Undifferentiated sarcoma 3
Table 4. Soft tissue sarcomas for which the histotype determines the biological
behavior / grade (adapted from (6) and (14)).
4 ADDITIONAL TECHNIQUES
4.1 Immunohistochemistry
Muscle differentiation
Desmin, smooth muscle actin, muscle specific actin (HHF35),
Myogenic transcription factors (MyoD1, Myf4 (myogenin)),
myoglobin, heavy caldesmon, calponin
Nerve sheath differentiation
S100, CD57
Melanocytic differentiation
HMB-45, Melan-A (MART-1), tyrosinase, microphtalmia
transcription factor
Endothelial differentiation
Von Willebrand Factor (Factor VIII-related antigen), CD34 (human
haematopoetic progenitor cell antigen), CD31 (platelet endothelial
cell adhesion molecule-1), Ulex Europaeus Lectin
Fibro-histiocytic differentiation
CD68, Factor 13A, vimentin
Epithelial differentiation
EMA (epithelial membrane antigen), cytokeratin
95
5 REFERENCES
7. Costa J, Wesley RA, Glatstein E, Rosenberg SA. The grading of soft tissue sarcomas.
Results of a clinicohistopathologic correlation in a series of 163 cases. Cancer 1984; 53:530-
541.
8. Trojani M, Contesso G, Coindre JM, Rouesse J, Bui NB, De Mascarel A et al. Soft-tissue
sarcomas of adults; study of pathological prognostic variables and definition of a
histopathological grading system. Int J Cancer 1984; 33(1):37-42.
9. Guillou L, Coindre JM, Bonichon F, Nguyen BB, Terrier P, Collin F et al. Comparative
study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group
grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol
1997; 15(1):350-362.
10. Coindre JM, Trojani M, Contesso G, David M, Rouesse J, Binh Bui N et al.
Reproducibility of a histopathologic grading system for adult soft tissue sarcoma. Cancer 1986;
58:306-309.
11. Weiss SJ, Goldblum JR. Soft Tissue Tumors. 4 ed. St.Louis: the C.V. Mosby Company,
2001.
12. Brown FM, Fletcher CD. Problems in grading soft tissue sarcomas. Am J Clin Pathol 2000;
114 Suppl:S82-S89.
13. Coindre JM, Terrier P, Guillou L, Le D, V, Collin F, Ranchere D et al. Predictive value of
grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a
study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer
2001; 91(10):1914-1926.
14. Recommendations for the reporting of soft tissue sarcomas. Association of Directors of
Anatomic and Surgical Pathology. Hum Pathol 1999; 30(1):3-7.
15. Hashimoto H, Daimaru Y, Takeshita S, Tsuneyoshi M, Enjoji M. Prognostic significance
of histologic parameters of soft tissue sarcomas. Cancer 1992; 70:2816-2822.
16. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ et al. Diagnosis of
gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002; 33(5):459-465.
17. Oliveira AM, Nascimento AG. Grading in soft tissue tumors: principles and problems.
Skeletal Radiol 2001; 30(10):543-559.
18. Graadt van Roggen JF, Van Velthuysen MLF, Hogendoorn PCW. The histopathological
differential diagnosis of gastrointestinal stromal tumours. J Clin Pathol 2001;(54):96-103.
19. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ
et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N
Engl J Med 2002; 347(7):472-480.
20. Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D et
al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal
stromal tumor. N Engl J Med 2001; 344(14):1052-1056.
21. Van Oosterom AT, Judson 1, Verweij J, Stroobants S, Donato dP, Dimitrijevic S et al.
Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase
I study. Lancet 2001; 358(9291):1421-1423.
This page intentionally left blank
Chapter 6
Correspondence to :
Jonathan A Fletcher, MD
Department of Pathology;
Brigham and Womens Hospital;
75 Francis Street
Boston, MA 02115
USA
100
1 INTRODUCTION
restoring the lost tumor suppressor function to the neoplastic cells. It has
been difficult to devise methods in which such restoration of function is
accomplished with high efficiency and at physiological levels across a
heterogeneous neoplastic cell population. On the other hand, tumor suppressor
mutations result inevitably in activation of downstream proteins whose
function would normally be inhibited by the tumor suppressor. These
downstream proteins might be more tractable to targeted therapies than the
tumor suppressor proteins themselves.
2 METHODOLOGICAL CONSIDERATIONS
3 CYTOGENETIC MECHANISMS
the chromosome 11 FLI1 gene with the chromosome 22 EWS gene (30-
33). FLI1 encodes a transcription factor belonging to the ETS family of
transcription factors, and the oncogenic EWS-FLI1 fusion gene encodes
an activated version of this transcription factor. A smaller subset of
Ewing tumors, perhaps 5-15% of the total, have variant translocations in
which the EWS gene is fused with other ETS family transcription factor
genes (Table 1) (34-38). The Ewings gene translocations are considered
to be essential genetic aberrations because they are found in virtually all
cases and are assumed to be the critical genetic aberration in these
tumors. However, targeted therapies for the EWS oncoproteins are still
developmental, with no substantial clinical responses in early studies of
vaccine therapies to EWS (39). Alternate targets might be found amongst
the kinase protein family, but thus far have not shown great promise in
preclinical studies (40-42).
long arm are seen in occasional desmoids, resulting in loss of the APC
tumor suppressor gene, and the remaining APC allele in these cases is
typically inactivated by a point mutation (51,52). The most common
known mutations in sporadic desmoid tumors are activating beta-catenin
mutations, which were demonstrated in 22 of 42 desmoids by Alman et
al. (48,49). These mutations result in stabilization, and resultant
overexpression, of the beta-catenin protein. Therefore, it is likely that
targeted therapies of the Wnt-APC-beta-catenin pathway, will be useful
in treatment of patients with advanced desmoid tumors. Notably,
PDGFRB activation plays a highly mitogenic role in myofibroblasts, and
this knowledge has led to therapeutic evaluation of PDGFRB inhibition
(by imatinib) with promising preliminary results (53). It is unkown
presently whether PDGFRB activation in desmoids results from Wnt-
APC-beta-catenin pathway perturbations, or whether this is an unrelated
biological mechanism.
4.12 Rhabdomyosarcoma
5 REFERENCES
1. Greco, A., Roccato, E., Miranda, C., Cleris, L., Formelli, F., and Pierotti, M. A.
Growth-inhibitory effect of STI571 on cells transformed by the COL1A1/PDGFB
rearrangement. Int. J. Cancer, 92: 354-360, 2001.
2. OBrien, K. P., Seroussi, E., Dal Cin, P., Sciot, R., Mandahl, N., Fletcher, J. A., Turc-
Carel, C., and Dumanski, J. P. Various regions within the alpha-helical domain of the
COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas
and giant-cell fibroblastomas. Genes Chromosomes. Cancer, 23: 187-193, 1998.
3. Hirota, S., Isozaki, K., Moriyama, Y., Hashimoto, K., Nishida, T., Ishiguro, S.,
Kawano, K., Hanada, M., Kurata, A., Takeda, M., Muhammad Tunio, G., Matsuzawa, Y.,
Kanakura, Y., Shinomura, Y., and Kitamura, Y. Gain-of-function mutations of c-kit in
human gastrointestinal stromal tumors. Science, 279: 577-580, 1998.
4. Sandberg, A. A., Turc-Carel, C., and Gemmill, R. M. Chromosomes in solid tumors
and beyond. Cancer Res., 48: 1049-1059, 1988.
5. Fletcher, J. A., Kozakewich, H. P., Hoffer, F. A., Lage, J. M., Weidner, N., Tepper, R.,
Pinkus, G. S., Morton, C. C., and Corson, J. M. Diagnostic relevance of clonal
cytogenetic aberrations in malignant soft-tissue tumors. N. Engl. J. Med., 324: 436-442,
1991.
6. Sandberg, A. A. and Bridge, J. A. The Cytogenetics of Bone and Soft Tissue
Tumors.Austin: R.G. Landes Company, 1995.
7. Heim, S. and Mitelman, F. Cancer Cytogenetics, Second ed.New York: Wiley-Liss,
1995.
8. Sreekantaiah, C., Ladanyi, M., Rodriguez, E., and Chaganti, R. S. Chromosomal
aberrations in soft tissue tumors. Relevance to diagnosis, classification, and molecular
mechanisms. Am. J. Pathol., 144: 1121-1134, 1994.
9. Tontonoz, P., Singer, S., Forman, B. M., Sarraf, P., Fletcher, J. A., Fletcher, C. D.,
Brun, R. P., Mueller, E., Altiok, S., Oppenheim, H., Evans, R. M., and Spiegelman, B. M.
Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome
proliferator-activated receptor gamma and the retinoid X receptor. Proc. Natl. Acad. Sci.
U. S. A., 94: 237-241, 1997.
10. Demetri, G. D., Fletcher, C. D., Mueller, E., Sarraf, P., Naujoks, R., Campbell, N.,
Spiegelman, B. M., and Singer, S. Induction of solid tumor differentiation by the
peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with
liposarcoma. Proc. Natl. Acad. Sci. U. S. A, 96: 3951-3956, 1999.
11. Turc-Carel, C., Limon, J., Dal Cin, P., Rao, U., Karakousis, C., and Sandberg, A. A.
Cytogenetic studies of adipose tissue tumors. II. Recurrent reciprocal translocation
t(12;16)(q13;p11) in myxoid liposarcomas. Cancer Genet. Cytogenet., 23: 291-299, 1986.
12. Sreekantaiah, C., Karakousis, C. P., Leong, S. P., and Sandberg, A. A. Cytogenetic
findings in liposarcoma correlate with histopathologic subtypes. Cancer, 69: 2484-2495,
1992.
13. Fletcher, C. D., Akerman, M., Dal Cin, P., De Wever, I., Mandahl, N., Mertens, F.,
Mitelman, F., Rosai, J., Rydholm, A., Sciot, R., Tallini, G., Van Den Berghe, H., Van de
Ven, W., Vanni, R., and Willen, H. Correlation between clinicopathological features and
karyotype in lipomatous tumors. A report of 178 cases from the Chromosomes and
Morphology (CHAMP) Collaborative Study Group. Am. J. Pathol., 148: 623-630, 1996.
112
14. Hisaoka, M., Tsuji, S., Morimitsu, Y., Hashimoto, H., Shimajiri, S., Komiya, S., and
Ushijima, M. Detection of TLS/FUS-CHOP fusion transcripts in myxoid and round cell
liposarcomas by nested reverse transcription-polymerase chain reaction using archival
paraffin-embedded tissues. Diagn. Mol. Pathol., 7: 96-101, 1998.
15. Kuroda, M., Ishida, T., Horiuchi, H., Kida, N., Uozaki, H., Takeuchi, H., Tsuji, K.,
Imamura, T., Mori, S., and Machinami, R. Chimeric TLS/FUS-CHOP gene expression
and the heterogeneity of its junction in human myxoid and round cell liposarcoma. Am. J.
Pathol., 147: 1221-1227, 1995.
16. Aman, P., Ron, D., Mandahl, N., Fioretos, T., Heim, S., Arheden, K., Willen, H.,
Rydholm, A., and Mitelman, F. Rearrangement of the transcription factor gene CHOP in
myxoid liposarcomas with t(12;16)(q13;p11). Genes Chromosom. Cancer, 5: 278-285,
1992.
17. Crozat, A., Aman, P., Mandahl, N., and Ron, D. Fusion of CHOP to a novel RNA-
binding protein in human myxoid liposarcoma. Nature, 363: 640-644, 1993.
18. Mandahl, N., Heim, S., Arheden, K., Rydholm, A., Willen, H., and Mitelman, F.
Rings, dicentrics, and telomeric association in histiocytomas. Cancer Genet. Cytogenet.,
30: 23-33, 1988.
19. Turc-Carel, C., Dal Cin, P., Rao, U., Karakousis, C., and Sandberg, A. A. Recurrent
breakpoints at 9q31 and 22q12.2 in extraskeletal myxoid chondrosarcoma. Cancer Genet.
Cytogenet., 30: 145-150, 1988.
20. Pedeutour, F., Forus, A., Coindre, J. M., Berner, J. M., Nicolo, G., Michiels, J. F.,
Terrier, P., Ranchere-Vince, D., Collin, F., Myklebost, O., and Turc-Carel, C. Structure of
the supernumerary ring and giant rod chromosomes in adipose tissue tumors. Genes
Chromosomes. Cancer, 24: 30-41, 1999.
21. Zucman, J., Delattre, O., Desmaze, C., Epstein, A. L., Stenman, G., Speleman, F.,
Fletchers, C. D., Aurias, A., and Thomas, G. EWS and ATF-1 gene fusion induced by
t(12;22) translocation in malignant melanoma of soft parts. Nat. Genet., 4: 341-345, 1993.
22. Brown, A. D., Lopez-Terrada, D., Denny, C., and Lee, K. A. Promoters containing
ATF-binding sites are de-regulated in cells that express the EWS/ATF1 oncogene.
Oncogene, 10: 1749-1756, 1995.
23. Gerald, W. L., Miller, H. K., Battifora, H., Miettinen, M., Silva, E. G., and Rosai, J.
Intra-abdominal desmoplastic small round-cell tumor. Report of 19 cases of a distinctive
type of high-grade polyphenotypic malignancy affecting young individuals. Am. J. Surg.
Pathol., 15: 499-513, 1991.
24. Ladanyi, M. and Gerald, W. Fusion of the EWS and WT1 genes in the desmoplastic
small round cell tumor. Cancer Res., 54: 2837-2840, 1994.
25. Gerald, W. L., Ladanyi, M., de Alava, E., Cuatrecasas, M., Kushner, B. H.,
LaQuaglia, M. P., and Rosai, J. Clinical, pathologic, and molecular spectrum of tumors
associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. J.
Clin. Oncol., 16: 3028-3036, 1998.
26. Rodriguez, E., Sreekantaiah, C., Gerald, W., Reuter, V. E., Motzer, R. J., and
Chaganti, R. S. A recurring translocation, t(11;22)(p13;q11.2), characterizes intra-
abdominal desmoplastic small round-cell tumors. Cancer Genet. Cytogenet., 69: 17-21,
1993.
27. Biegel, J. A., Conard, K., and Brooks, J. J. Translocation (11;22)(p13;q12): primary
change in intra- abdominal desmoplastic small round cell tumor. Genes Chromosom.
Cancer, 7: 119-121, 1993.
28. Lee, S. B., Kolquist, K. A., Nichols, K., Englert, C., Maheswaran, S., Ladanyi, M.,
Gerald, W. L., and Haber, D. A. The EWS-WT1 translocation product induces PDGFA in
desmoplastic small round-cell tumour. Nat. Genet., 17: 309-313, 1997.
29. Kelly, J. D., Haldeman, B. A., Grant, F. J., Murray, M. J., Seifert, R. A., Bowen-Pope,
D. F., Cooper, J. A., and Kazlauskas, A. Platelet-derived growth factor (PDGF) stimulates
PDGF receptor subunit dimerization and intersubunit trans-phosphorylation. J. Biol.
Chem., 266: 8987-8992, 1991.
30. Delattre, O., Zucman, J., Plougastel, B., Desmaze, C., Melot, T., Peter, M., Kovar, H.,
Joubert, I., de Jong, P., Rouleau, G., and et al Gene fusion with an ETS DNA-binding
domain caused by chromosome translocation in human tumours. Nature, 359: 162-165,
1992.
113
31. Turc-Carel, C., Philip, I., Berger, M. P., Philip, T., and Lenoir, G. M. Chromosome
study of Ewings sarcoma (ES) cell lines. Consistency of a reciprocal translocation
t(11;22)(q24;q12). Cancer Genet. Cytogenet., 12: 1-19, 1984.
32. Turc-Carel, C., Aurias, A., Mugneret, F., Lizard, S., Sidaner, I., Volk, C., Thiery, J. P.,
Olschwang, S., Philip, I., Berger, M. P., and et al Chromosomes in Ewings sarcoma. I. An
evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12). Cancer Genet.
Cytogenet., 32: 229-238, 1988.
33. Ewen, M. E., Ludlow, J. W., Marsilio, E., DeCaprio, J. A., Millikan, R. C., Cheng, S.
H., Paucha, E., and Livingston, D. M. An N-terminal transformation-governing sequence
of SV40 large T antigen contributes to the binding of both p110Rb and a second cellular
protein, p120. Cell, 58: 257-267, 1989.
34. Buckler, A. J., Chang, D. D., Graw, S. L., Brook, J. D., Haber, D. A., Sharp, P. A.,
and Housman, D. E. Exon amplification: a strategy to isolate mammalian genes based on
RNA splicing. Proc. Natl. Acad. Sci. U. S. A., 88: 4005-4009, 1991.
35. Jeon, I. S., Davis, J. N., Braun, B. S., Sublett, J. E., Roussel, M. F., Denny, C. T., and
Shapiro, D. N. A variant Ewings sarcoma translocation (7;22) fuses the EWS gene to the
ETS gene ETV1. Oncogene, 10: 1229-1234, 1995.
36. Peter, M., Couturier, J., Pacquement, H., Michon, J., Thomas, G., Magdelenat, H., and
Delattre, O. A new member of the ETS family fused to EWS in Ewing tumors. Oncogene,
14: 1159-1164, 1997.
37. Kaneko, Y., Yoshida, K., Handa, M., Toyoda, Y., Nishihira, H., Tanaka, Y., Sasaki,
Y., Ishida, S., Higashino, F., and Fujinaga, K. Fusion of an ETS-family gene, EIAF, to
EWS by t(17;22)(q12;q12) chromosome translocation in an undifferentiated sarcoma of
infancy. Genes Chromosomes. Cancer, 15: 115-121, 1996.
38. Ishida, S., Yoshida, K., Kaneko, Y., Tanaka, Y., Sasaki, Y., Urano, F., Umezawa, A.,
Hata, J., and Fujinaga, K. The genomic breakpoint and chimeric transcripts in the
EWSR1- ETV4/E1AF gene fusion in Ewing sarcoma. Cytogenet. Cell Genet., 82: 278-
283, 1998.
39. Dagher, R., Long, L. M., Read, E. J., Leitman, S. F., Carter, C. S., Tsokos, M., Goletz,
T. J., Avila, N., Berzofsky, J. A., Helman, L. J., and Mackall, C. L. Pilot trial of tumor-
specific peptide vaccination and continuous infusion interleukin-2 in patients with
recurrent Ewing sarcoma and alveolar rhabdomyosarcoma: an inter-institute NIH study.
Med. Pediatr. Oncol., 38: 158-164, 2002.
40. Hotfilder, M., Lanvers, C., Jurgens, H., Boos, J., and Vormoor, J. c-KIT-expressing
Ewing tumour cells are insensitive to imatinib mesylate (STI571). Cancer Chemother.
Pharmacol., 50: 167-169, 2002.
41. Scotlandi, K., Manara, M. C., Strammiello, R., Landuzzi, L., Benini, S., Perdichizzi,
S., Serra, M., Astolfi, A., Nicoletti, G., Lollini, P. L., Bertoni, F., Nanni, P., and Picci, P.
C-kit receptor expression in Ewings sarcoma: lack of prognostic value but therapeutic
targeting opportunities in appropriate conditions. J. Clin. Oncol., 21: 1952-1960, 2003.
42. Ye, D., Maitra, A., Timmons, C. F., Leavey, P. J., Ashfaq, R., and Ilaria Jr, R. L. The
Epidermal Growth Factor Receptor HER2 Is Not a Major Therapeutic Target in Ewing
Sarcoma. J. Pediatr. Hematol. Oncol., 25: 459-466, 2003.
43. Pedeutour, F., Simon, M. P., Minoletti, F., Sozzi, G., Pierotti, M. A., Hecht, F., and
Turc-Carel, C. Ring 22 chromosomes in dermatofibrosarcoma protuberans are low- level
amplifiers of chromosome 17 and 22 sequences. Cancer Res., 55: 2400-2403, 1995.
44. Naeem, R., Lux, M. L., Huang, S. F., Naber, S. P., Corson, J. M., and Fletcher, J. A.
Ring chromosomes in dermatofibrosarcoma protuberans are composed of interspersed
sequences from chromosomes 17 and 22. Am. J. Pathol., 147: 1553-1558, 1995.
45. Simon, M. P., Pedeutour, F., Sirvent, N., Grosgeorge, J., Minoletti, F., Coindre, J. M.,
Terrier-Lacombe, M. J., Mandahl, N., Craver, R. D., Blin, N., Sozzi, G., Turc-Carel, C.,
OBrien, K. P., Kedra, D., Fransson, I., Guilbaud, C., and Dumanski, J. P. Deregulation of
the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in
dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat. Genet., 15: 95-98,
1997.
46. Maki, R. G., Awan, R. A., Dixon, R. H., Jhanwar, S., and Antonescu, C. R.
Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from
dermatofibrosarcoma protuberans. Int. J. Cancer, 100: 623-626, 2002.
114
47. Rubin, B. P., Schuetze, S. M., Eary, J. F., Norwood, T. H., Mirza, S., Conrad, E. U.,
and Bruckner, J. D. Molecular targeting of platelet-derived growth factor B by imatinib
mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J. Clin. Oncol.,
20: 3586-3591, 2002.
48. Alman, B. A., Li, C., Pajerski, M. E., Diaz-Cano, S., and Wolfe, H. J. Increased beta-
catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid
tumors). Am. J. Pathol, 151: 329-334, 1997.
49. Tejpar, S., Nollet, F., Li, C., Wunder, J. S., Michils, G., Dal Cin, P., Van Cutsem, E.,
Bapat, B., van Roy, F., Cassiman, J. J., and Alman, B. A. Predominance of beta-catenin
mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid
tumor). Oncogene, 18: 6615-6620, 1999.
50. Fletcher, J. A., Naeem, R., Xiao, S., and Corson, J. M. Chromosome aberrations in
desmoid tumors. Trisomy 8 may be a predictor of recurrence. Cancer Genet. Cytogenet.,
79: 139-143, 1995.
51. Miyaki, M., Konishi, M., Kikuchi-Yanoshita, R., Enomoto, M., Tanaka, K.,
Takahashi, H., Muraoka, M., Mori, T., Konishi, F., and Iwama, T. Coexistence of somatic
and germ-line mutations of APC gene in desmoid tumors from patients with familial
adenomatous polyposis. Cancer Res., 53: 5079-5082, 1993.
52. Sen-Gupta, S., Van der Luijt, R. B., Bowles, L. V., Meera Khan, P., and Delhanty, J.
D. Somatic mutation of APC gene in desmoid tumour in familial adenomatous polyposis.
Lancet, 342: 552-553, 1993.
53. Mace, J., Sybil, B. J., Sondak, V., McGinn, C., Hayes, C., Thomas, D., and Baker, L.
Response of extraabdominal desmoid tumors to therapy with imatinib mesylate. Cancer,
95: 2373-2379, 2002.
54. Schofield, D. E., Fletcher, J. A., Grier, H. E., and Yunis, E. J. Fibrosarcoma in infants
and children. Application of new techniques. Am. J. Surg. Pathol., 18: 14-24, 1994.
55. Schofield, D. E., Yunis, E. J., and Fletcher, J. A. Chromosome aberrations in
mesoblastic nephroma. Am. J. Pathol., 143: 714-724, 1993.
56. Knezevich, S. R., McFadden, D. E., Tao, W., Lim, J. F., and Sorensen, P. H. A novel
ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat. Genet., 18: 184-187, 1998.
57. Rubin, B. P., Chen, C. J., Morgan, T. W., Xiao, S., Grier, H. E., Kozakewich, H. P.,
Perez-Atayde, A. R., and Fletcher, J. A. Congenital mesoblastic nephroma t(12;15) is
associated with ETV6- NTRK3 gene fusion: cytogenetic and molecular relationship to
congenital (infantile) fibrosarcoma. Am. J. Pathol., 153: 1451-1458, 1998.
58. Knezevich, S. R., Garnett, M. J., Pysher, T. J., Beckwith, J. B., Grundy, P. E., and
Sorensen, P. H. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link
between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res., 58: 5046-5048,
1998.
59. Bolande, R. P. Congenital mesoblastic nephroma of infancy. Perspect. Pediatr.
Pathol., 1: 227-250, 1973.
60. Chung, E. B. and Enzinger, F. M. Infantile fibrosarcoma. Cancer, 38: 729-739, 1976.
61. Treissman, S. P., Gillis, D. A., Lee, C. L., Giacomantonio, M., and Resch, L.
Omental-mesenteric inflammatory pseudotumor. Cytogenetic demonstration of genetic
changes and monoclonality in one tumor. Cancer, 73: 1433-1437, 1994.
62. Snyder, C. S., DellAquila, M., Haghighi, P., Baergen, R. N., Suh, Y. K., and Yi, E. S.
Clonal changes in inflammatory pseudotumor of the lung: a case report. Cancer, 76: 1545-
1549, 1995.
63. Su, L. D., Atayde-Perez, A., Sheldon, S., Fletcher, J. A., and Weiss, S. W.
Inflammatory myofibroblastic tumor: cytogenetic evidence supporting clonal origin. Mod.
Pathol., 11: 364-368, 1998.
64. Lawrence, B., Perez-Atayde, A., Hibbard, M. K., Rubin, B. P., Dal Cin, P., Pinkus, J.
L., Pinkus, G. S., Xiao, S., Yi, E. S., Fletcher, C. D., and Fletcher, J. A. TPM3-ALK and
TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am. J. Pathol, 157: 377-
384, 2000.
65. Rubin, B. P., Singer, S., Tsao, C., Duensing, A., Lux, M. L., Ruiz, R., Hibbard, M. K.,
Chen, C. J., Xiao, S., Tuveson, D. A., Demetri, G. D., Fletcher, C. D., and Fletcher, J. A.
KIT Activation Is a Ubiquitous Feature of Gastrointestinal Stromal Tumors. Cancer Res.,
61: 8118-8121, 2001.
66. Heinrich, M. C., Corless, C. L., Duensing, A., McGreevey, L., Chen, C. J., Joseph, N.,
Singer, S., Griffith, D. J., Haley, A., Town, A., Demetri, G. D., Fletcher, C. D., and
115
84. Biegel, J. A., Zhou, J. Y., Rorke, L. B., Stenstrom, C., Wainwright, L. M., and
Fogelgren, B. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid
tumors. Cancer Res., 59: 74-79, 1999.
85. Sevenet, N., Sheridan, E., Amram, D., Schneider, P., Handgretinger, R., and Delattre,
O. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers.
Am. J. Hum. Genet., 65: 1342-1348, 1999.
86. Roberts, C. W., Galusha, S. A., McMenamin, M. E., Fletcher, C. D., and Orkin, S. H.
Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid
tumors in mice. Proc. Natl. Acad. Sci. U. S. A, 97: 13796-13800, 2000.
87. Galili, N., Davis, R. J., Fredericks, W. J., Mukhopadhyay, S., Rauscher, F. J. 3.,
Emanuel, B. S., Rovera, G., Barr, F. G., and Rauscher, F. J. Fusion of a fork head domain
gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat. Genet., 5: 230-235,
1993.
88. Barr, F. G., Galili, N., Holick, J., Biegel, J. A., Rovera, G., and Emanuel, B. S.
Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar
rhabdomyosarcoma. Nat. Genet., 3: 113-117, 1993.
89. Shapiro, D. N., Sublett, J. E., Li, B., Downing, J. R., and Naeve, C. W. Fusion of
PAX3 to a member of the forkhead family of transcription factors in human alveolar
rhabdomyosarcoma. Cancer Res., 53: 5108-5112, 1993.
90. Davis, R. J., DCruz, C. M., Lovell, M. A., Biegel, J. A., and Barr, F. G. Fusion of
PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar
rhabdomyosarcoma. Cancer Res., 54: 2869-2872, 1994.
91. Fredericks, W. J., Galili, N., Mukhopadhyay, S., Rovera, G., Bennicelli, J., Barr, F.
G., Rauscher, F. J. 3., and Rauscher, F. J. r. The PAX3-FKHR fusion protein created by
the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional
activator than PAX3. Mol. Cell Biol., 15: 1522-1535, 1995.
92. Bennicelli, J. L., Fredericks, W. J., Wilson, R. B., Rauscher, F. J. 3., and Barr, F. G.
Wild type PAX3 protein and the PAX3-FKHR fusion protein of alveolar
rhabdomyosarcoma contain potent, structurally distinct transcriptional activation domains.
Oncogene, 11: 119-130, 1995.
93. Sharp, R., Recio, J. A., Jhappan, C., Otsuka, T., Liu, S., Yu, Y., Liu, W., Anver, M.,
Navid, F., Helman, L. J., DePinho, R. A., and Merlino, G. Synergism between
INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis.
Nat. Med., 8: 1276-1280, 2002.
94. Nanni, P., Nicoletti, G., De Giovanni, C., Croci, S., Astolfi, A., Landuzzi, L., Di
Carlo, E., Iezzi, M., Musiani, P., and Lollini, P. L. Development of Rhabdomyosarcoma
in HER-2/neu Transgenic p53 Mutant Mice. Cancer Res., 63: 2728-2732, 2003.
95. Kalebic, T., Tsokos, M., and Helman, L. J. In vivo treatment with antibody against
IGF-1 receptor suppresses growth of human rhabdomyosarcoma and down-regulates
p34cdc2. Cancer Res., 54: 5531-5534, 1994.
96. Kalebic, T., Blakesley, V., Slade, C., Plasschaert, S., Leroith, D., and Helman, L. J.
Expression of a kinase-deficient IGF-I-R suppresses tumorigenicity of
rhabdomyosarcoma cells constitutively expressing a wild type IGF-I-R. Int. J. Cancer, 76:
223-227, 1998.
97. Clark, J., Rocques, P. J., Crew, A. J., Gill, S., Shipley, J., Chan, A. M., Gusterson, B.
A., and Cooper, C. S. Identification of novel genes, SYT and SSX, involved in the
t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat. Genet., 7: 502-
508, 1994.
98. Matsuzaki, A., Suminoe, A., Hattori, H., Hoshina, T., and Hara, T. Immunotherapy
with autologous dendritic cells and tumor-specific synthetic peptides for synovial
sarcoma. J. Pediatr. Hematol. Oncol., 24: 220-223, 2002.
99. Allander, S. V., Illei, P. B., Chen, Y., Antonescu, C. R., Bittner, M., Ladanyi, M., and
Meltzer, P. S. Expression profiling of synovial sarcoma by cDNA microarrays:
association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation. Am. J. Pathol.,
161: 1587-1595, 2002.
Chapter 7
Jaap Verweij
Dept. of Medical Oncology, Erasmus University Medical Centre-Daniel den Hoed Cancer
Centre, Rotterdam, the Netherlands
Correspondence to:
Jaap Verweij, MD, PhD
Dept. of Medical Oncology,
Erasmus University Medical Centre-Daniel den Hoed Cancer Centre,
Groene Hilledijk 301
3075 EA Rotterdam, the Netherlands
118
1 INTRODUCTION
2 IMATINIB
4 KIT-DRIVEN GIST
patients, 35 of whom had GIST. The other 5 sarcomas did not express
KIT. By common toxicity criteria of the National Cancer Institute (NCI-
CTC version 2.0) [45], at the 500 mg twice daily dose-level 5 of 8
patients showed a dose-limiting toxicity (DLT), including nausea,
vomiting, edema, and skin rash. A maximum tolerated dose of 800 mg
per day, 400 mg bid, was advised for future studies. At a follow-up of 9-
12 months, 82% of the included GIST patients still benefited from
imatinib therapy (Table 1).
At the same time an initial phase II study was performed by
investigators in the USA and Finland to formally assess activity and
safety in metastatic or unresectable GIST patients [39]. In this study, 147
patients were included. In 135 patients KIT positive GIST was confirmed
by expression of CD117. In 10 cases no material was available to confirm
this diagnosis. Patients were randomized to receive either a daily dose
patients treated with 400 mg imatinib bid. GIST patients again showed a
high response rate, even one complete remission [46].
In view of remaining questions on dose-response relationships,
subsequently 2 randomized phase III studies have been performed in
pretreated patients with CD117-positive GIST receiving an oral dose of
either 400 mg or 800 mg per day. Primary study objectives differ slightly.
The study coordinated by the EORTC, in cooperation with the Italian
Sarcoma Group and the Australian Gastrointestinal Tumors Group, has
included 946 patients and had time to progression of disease as primary
endpoint [47, 48], whereas the study coordinated by the South West
Oncology Group (SWOG) accruing 746 patients has overall survival as
primary endpoint [49, 50]. With a median follow-up of 8.4 months, at the
time of the latest interim analysis, the EORTC study does show a better
progression free survival for the higher dose group [48] (progression free
survival at 6 and 12 months 78% and 69% versus 73% and 64%).
Objective response rates by RECIST criteria [51] are reported to be
identical in both dose groups (43%), with 2% to 3% complete responses.
The SWOG study does not show significant differences between
both dose groups at their most recent interim analysis as well [50].
Objective response rates by RECIST criteria [51] are reported to be
comparable as well (Table 1). Data from cross-over from 400 to 800 mg
are currently not yet available.
Little is yet known about the potential of imatinib as neo-
adjuvant and/or adjuvant treatment. One study presents data of only 5
patients, who received adjuvant imatinib therapy after radical surgery.
With a follow up of 7 to 13 months, none of these patients has developed
recurrent disease yet [52], but clearly publishing such data is strange
based upon flawed methodology, and surely these data to not justify
routine use of the approach.
The data on neo-adjuvant treatment are similarly scantly and
incoclusive. A small study involved only 18 GIST patients that were
operated after a period of imatinib treatment [53]. Radical resection was
achieved in seven out of eight patients, who underwent the surgery
because of residual tumor mass and had a partial response, and in two out
of ten patients, who were operated because of progressive disease.
Currently, various phase II and phase III studies are being performed
investigating the potential role of imatinib in the treatment of resectable
GISTs. Clearly only phase III studies can yield undebatable results in this
setting.
Most gain-of-function KIT mutations in GISTs are within the
juxtamembrane region, encoded by exon 11 [54]. Mutations are also
found in exon 9, and to a much lesser extent in exons 13 and 17, encoding
for the extracellular region, the first part of the split kinase domain, and
for the catalytic activation loop in the second part of the kinase domain,
respectively [54, 55]. From in vitro studies, it was suggested that GISTs
with a mutation of KIT in its regulatory part would respond better on
imatinib as those with a KIT mutation in its enzymatic part [56].
Recently, it was reported that GIST patients with a KIT mutation in exon
11 have a significant higher partial response rate than patients with a
123
6 CONCLUSION
7 REFERENCES
1. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred
Gastrointestinal Stromal Tumors: Recurrence patterns and prognostic factors for survival. Ann
Surg. 231(1), 51-58 (2000).
2. Miettinen M, Lasota J. Gastrointestinal stromal tumors--definition, clinical, histological,
immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch.
438(1), 1-12 (2001).
3. Emory TS, Sobin LH, Lukes L, Lee DH, OLeary TJ. Prognosis of gastrointestinal smooth-
muscle (stromal) tumors: Dependence on anatomic site. Am J Surg Pathol. 23(1), 82-87 (1999).
4. Fletcher CD, Berman JJ, Corless C et al. Diagnosis of Gastrointestinal Stromal Tumors: A
consensus approach. Hum Pathol. 33(5), 459-465 (2002).
5. Blanke CD, Eisenberg BL, Heinrich MC. Gastrointestinal Stromal Tumors. Curr Treat Options
Oncol. 2(6), 485-491 (2001).
6. Mazur MT, Clark HB. Gastric Stromal Tumors. Reappraisal of histogenesis. Am J Surg Pathol.
7(6), 507-519 (1983).
7. Hirota S, Isozaki K, Moriyama Y et al. Gain-of-function mutations of c-KIT in human
Gastrointestinal Stromal Tumors. Science. 279(5350), 577-580 (1998).
8. Giebel LB, Strunk KM, Holmes SA, Spritz RA. Organization and nucleotide sequence of the
human KIT (mast/stem cell growth factor receptor) proto-oncogene. Oncogene. 7(11), 2207-2217
(1992).
9. Lux ML, Rubin BP, Biase TL et al. KIT extracellular and kinase domain mutations in
Gastrointestinal Stromal Tumors. Am J Pathol. 156(3), 791-795 (2000).
10. Rubin BP, Singer S, Tsao C et al. Kit activation is a ubiquitous feature of Gastrointestinal
Stromal Tumors. Cancer Res. 61(22), 8118-8121 (2001).
125
34. Joensuu H, Roberts PJ, Sarlomo-Rikala M et al. Effect of the tyrosine kinase inhibitor STI571
in a patient with a metastatic Gastrointestinal Stromal Tumor. N Engl J Med. 344(14), 1052-1056
(2001).
35. van Oosterom AT, Judson I, Verweij J et al. Safety and efficacy of Imatinib (STI571) in
metastatic Gastrointestinal Stromal Tumours: A phase I study. Lancet. 358(9291), 1421-1423
(2001).
36. (imatinib mesylate) tablets prescribing information. 2003, East Hanover, New
Jersey, USA: Novartis Pharmaceuticals Corporation.
37. Reckmann AH, Fischer T, Peng B et al. Effect of food on STI571 Glivec pharmacokinetics
and bioavailability. Proc. Am. Soc. Clin. Oncol. 20, abstract 1223 (2001).38. Glivec. Gist clinical
monograph. 2002, Basel, Switserland: Novartis Pharma AG.
39. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of Imatinib Mesylate in
advanced Gastrointestinal Stromal Tumors. N Engl J Med. 347(7), 472-480 (2002).
40. Judson IR, Donato Di Paola E, Verweij J et al. Population pharmacokinetic (pk) analysis and
pk-pharmacodynamic (pd) correlations in phase I / II trial of Imatinib in Gastrointestinal Stromal
Tumours (GIST) conducted by the European Organisation for Research and Treatment of Cancer
Soft Tissue and Bone Sarcoma Group. Proc. Am. Soc. Clin. Oncol. 22, abstract 3287 (2003).
41. Ramanathan RK, Remick SC, Mulkerin D et al. P-5331: A phase I pharmacokinetic (pk)
study of STI571 in patients (pts) with advanced malignancies and varying degrees of liver
dysfunction (ld). Proc. Am. Soc. Clin. Oncol. 22, abstract 502 (2003).
42. OBrien SG, Peng B, Dutrix C et al. A pharmacokinetic interaction of Glivec and Simvastatin,
a cytochrome 3a4 substrate, in a patients with Chronic Myeloid Leukemia. Proc. Am. Soc.
Hematology 98, 141a, abstract 593 (2001).
43. Remick SC, Ramanathan RK, Mulkerin D et al. P-5340: A phase I pharmacokinetic study of
STI-571 in patients (pts) with advanced malignancies and varying degrees of renal dysfunction.
Proc. Am. Soc. Clin. Oncol. 22, abstract 503 (2003).
44. Gurney H, Wong M, Rivory L et al. Imatinib elimination: Characterisation by in vivo testing
of phenotype and genotype. Proc. Am. Soc. Clin. Oncol. 22, abstract 775 (2003).
45. Cancer therapy evaluation program. Common toxicity criteria, version 2.0. 1998, Bethesda,
USA: National Cancer Institute.
46. Verweij J, van Oosterom A, Blay JY et al. Imatinib Mesylate (STI-571 Glivec, Gleevec) is
an active agent for Gastrointestinal Stromal Tumours, but does not yield responses in other soft-
tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue
and Bone Sarcoma Group phase II study. Eur J Cancer. 39(14), 2006-2011 (2003).
47. Casali PG, Verweij J, Zalcberg J et al. Imatinib (Glivec) 400 vs 800 mg daily in patients with
Gastrointestinal Stromal Tumors (GIST): A randomized phase III trial from the EORTC Soft
Tissue and Bone Sarcoma Group, the Italian Sarcoma Group (ISG), and the Australasian Gastro-
Intestinal Trials Group (AGITG). A toxicity report. Proc. Am. Soc. Clin. Oncol. 21, abstract 1650
(2002).
48. Verweij J, Casali PG, Zalcberg J et al. Early efficacy comparison of two doses of Imatinib for
the treatment of advanced Gastro-Intestinal Stromal Tumors (GIST): Interim results of a
randomized phase III trial from the EORTC-STBSG, ISG and AGITG. Proc. Am. Soc. Clin.
Oncol. 22, abstract 3272 (2003).
49. Demetri GD, Rankin C, Fletcher C et al. Phase III dose-randomized study of Imatinib
Mesylate (Gleevec, STI571) for GIST: Intergroup s0033 early results. Proc. Am. Soc. Clin. Oncol.
21, abstract 1651 (2002).
50. Benjamin RS, Rankin C, Fletcher C et al. Phase III dose-randomized study of Imatinib
Mesylate (STI571) for GIST: Intergroup s0033 early results. Proc. Am. Soc. Clin. Oncol. 22,
abstract 3271 (2003).
51. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to
treatment in solid tumors. European Organization for Research and Treatment of Cancer, National
Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst.
92(3), 205-216 (2000).
52. Bumming P, Andersson J, Meis-Kindblom JM et al. Neoadjuvant, adjuvant and palliative
treatment of Gastrointestinal Stromal Tumours (GIST) with imatinib: A centre-based study of 17
patients. Br J Cancer. 89(3), 460-464 (2003).
53. Hohenberger P, Bauer S, Schneider U et al. Tumor resection following imatinib pretreatment
in GI Stromal Tumors. Proc. Am. Soc. Clin. Oncol. 22, abstract 3288 (2003).
127
54. Fletcher JA, Fletcher CD, Rubin BP, Ashman LK, Corless CL, Heinrich MC. KIT gene
mutations in Gastrointestinal Stromal Tumors: More complex than previously recognized? Am J
Pathol. 161(2), 737-738; author reply 738-739 (2002).
55. Heinrich MC, Corless CL, Blanke C et al. KIT mutational status predicts clinical response to
STI571 in patients with metastatic Gastrointestinal Stromal Tumors (GISTs). Proc. Am. Soc. Clin.
Oncol. 21, abstract 6 (2002).
56. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of
Gastrointestinal Stromal Tumors: KIT activation and cytogenetic alterations. Hum Pathol. 33(5),
484-495 (2002)
57. Heinrich MC, Corless CL, Von Mehren M et al. PDGFRA and KIT mutations correlate with
the clinical responses to Imatinib Mesylate in patients with advanced Gastrointestinal Stromal
Tumors (GIST). Proc. Am. Soc. Clin. Oncol. 22, abstract 3274 (2003).
58. Heinrich MC, Corless CL, Duensing A et al. Pdgfra activating mutations in Gastrointestinal
Stromal Tumors. Science. 299(5607), 708-710 (2003).
59. Deininger MW, Druker BJ. Specific targeted therapy of Chronic Myelogenous Leukemia with
imatinib. Pharmacol Rev. 55(3), 401-423 (2003).
60. Fletcher JA, Corless CL, Dimitrijevic S et al. Mechanisms of resistance to Imatinib Mesylate
(IM) in advanced Gastrointestinal Stromal Tumor (GIST). 22, abstract 3275 (2003).
61. Andersson J, Sjogren H, Meis-Kindblom JM, Stenman G, Aman P, Kindblom LG. The
complexity of KIT gene mutations and chromosome rearrangements and their clinical correlation
in Gastrointestinal Stromal (pacemaker cell) Tumors. Am J Pathol. 160(1), 15-22 (2002).
62. Eisenberg BL, von Mehren M. Pharmacotherapy of Gastrointestinal Stromal Tumours. Expert
Opin Pharmacother. 4(6), 869-874 (2003).
63. Van Glabbeke MM, Verweij J, Casali PG et al. Prognostic factors of toxicity and efficacy in
patients with Gastro-Intestinal Stromal Tumors (GIST) treated with imatinib: A study of the
EORTC-STBSG, ISG and AGITG. Proc. Am. Soc. Clin. Oncol. 22, abstract 3286 (2003).
64. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in
gastrointestinal Stromal tumors. Science 229, 708-710 (2003).
65. Rubin BP, Schuetze SM, Eary JF, et al. Molecular targeting of platelet-derived growth factor
B by Imatinib mesylate in a patient with metastatic dermatofibrosarcoma protruberans.
J.Clin.Oncol. 20:3586-3591 (2002)
66..Mace J, Biermann JS, Sondak V, et al. Response of extraabdominal desmoid tumors to therapy
with imatinib mesylate. Cancer 95:2372-2370 (2002)
This page intentionally left blank
Chapter 8
Correspondence to:
Michael C.Heinrich, MD
Departments of Medicine and Pathology,
Oregon Health Science University Cancer Institute and Portland VA Medical Center,
3710 SW US Veterans Hospital Road
Portland, OR 97201
USA
130
1 INTRODUCTION
supporting the view that activation of KIT plays an important role in the
growth and survival of GISTs.
The reported frequency of exon 11 mutations in GISTs
has varied over a wide range (20% to 92%), but the highest frequencies
have come from studies based on cDNA prepared from frozen tumor
samples. Hirota and colleagues observed exon 11 mutations in 5 of 6
tumors (83%), while Rubin et al. uncovered 34 exon 11 mutations in 48
tumors (71%).17,18 In most studies that have used genomic DNA extracted
out of paraffin-embedded tumor tissue the frequency has been lower
(20% to 57%).19-24 This likely reflects technical issues related to the lower
quality of DNA obtainable from such samples. In addition, the PCR
primers used to amplify exon 11 in some paraffin-based studies did not
permit analysis of the entire exon. Screening methodologies are another
factor. Many investigators have relied on single strand conformation
polymorphism (SSCP) to look for the presence of a deletion or point
mutation, but this technique is not as sensitive as capillary gel
electrophoresis, which in a recent study by Emile et al. yielded exon 11
mutations in 67.5% of 40 GIST samples.25
Denaturing HPLC (D-HPLC) is another highly sensitive
screening methodology that has yielded high frequencies of
deletions/insertions and point mutations in KIT exon 11. In a series of 322
paraffin-embedded GISTs for KIT gene mutations screened by this
approach in our laboratory the frequency of sequence-confirmed exon 11
mutations was 66.1%. This series includes 127 malignant GISTs and 13
very low-risk GISTs that have previously been published.26,27 The
spectrum of mutations, was similar to that reported by other groups.
Deletions and insertions tend to affect the first part of the exon,
particularly codons 557-559. Point mutations are limited to just four of
the codons within the exon: 557, 559, 560 and 576. Internal tandem
duplications are observed near the end of the exon. A subset of the
tumors (17.8%) were either hemizygous or homozygous for the observed
mutation, suggesting that there is negative selective pressure on
expression of the wild-type KIT allele in exon 11-mutant tumors. In vitro
experiments demonstrating that a peptide corresponding to the wild-type
juxtamembrane domain is inhibitory to activated isoforms of KIT support
this view.16
Some GISTs are negative for mutations in the KIT gene, despite
best efforts to find these mutations, including complete cDNA
sequencing. Heinrich, Fletcher and colleagues recently applied a novel
methodology to search for other activated kinases in tumors wild-type for
KIT (KIT-WT).57 A cocktail of antibodies to epitopes shared by a wide
range of receptor tyrosine kinases was used to immunoprecipitate kinases
from extracts of these tumors, and western blotting with a phospho-
tyrosine specific antibody revealed a novel band that was identified as
PDGF receptor alpha (PDGFRA). Phosphorylated PDGFRA was
detectable in a subset of KIT-WT tumors, but was not present in extracts
of tumors with known KIT mutations. Conversely, extracts of KIT-mutant
tumors had phosphorylated KIT, but were negative for phosphorylated
PDGFRA. These results suggested that PDGFRA is the active kinase in
some KIT-WT tumors.
Examination of genomic DNA from KIT-WT tumors yielded a
variety of mutations in the juxtamembrane (exon 12) and activation loop
(exon 18) domains of the PDGFRA gene.57 When cloned and transfected
into CHO cells, the PDGFRA mutant isoforms were found to be
constitutively phosphorylated in the absence of PDGF-AA ligand,
consistent with oncogenic activation. The frequency of PDGFRA
mutations among KIT-WT GISTs is 34% (23/67 cases), and among all
GISTs is 7.1% (23/322). PDGFRA exon 12 mutations appear to be less
common than exon 18 mutations (1.5% versus 5.6%, respectively).
PDGFRA -mutant tumors tend to have an epithelioid morphology,
but are not histologically distinguishable from KIT-mutant tumors.
Likewise, the signal transduction profiles for the two types of tumors are
similar.57 No PDGFRA mutations have been found in 146 KIT-mutant
tumors, so the activation of the two genes appears to be mutually
exclusive. Although not as extensively studied as KIT mutations in
GISTs, it seems likely that PDGFRA mutations might be an initiating
event in some GISTs lacking KIT mutations. The impact of PDGFRA
mutations on the diagnosis and treatment of GISTs is considered in later
sections.
136
11 REFERENCES
1. Besmer, P., Murphy, J. E., George, P. C., Qiu, F., Bergold, P. J., Lederman, L.,
Snyder, H. W., Jr., Brodeur, D., Zuckerman, E. E., and Hardy, W. D. A new acute
transforming feline retrovirus and relationship of its oncogene v-kit with the protein
kinase gene family. Nature., 320: 415-419, 1986.
2. Yarden, Y., Kuang, W.-J., Yang-Feng, T., Coussens, L., Munemitsu, S., Dull,
T. J., Chen, E., Schlessinger, J., Francke, U., and Ullrich, A. Human proto-oncogene c-kit:
a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J., 11: 3341-
3351, 1987.
3. Rousset, D., Agnes, F., Lachaume, P., Andre, C., and Galibert, F. Molecular
evolution of the genes encoding receptor tyrosine kinase with immunoglobulinlike
domains. Journal of Molecular Evolution, 41: 421-429, 1995.
4. Small, D., Levenstein, M., Kim, E., Carow, C., Amin, S., Rockwell, P., Witte,
L., Burrow, C., Ratajczak, M. Z., Gewirtz, A. M., and et al STK-1, the human homolog of
Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved
in the proliferation of early progenitor/stem cells. Proc.Natl.Acad.Sci.U.S.A., 91: 459-
463, 1994.
5. Ishikawa, K., Komuro, T., Hirota, S., and Kitamura, Y. Ultrastructural
identification of the c-kit-expressing interstitial cells in the rat stomach: a comparison of
control and Ws/Ws mutant rats. Cell & Tissue Research, 289: 137-143, 1997.
6. Natali, P. G., Nicotra, M. R., Sures, I., Santoro, E., Bigotti, A., and Ullrich, A.
Expression of c-kit receptor in normal and transformed human nonlymphoid tissues.
Cancer Res., 52: 6139-6143, 1992.
7. Nocka, K., Majumder, S., Chabot, B., Ray, P., Cervone, M., Bernstein, A.,
Besmer, and P. Expression of c-kit gene products in known cellular targets of W
mutations in normal and W mutant mice-evidence for an impaired c- kit kinase in mutant
mice. Genes Dev., 3: 816-826, 1989.
8. Russell, E. S. Hereditary anemias of the mouse: A review for geneticists.
Adv.Genet., 20: 357-359, 1979.
9. Turner, A. M., Zsebo, K. M., Martin, F., Jacobsen, F. W., Bennett, L. G., and
Broudy, V. C. Nonhematopoietic tumor cell lines express stem cell factor and display c-
kit receptors. Blood, 80: 374-381, 1992.
10. Blume-Jensen, P., Claesson-Welsh, L., Siegbahn, A., Zsebo, K. M.,
Westermark, B., and Heldin, C. H. Activation of the human c-kit product by ligand-
induced dimerization mediates circular actin reorganization and chemotaxis. EMBO J.,
10: 4121-4128, 1991.
11. Huang, E., Nocka, K., Beier, D. R., Chu, T. Y., Buck, J., Lahm, H. W., Wellner,
D., Leder, P., and Besmer, P. The hematopoietic growth factor KL is encoded by the Sl
locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell, 63:
225-233, 1990.
12. Blume-Jensen, P. and Hunter, T, Oncogenic kinase signalling. Nature., 411:
355-365, 2001.
13. Irusta, P. M. and DiMaio, D. A single amino acid substitution in a WW-like
domain of diverse members of the PDGF receptor subfamily of tyrosine kinases causes
constitutive receptor activation. EMBO J., 17: 6912-6923, 1998.
14. Kitayama, H., Kanakura, Y., Furitsu, T., Tsujimura, T., Oritani, K., Ikeda, H.,
Sugahara, H., Mitsui, H., Kanayama, Y., Kitamura, Y., and et al. Constitutively activating
mutations of c-kit receptor tyrosine kinase confer factor-independent growth and
tumorigenicity of factor-dependent hematopoietic cell lines. Blood, 85: 790-798, 1995.
15. Ma, Y., Cunningham, M. E., Wang, X., Ghosh, I., Regan, L., and Longley, B. J.
Inhibition of spontaneous receptor phosphorylation by residues in a putative alpha-helix
in the KIT intracellular juxtamembrane region. J.Biol.Chem., 274: 13399-13402, 1999.
16. Chan, P. M., Ilangumaran, S., La Rose, J., Chakrabartty, A., and Rottapel, R.
Autoinhibition of the Kit Receptor Tyrosine Kinase by the Cytosolic Juxtamembrane
Region. Mol.Cell Biol., 23: 3067-3078, 2003.
17. Hirota, S., Isozaki, K., Moriyama, Y., Hashimoto, K., Nishida, T., Ishiguro, S.,
Kawano, K., Hanada, M., Kurata, A., Takeda, M., Muhammad Tunio, G., Matsuzawa, Y.,
Kanakura, Y., Shinomura, Y., and Kitamura, Y. Gain-of-function mutations of c-kit in
human gastrointestinal stromal tumors. Science, 279: 577-580, 1998.
145
18. Rubin, B. P., Singer, S., Tsao, C., Duensing, A., Lux, M. L., Ruiz, R., Hibbard,
M. K., Chen, C. J., Xiao, S., Tuveson, D. A., Demetri, G. D., Fletcher, C. D. M., and
Fletcher, J. A. KIT Activation Is a Ubiquitous Feature of Gastrointestinal Stromal
Tumors. Cancer Res, 61: 8118-8121, 2001.
19. Ernst, S. I., Hubbs, A. E., Przygodzki, R. M., Emory, T. S., Sobin, L. H., and
OLeary, T. J. KIT mutation portends poor prognosis in gastrointestinal stromal/smooth
muscle tumors. Laboratory Investigation, 78: 1633-1636, 1998.
20. Lasota, J., Jasinski, M., Sarlomo-Rikala, M., and Miettinen, M. Mutations in
exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal
tumors and do not occur in leiomyomas or leiomyosarcomas. Am.J.Pathol., 154: 53-60,
1999.
21. Li, S. Q., OLeary, T. J., Sobin, L. H., Erozan, Y. S., Rosenthal, D. L., and
Przygodzki, R. M. Analysis of KIT mutation and protein expression in fine needle
aspirates of gastrointestinal stromal/smooth muscle tumors. Acta Cytologica, 44: 981-986,
2000.
22. Moskaluk, C. A., Tian, Q., Marshall, C. R., Rumpel, C. A., Franquemont, D.
W., Frierson, and Jr, H. F. Mutations of c-kit JM domain are found in a minority of
human gastrointestinal stromal tumors. Oncogene, 18: 1897-1902, 1999.
23. Singer, S., Rubin, B. P., Lux, M. L., Chen, C. J., Demetri, G. D., Fletcher, C.
D., and Fletcher, J. A. Prognostic Value of KIT Mutation Type, Mitotic Activity, and
Histologic Subtype in Gastrointestinal Stromal Tumors. J Clin.Oncol., 20: 3898-3905,
2002.
24. Taniguchi, M., Nishida, T., Hirota, S., Isozaki, K., Ito, T., Nomura, T., Matsuda,
H., and Kitamura, Y. Effect of c-kit mutation on prognosis of gastrointestinal stromal
tumors. Cancer Res, 59: 4297-4300, 1999.
25. Emile, J. F., Lemoine, A., Bienfait, N., Terrier, P., Azoulay, D., and Debuire, B.
Length analysis of polymerase chain reaction products: a sensitive and reliable technique
for the detection of mutations in KIT exon 11 in gastrointestinal stromal tumors.
Diagn.Mol.Pathol., 11: 107-112, 2002.
26. Heinrich, M. C., Corless, C. L., Demetri, G. D., Blanke, C. D., von Mehren, M.,
Joensuu, H., McGreevey, L. S., Chen, C. J., Van den Abbeele, A. D., Druker, B. J., Kiese,
B., Eisenberg, B., Roberts, P. J., Singer, S., Fletcher, C. D. M., Silberman, S.,
Dimitrijevic, S., and Fletcher, J. A. Kinase mutations and imatinib mesylate response in
patients with metastatic gastrointestinal stromal tumor. Journal of Clinical Oncology (in
press), 2003.
27. Corless, C. L., McGreevey, L., Haley, A., Town, A., and Heinrich, M. C. KIT
mutations are common in incidental gastrointestinal stromal tumors one centimeter or less
in size. Am.J.Pathol., 160: 1567-1572, 2002.
28. Lux, M. L., Rubin, B. P., Biase, T. L., Chen, C. J., Maclure, T., Demetri, G.,
Xiao, S., Singer, S., Fletcher, C. D. M., and Fletcher, J. A. KIT extracellular and kinase
domain mutations in gastrointestinal stromal tumors. Am.J.Pathol., 156: 791-795, 2000.
29. Hirota, S., Nishida, T., Isozaki, K., Taniguchi, M., Nakamura, J., Okazaki, T.,
and Kitamura, Y. Gain-of-function mutation at the extracellular domain of KIT in
gastrointestinal stromal tumours. Journal of Pathology, 193: 505-510, 2001.
30. Lasota, J., Wozniak, A., Sarlomo-Rikala, M., Rys, J., Kordek, R., Nassar, A.,
Sobin, L. H., and Miettinen, M. Mutations in exons 9 and 13 of KIT gene are rare events
in gastrointestinal stromal tumors : A study of 200 cases. Am.J Pathol., 157: 1091-1095,
2000.
31. Sakurai, S., Oguni, S., Hironaka, M., Fukayama, M., Morinaga, S., and Saito,
K. Mutations in c-kit gene exons 9 and 13 in gastrointestinal stromal tumors among
Japanese. Jpn.J.Cancer Res., 92: 494-498, 2001.
32. Miettinen, M., Kopczynski, J., Makhlouf, H. R., Sarlomo-Rikala, M., Gyorffy,
H., Burke, A., Sobin, L. H., and Lasota, J. Gastrointestinal stromal tumors, intramural
leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic,
immunohistochemical, and molecular genetic study of 167 cases. Am.J Surg.Pathol., 27:
625-641, 2003.
33. Kinoshita, K., Isozaki, K., Hirota, S., Nishida, T., Chen, H., Nakahara, M.,
Nagasawa, Y., Ohashi, A., Shinomura, Y., Kitamura, Y., and Matsuzawa, Y. c-kit Gene
146
of interstitial cells of Cajal is germline mutation of the c-kit gene [letter]. American
Journal of Surgical Pathology, 24: 326-327, 2000.
50. Nishida, T., Hirota, S., Taniguchi, M., Hashimoto, K., Isozaki, K., Nakamura,
H., Kanakura, Y., Tanaka, T., Takabayashi, A., Matsuda, H., and Kitamura, Y. Familial
gastrointestinal stromal tumours with germline mutation of the KIT gene. Nature
Genetics, 19: 323-324, 1998.
51. Isozaki, K., Terris, B., Belghiti, J., Schiffman, S., Hirota, S., and Vanderwinden,
J.-M, Germline-activating mutation in the kinase domain of KIT gene in familial
gastrointestinal stromal tumors. Am.J Pathol., 157: 1581-1585, 2000.
52. Chen, H., Hirota, S., Isozaki, K., Sun, H., Ohashi, A., Kinoshita, K., OBrien, P.,
Kapusta, L., Dardick, I., Obayashi, T., Okazaki, T., Shinomura, Y., Matsuzawa, Y., and
Kitamura, Y. Polyclonal nature of diffuse proliferation of interstitial cells of Cajal in
patients with familial and multiple gastrointestinal stromal tumours. Gut, 51: 793-796,
2002.
53. Sommer, G., Agosti, V., Ehlers, I., Rossi, F., Corbacioglu, S., Farkas, J., Moore,
M., Manova, K., Antonescu, C. R., and Besmer, P. Gastrointestinal stromal tumors in a
mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc
Natl.Acad.Sci.U.S.A, 100: 6706-6711, 2003.
54. Frost, D., Lasota, J., and Miettinen, M. Gastrointestinal stromal tumors and
leiomyomas in the dog: a histopathologic, immunohistochemical, and molecular genetic
study of 50 cases. Vet.Pathol, 40: 42-54, 2003.
55. Heinrich, M. C., Rubin, B. P., Longley, B. J., and Fletcher, J. A. Biology and
genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic
alterations. Hum.Pathol, 33: 484-495, 2002.
56. Faderl, S., Talpaz, M., Estrov, Z., OBrien, S., Kurzrock, R., and Kantarjian, H.
M. The biology of chronic myeloid leukemia. N.Engl.J Med., 341: 164-172, 1999.
57. Heinrich, M. C., Corless, C. L., Duensing, A., McGreevey, L., Chen, C. J.,
Joseph, N., Singer, S., Griffith, D. J., Haley, A., Town, A., Demetri, G. D., Fletcher, C.
D., and Fletcher, J. A. PDGFRA Activating Mutations in Gastrointestinal Stromal
Tumors. Science, 299: 708-710, 2003.
58. Carney, J. A., Sheps, S. G., Go, V. L., and Gordon, H. The triad of gastric
leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma.
N.Engl.J.Med., 296: 1517-1518, 1977.
59. Carney, J. A. Gastric stromal sarcoma, pulmonary chondroma, and extra-
adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and
possible familial occurrence. Mayo Clin.Proc., 74: 543-552, 1999.
60. Kerr, J. Z., Hicks, M. J., Nuchtern, J. G., Saldivar, V., Heim-Hall, J., Shah, S.,
Kelly, D. R., Cain, W. S., and Chintagumpala, M. M. Gastrointestinal autonomic nerve
tumors in the pediatric population: a report of four cases and a review of the literature.
Cancer, 85: 220-230, 1999.
61. Li, P., Wei, J., West, A. B., Perle, M., Greco, M. A., and Yang, G. C.
Epithelioid gastrointestinal stromal tumor of the stomach with liver metastases in a 12-
year-old girl: aspiration cytology and molecular study. Pediatr.Dev.Pathol., 5: 386-394,
2002.
62. Hamanaka, S., Hamanaka, Y., Yamashita, Y., and Otsuka, F. Leiomyoblastoma
and leiomyomatosis of the small intestine in a case of von Recklinghausens disease.
J.Dermatol., 24: 117-119, 1997.
63. Ishida, T., Wada, I., Horiuchi, H., Oka, T., and Machinami, R. Multiple small
intestinal stromal tumors with skeinoid fibers in association with neurofibromatosis 1
(von Recklinghausens disease). Pathol.Int., 46: 689-695, 1996.
64. Min, K. W. and Balaton, A. J. Small intestinal stromal tumors with skeinoid
fibers in neurofibromatosis: report of four cases with ultrastructural study of skeinoid
fibers from paraffin blocks. Ultrastruct.Pathol., 17: 307-314, 1993.
65. Schaldenbrand, J. D. and Appelman, H. D. Solitary solid stromal
gastrointestinal tumors in von Recklinghausens disease with minimal smooth muscle
differentiation. Hum Pathol, 15: 229-232, 1984.
66. Walsh, N. M. and Bodurtha, A. Auerbachs myenteric plexus. A possible site of
origin for gastrointestinal stromal tumors in von Recklinghausens neurofibromatosis.
Arch.Pathol.Lab Med., 114: 522-525, 1990.
148
67. Boldorini, R., Tosoni, A., Leutner, M., Ribaldone, R., Surico, N., Comello, E.,
and Min, K. W. Multiple small intestinal stromal tumours in a patient with previously
unrecognised neurofibromatosis type 1: immunohistochemical and ultrastructural
evaluation. Pathology, 33: 390-395, 2001.
68. Zoller, M. E., Rembeck, B., Oden, A., Samuelsson, M., and Angervall, L.
Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined
Swedish population. Cancer, 79: 2125-2131, 1997.
69. Blanke, C. D., Eisenberg, B. L., and Heinrich, M. C. Gastrointestinal stromal
tumors. Current Treatment Options in Oncology, 2: 485-491, 2001.
70. Ng, E. H., Pollock, R. E., and Romsdahl, M. M. Prognostic implications of
patterns of failure for gastrointestinal leiomyosarcomas. Cancer, 69: 1334-1341, 1992.
71. van Glabbeke, M., Hogendoorn, P. C., Mouridsen, H., Radford, J. A., Verweij,
J., Rodenhuis, S., le Cesne, A., Buesa, J., Keizer, H. J., Van Oosterom, A., and Nielsen,
O. Progression free fate as the principal end-point for phase II trial on soft tissue sarcoma:
what should be the target? Proc Am Soc Clin Oncol 20, 345a. 2001.
72. Edmonson, J., Marks, R., Buckner, J., and Mahoney, M. Contrast of response to
D-MAP + Sargramostim between patients with advance malignant gastrointestinal
stromal tumors and patients with other advanced leiomyosarcomas. Proc Am Soc Clin
Oncol 18, 541a. 1999.
73. Tuveson, D. A., Willis, N. A., Jacks, T., Griffin, J. D., Singer, S., Fletcher, C.
D., Fletcher, J. A., and Demetri, G. D. STI571 inactivation of the gastrointestinal stromal
tumor c-KIT oncoprotein: biological and clinical implications. Oncogene, 20: 5054-5058,
2001.
74. Heinrich, M. C., Griffith, D. J., Druker, B. J., Wait, C. L., Ott, K. A., and Zigler,
A. J. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine
kinase inhibitor. Blood, 96: 925-932, 2000.
75. Joensuu, H., Roberts, P. J., Sarlomo-Rikala, M., Andersson, L. C.,
Tervahartiala, P., Tuveson, D., Silberman, S. L., Capdeville, R., Dimitrijevic, S., Druker,
B. J., and Demetri, G. D. Effect of the tyrosine kinase inhibitor STI571 in a patient with a
metastatic gastrointestinal stromal tumor. N Engl J Med, 1052: 1052-1056, 2001.
76. Van Oosterom, A. T., Judson, I., Verweij, J., Di Paola, E., Dimitrijevic, S.,
Dumez, H., Scurr, M., Sciot, R., Silberman, S., van Glabbeke, M., and Nielsen, O. S.
Update of the Imatinib (STI571, Glivec) phase I study in gastro intestinal stromal tumours
(GISTs). Proc Am Soc Clin Oncol 21, 82a. 2002.
77. Van Oosterom, A. T., Judson, I., Verweij, J., Stroobants, S., Donato, d. P.,
Dimitrijevic, S., Martens, M., Webb, A., Sciot, R., van Glabbeke, M., Silberman, S., and
Nielsen, O. S. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal
stromal tumours: a phase I study. Lancet, 358: 1421-1423, 2001.
78. Demetri, G. D., von Mehren, M., Blanke, C. D., Van den Abbeele, A. D.,
Eisenberg, B., Roberts, P. J., Heinrich, M. C., Tuveson, D. A., Singer, S., Janicek, M.,
Fletcher, J. A., Silverman, S. G., Silberman, S. L., Capdeville, R., Kiese, B., Peng, B.,
Dimitrijevic, S., Druker, B. J., Corless, C., Fletcher, C. D., and Joensuu, H. Efficacy and
safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N.Engl.J Med.,
347: 472-480, 2002.
79. von Mehren, M., Blanke, C. D., Joensuu, H., Heinrich, M. C., Roberts, P. J.,
Eisenberg, B. L., Silberman, S., Dimitrijevic, S., Kiese, B., Fletcher, Jonathan A.,
Fletcher, Christopher D. M., and Demetri, G. D. High incidence of durable responses
induced by imatinib mesylate (Gleevec) in patients with unresectable and metastatic
gastrointestinal stromal tumors (GISTs). Proc Am Soc Clin Oncol 21, 403a. 2002.
80. Fletcher, C. D. and Fletcher, J. A. Testing for KIT (CD117) in gastrointestinal
stromal tumors: another HercepTest? Am J Clin.Pathol, 118: 163-164, 2002.
81. Hornick, J. L. and Fletcher, C. D. Immunohistochemical staining for KIT
(CD117) in soft tissue sarcomas is very limited in distribution. Am J Clin.Pathol, 117:
188-193, 2002.
82. Mace, J., Sybil, B. J., Sondak, V., McGinn, C., Hayes, C., Thomas, D., and
Baker, L. Response of extraabdominal desmoid tumors to therapy with imatinib mesylate.
Cancer, 95: 2373-2379, 2002.
83. Miettinen, M., Sobin, L. H., and Sarlomo-Rikala, M. Immunohistochemical
spectrum of GISTs at different sites and their differential diagnosis with a reference to
CD117 (KIT). Mod.Pathol., 13: 1134-1142, 2000.
149
84. Miettinen, M. Are desmoid tumors KIT positive? Am.J.Surg.Pathol., 25: 549-
550, 2001.
85. Montgomery, E., Torbenson, M. S., Kaushal, M., Fisher, C., and Abraham, S.
C. Beta-catenin immunohistochemistry separates mesenteric fibromatosis from
gastrointestinal stromal tumor and sclerosing mesenteritis. Am.J.Surg.Pathol., 26: 1296-
1301, 2002.
86. Sarlomo-Rikala, M., Kovatich, A. J., Barusevicius, A., and Miettinen, M.
CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than
CD34. Mod.Pathol., 11: 728-734, 1998.
87. Sabah, M., Leader, M., and Kay, E. The Problem With KIT: Clinical
Implications and Practical Difficulties With CD117 Immunostaining.
Appl.Immunohistochem.Mol.Morphol., 11: 56-61, 2003.
88. Bauer, S., Corless, C. L., Heinrich, M. O., Dirsch, O., Antoch, G., Kanja, J.,
Seeber, S., and Schutte, J. Response to imatinib mesylate of a gastrointestinal stromal
tumor with very low expression of KIT. Cancer Chemother.Pharmacol., 51: 261-265,
2003.
89. Van den Abbeele, A. D., Badawi, R. D., Cliche, J., Janicek, M. J., Tetrault, R.,
Spangler, T., Potter, A., Merriam, P., Silberman, S., Dimitrijevic, S., and Demetri , G.
18F-FDG-PET predicts response to imatinib mesylate (Gleevec) in patients with advanced
gastrointestinal stromal tumors (GIST). Proc Am Soc Clin Oncol 21, 403a. 2002.
90. OBrien, S. G., Guilhot, F., Larson, R. A., Gathmann, I., Baccarani, M.,
Cervantes, F., Cornelissen, J. J., Fischer, T., Hochhaus, A., Hughes, T., Lechner, K.,
Nielsen, J. L., Rousselot, P., Reiffers, J., Saglio, G., Shepherd, J., Simonsson, B.,
Gratwohl, A., Goldman, J. M., Kantarjian, H., Taylor, K., Verhoef, G., Bolton, A. E.,
Capdeville, R., and Druker, B. J. Imatinib compared with interferon and low-dose
cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N.Engl.J Med.,
348: 994-1004, 2003.
91. Druker, B. J., Talpaz, M., Resta, D. J., Peng, B., Buchdunger, E., Ford, J. M.,
Lydon, N. B., Kantarjian, H., Capdeville, R., Ohno-Jones, S., and Sawyers, C. L. Efficacy
and safety of a specific inhibitor of the bcr-abl tyrosine kinase in chronic myeloid
leukemia. N Engl J Med, 344: 1031-1037, 2001.
92. Druker, B. J., Sawyers, C. L., Kantarjian, H., Resta, D. J., Reese, S. F., Ford, J.
M., Capdeville, R., and Talpaz, M. Activity of a specific inhibitor of the BCR-ABL
tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic
leukemia with the Philadelphia chromosome. N Engl.J Med., 344: 1038-1042, 2001.
93. Apperley, J. F., Gardembas, M., Melo, J. V., Russell-Jones, R., Bain, B. J.,
Baxter, E. J., Chase, A., Chessells, J. M., Colombat, M., Dearden, C. E., Dimitrijevic, S.,
Mahon, F. X., Marin, D., Nikolova, Z., Olavarria, E., Silberman, S., Schultheis, B., Cross,
N. C. P., and Goldman, J. M. Response to Imatinib Mesylate in Patients with Chronic
Myeloproliferative Diseases with Rearrangements of the Platelet-Derived Growth Factor
Receptor Beta. The New England Journal of Medicine, 347: 481-487, 2002.
94. Cools, J., DeAngelo, D. J., Gotlib, J., Stover, E. H., Legare, R. D., Cortes, J.,
Kutok, J., Clark, J., Galinsky, I., Griffin, J. D., Cross, N. C., Tefferi, A., Malone, J., Alam,
R., Schrier, S. L., Schmid, J., Rose, M., Vandenberghe, P., Verhoef, G., Boogaerts, M.,
Wlodarska, I., Kantarjian, H., Marynen, P., Coutre, S. E., Stone, R., and Gilliland, D. G.
A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic
target of imatinib in idiopathic hypereosinophilic syndrome. N.Engl.J.Med., 348: 1201-
1214, 2003.
95. McArthur, G, Demetri, G., Heinrich, M., Van Oosterom, A., Fletcher, C.,
Corless, C., Fletcher, J. A., Dimitrijevic, S., and Nikolova, Z. Molecular and clinical
analysis of response to imatinib for locally advanced dermatofibrosarcoma protuberans.
Proceedings of ASCO 2003, 195. 2003.
96. Maki, R. G., Awan, R. A., Dixon, R. H., Jhanwar, S., and Antonescu, C. R.
Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from
dermatofibrosarcoma protuberans. Int.J Cancer, 100: 623-626, 2002.
97. Rubin, B. P., Schuetze, S. M., Eary, J. F., Norwood, T. H., Mirza, S., Conrad, E.
U., and Bruckner, J. D. Molecular targeting of platelet-derived growth factor B by
imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J
Clin.Oncol., 20: 3586-3591, 2002.
150
3. Dpartement de Mdecine
Centre Lon Brard, 28, rue Lannec
69008 Lyon
4. Departement of Pathology
Centre Lon Brard, 28, rue Lannec
69008 Lyon
Correspondance to:
JY Blay
Equipe Cytokine et Cancer, Unit INSERM 590
Centre Lon Brard
28, rue Lannec 69008 Lyon
152
1 INTRODUCTION
3 SYNOVIAL SARCOMA
most series, mostly in the lung, lymph nodes and bones. 5 year survival
rates range between 50 and 80% are reported in most series (12-14).
Matrix proteins
COLIXa3 Collagen IX 25
COLXVIII A1 Collagen XVIII 24
THSB3 Thrombospondin 3 24
159
Adhesion molecules
CDH1 E Cadherin 26
PCAD P Cadherin 25
GYPB Glycophorin B 26
ICAM1/CD54 Ig gene superfamily 26
ITGAM Integrin 26
SELL L selectin 26
Cytosketon
ACTA2 Alpha actin 24
ARPC1B Actin polym. regulator 24
BAT8 Actin associated protein 24
CTNNA Alpha catenin 24
Ectodermal-neural cortex 1 Actin associated protein 23
MSN Moesin 24
Neurofilament heavy polypeptide, - 25
Neuron specific proteins Hs 79404 - 23,25
Spectrin Actin associated protein 26
4 LIPOSARCOMA
6 REFERENCES
1. Storm H.H. Survival of adult patients with cancer of soft tissues or bone in Europe.
Eur J Cancer 1998; 34:2212-2217.
2. Pathology and Genetics. Tumors of Soft Tissue and Bone.Christopher
DM Fletcher, K. Krishnan Unni, Fredrick Mertens eds. Lyon: IARC press
3. Fletcher, Jonathan. Cytogenetic analysis of soft tissue tumors. in Enzinger and
Weisss Soft Tissue Tumors 4th. edition , Sharon Weiss, John R. Goldblum eds. St-
Louis, MO: Mosby, 2001.
4. Leibel S.A., Tranbaugh R.F., Wara W.M. et al.: Soft tissue sarcomas of the
extremities. Survival and patterns of failure with conservative surgery and postoperative
irradiation compared to surgery alone. Cancer 50: 1076-1083, 1982.
5. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-
analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 350: 1647-54
6. Nielsen OS, Blay JY, Judson IR, van Glabekke M, Verweij J, van Oosterom A,.
Metastatic Soft Tissue Sarcoma in adults. Prognosis and treatment options. Am. J. Cancer
2003:2:1-12.
7. Van Glabbeke M., van Oosterom AT., Oosterhuis JW et al. Pronostic factors in
advanced soft tissue sarcoma (STS): analysis of 2185 patients treated with doxorubicin
containing first line regimens- A European Organization for Research and Treatment of
Cancer Soft Tissue and Bone Sarcoma Group study. J. Clin. Oncol. 1999: 17:150-157
8. Blay JY, van Glabbeke M, Verweij J, et al. Advanced soft-tissue sarcoma: a disease
that is potentially curable for a subset of patients treated with chemotherapy. Eur J
Cancer. 2003; 39: 64-9.
9. Van Oosterom A, Judson I, Verwej J, et al. Safety and efficacy of Imatimib (STI-571)
in metastatic gastrointestinal stromal tumors: a phase I study. Lancet 2001, 358: 1421-3
10. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib
mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347: 472-80.
11. Maki RG, Awan RA, Dixon RH, Jhanwar S, Antonescu CR. Differential sensitivity to
imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma
protuberans. Int J Cancer 2002; 100: 623-6.
12. Weiss SW, Goldblum JR. Malignant soft tissue tumors of uncertain type. in
Enzinger and Weisss Soft Tissue Tumors 4th. edition, Sharon Weiss, John R. Goldblum
eds. St-Louis, MO: Mosby, 2001.
13. Trassard M, Le Doussal V, Hacene K, et al. Prognostic factors in localized primary
synovial sarcoma: a multicenter study of 128 adult patients. J Clin Oncol 2001; 19:525-
34.
14. Okcu MF, Munsell M, Treuner J, et al. Synovial sarcoma of childhood and
adolescence: a multicenter, multivariate analysis of outcome. J Clin Oncol. 2003; 21:
1602-11.
15. Ladanyi M. Fusions of the SYT and SSX genes in synovial sarcoma. Oncogene. 2001;
20: 5755-62.
16. Sandberg AA, Bridge JA.Updates on the cytogenetics and molecular genetics of bone
and soft tissue tumors. Synovial sarcoma. Cancer Genet Cytogenet 2002;133:1-23
17. Guillou L, Coindre J, Gallagher G, et al. Detection of the synovial sarcoma
translocation t(X;18) (SYT;SSX) in paraffin-embedded tissues using reverse
transcriptase-polymerase chain reaction: a reliable and powerful diagnostic tool for
pathologists. A molecular analysis of 221 mesenchymal tumors fixed in different
fixatives. Hum Pathol. 2001; 32:105-12.
18. Kawai A, Woodruff J, Healey JH, Brennan MF, Antonescu CR, Ladanyi M. SYT-
SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N
Engl J Med 1998 ; 338:153-60
19. Nilsson G, Skytting B, Xie Y, et al. The SYT-SSX1 variant of synovial sarcoma is
associated with a high rate of tumor cell proliferation and poor clinical outcome. Cancer
Res. 1999; 59:3180-4.
20. Mezzelani A, Mariani L, Tamborini E, et al. SYT-SSX fusion genes and prognosis in
synovial sarcoma. Br J Cancer 2001; 85: 1535-9
21. Ladanyi M, Antonescu CR, Leung DH, et al. Impact of SYT-SSX fusion type on the
clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243
patients. Cancer Res. 2002 Jan 1;62(1):135-40.
167
22. De Alava E., Gerald W. Molecular diagnosis of the Ewing family of tumors. J Clin
Oncol 2000;18:204-213.
23. Nielsen TO, West RB, Linn SC, et al. Molecular characterisation of soft tissue
tumours: a gene expression study. Lancet 002;359: 1301-7
24. Allander SV, Illei PB, Chen Y, et al. Expression profiling of synovial sarcoma by
cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial
differentiation. Am J Pathol. 2002;161:1587-95.
25. Nagayama S, Katagiri T, Tsunoda T, et al. Genome-wide analysis of gene expression
in synovial sarcomas using a cDNA microarray.
Cancer Res. 2002; 62: 5859-66.
26. Lee YF, John M, Edwards S, et al. Molecular classification of synovial sarcomas,
leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. Br J
Cancer. 2003; 88: 510-5.
27. Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF
receptor. Cell 2002; 110: 669-72
28. Olayioye MA, Neve RM, Lane HA, Hynes NE The ErbB signaling network: receptor
heterodimerization in development and cancer. EMBO J 2000; 19:3159-67.
29. Judson I, Verweij J, Van Oosterom A et al. Imatimib (Imatinib) an active agent for
gastrointestinal stromal tumors but not for other soft tissue sarcoma subtypes not
characterized for KIT and PDGR-R expression, results of EORTC phase II studies Proc
Am Soc Clin Onc 2002, 21 (abstract 1609).
30. Culy CR, Faulds D. Gefitinib. Drugs 2002; 62:2237-50
31. Bunn PA Jr, Franklin W. Epidermal growth factor receptor expression, signal
pathway, and inhibitors in non-small cell lung cancer. Semin Oncol 2002; 29(5 Suppl
14):38-44
32. Herbst RS, Kies MS. ZD1839 (Iressa) in non-small cell lung cancer. Oncologist
2002;7 Suppl 4:9-15
33. Weiss SW, Goldblum JR. Liposarcoma in Enzinger and Weisss Soft Tissue Tumors
4th. edition, Sharon Weiss, John R. Goldblum eds. St-Louis, MO: Mosby, 2001.
34. Knight JC, Renwick PJ, Cin PD, Van den Berghe H, Fletcher CD.Translocation
t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and
cytogenetic analysis. Cancer Res 1995; 55:24-7
35. Kuroda M, Ishida T, Takanashi M, et al. Oncogenic transformation and inhibition of
adipocytic conversion of preadipocytes by TLS/FUS-CHOP type II chimeric protein. Am
J Pathol. 1997; 151: 735-44
36. Tontonoz P, Singer S, Forman BM, et al. Terminal differentiation of human
liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor
gamma and the retinoid X receptor. Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):237-41.
37. Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I. & Spiegelman, B. M. mPPAR
gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994; 8, 1224-
1234
38. Van Glabbeke M, Verweij J, Judson I, Nielsen OS; EORTC Soft Tissue and Bone
Sarcoma Group. Progression-free rate as the principal end-point for phase II trials in soft-
tissue sarcomas. Eur J Cancer. 2002; 38:543-9.
39. Demetri GD, Fletcher CD, Mueller E, et al. Induction of solid tumor differentiation
by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients
with liposarcoma. Proc Natl Acad Sci USA. 1999; 96:3951-6
40. Demetri GD, Speigelman B, Fletcher CD, et al. Differenciation of liposarcomas in
patients treated with the PPAR-g ligand troglitazone: documentation of biological activity
in myxoid round cell and pleomorphic subtypes. Proc Am Soc Clin Oncol. 1999; 18: 535
a (abstract 2064).
41. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in
gastrointestinal stromal tumors. Science. 2003; 299:708-10.
This page intentionally left blank
Chapter 10
Correspondence to :
K. Hoekman, MD, PhD
Department of Medical Oncology,
Vrije Universiteit Medical Centre,
De Boelelaan 1117, 1007 MB Amsterdam, the Netherlands.
Telephone : 020 4444319
Fax : 020 4444355
E-mail : k.hoekman@vumc.nl
170
1 INTRODUCTION
2 ANGIOGENESIS
improve the design of animal studies and to look for theoretically optimal
combinations of biologicals and chemotherapeutic agents for the therapy of
patients with STS. In some STS patients the presence of large tumors offers
the opportunity to get tumor tissue samples before and after therapy.
Investigation of these tissues with microarrays and proteomic techniques will
deliver a better understanding of STS biology and the effects of therapeutic
interventions on these tumors (Borden et al., 2003); all of which will
ultimately lead to better therapies for patients with soft tissue sarcomas.
5 REFERENCES
1. Angelov L, Salhia B, Roncari L, et al: Inhibition of angiogenesis by blocking activation
of the vascular endothelial growth factor receptor 2 leads to decreased growth of
neurogenic sarcomas. Cancer Res 1999, 59:5536-41
2. Arasleh K, Hannah A. The role of vascular endothelial growth factor (VEGF) in AIDS-
related Kaposis sarcoma. Oncologist 2000, 5(suppl 1):28-31
3. Arbiser JL, Panigrathy D, Klauber N, et al: The antiangiogenic agents TNP-470 and 2-
methoxyestradiol inhibit the growth of angiosarcoma in mice J. Am Acad Dermatol
1999; 40:925-9
4. Ascher G, Sgadari C, Bugarini R, et al. Serum concentrations of fibroblast growth factor
2 are increased in HIV type 1-infected patients and inversely correlated to survival
probability. AIDS Res Hum Retrovirusses 2001; 17:1035-9
5. Boehm T, Folkman J, Browder T, OReilly MS. Antiangiogenic therapy of experimental
cancer does not induce acquired drug resistence. Nature 1997; 390:404-7
6. Borden EC, Baker LH, Bell RS, et al. Soft tissue sarcomas of adults: state of the
translational science. Clin Cancer Res 2003; 9:1941-56
7. Brizel DM, Scully SP, Harrelson J, et al. Tumor oxygenation predicts for the likelihood
of distant metastases in human soft tissue sarcoma. Cancer Res 1996; 56:941-3
8. Broxterman HJ, Lankelma J, Hoekman K. Resistance to cytotoxic and anti-angiogenic
anticancer agents: similarities and differences. Drug Resistance Updates 2003; 6:111-27
9. Cao Y, OReilly MS, Marshall B, Flynn E, Ji R-W, and Folkman J. Expression of
angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and
produces long-term dormancy of metastases. J Clin Investigation 1998; 101:1055-63
10. Chao C, Al-Saleem T, Brooks JJ, Rogatko A, Kraybill WG, Eisenberg B. Vascular
endothelial growth factor and soft tissue sarcomas: tumor expression correlates with
grade. Ann Surg Oncol 2001; 8:260-67
11. Choong PF, Ferno M, Akerman M, et al. Urokinase-plasminogen-activator levels and
prognosis in 69 soft-tissue sarcomas. Int J Cancer 1996; 69:268-72
12. Cianfrocca M, Cooley TP, Lee JY, et al. Matrix metalloprotease inhibitor COL-3 in the
treatment of AIDS-related Kaposis sarcoma: a phase I AIDS malignancy consortium
study. J Clin Oncol 2002; 20:153-9
13. Comandone A, Boglione E, Berardengo A, et al. Microvessel density (MVD) as a marker
of neoangiogenesis: prognostic significance in correlation with grading and stage in adult
soft tissue sarcomas (STS) of the extremities. A perspective study. ASCO 2003; abstract
3303
14. Dezube BJ, Von Roenn JH, Holden-Wiltse J, et al. Fumagillin analog in the treatment of
Kaposis sarcoma: a phase AIDS clinical trial group study, AIDS clinical trial group no
215 team. J Clin Oncol 1998; 16:1444-9
15. Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG. Heterogeneity
of angiogenesis and blood vessel maturation in human tumors: implications for
antiangiogenic tumor therapies. Cancer Research 2000; 60:1388-93
16. Feldman AL. Serum endostatin levels are elevated in patients with soft tissue sarcoma.
Cancer 2001; 91:1525-9
17. Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic
angiogenesis: therapeutic implications. Semin Oncol 2002; 29:10-4
178
18. Folkman J. Role of angiogenesis in tumor growth and metastases. Semin Oncol 2002;
29:15-8
19. Fujimoto M, Kiyosawa T, Murata S, et al. Vascular endothelial growth factor in
angiosarcoma. Anticancer Res 1998; 18:3725-30
20. Gerber HP, Kowalski J, Sherman D, Eberhard DA, Ferrara N. Complete inhibition of
rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both
tumor and host vascular endothelial growth factor. Cancer Res 2000; 60:6553-8
21. Graeven U, Andre N, Achilles E, et al: Serum levels of vascular endothelial growth factor
and basic fibroblast growth factor in patients with soft-tissue sarcoma, J Cancer Res Clin
Oncol 1999; 125:577-81
22. ten Hagen TL, van der Veen AH, Nooijen PT, van Tiel ST, Seynagen AL, Eggermont
AM. Low-dose tumor necrosis factor-alpha augments antitumor activity of stealth
liposomal doxorubicin (DOXIL) in soft tissue sarcoma-bearing rats. Int J Cancer 2000;
87:829-37
23. Hamano Y, Zeisberg M, Sugimoto H, et al. Pysiological levels of tumstatin, a fragment
of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress
angiogenesis via alphaVbeta3 integrin. Cancer Cell 2003; 3:589-601
24. Hansma AHG, van Hensbergen Y, Kuenen BC, et al. A patient with a VEGF and
endostatin producing gastrointestinal autonomic nerve tumor (GANT). Submitted.
25. Hashimoto M, Ohsawa M, Ohnishi A, et al. Expression of vascular endothelial growth
factor and its receptor mRNA in angiosarcoma. Lab Invest 1995; 73:859-63
26. Hata K, Hata T, and Miyazaki K. Expression of thymidine phosphorylase in uterine
sarcoma and uterine leiomyoma: association with microvessel density and Doppler blood
flow analysis. Ultrasound Obstet Gynecol 1997; 10:54-8
27. Heits F, Katschinski DM, Wiedeman GJ, Weiss C, Jelkman W. Serum vascular
endothelial growth factor (VEGF), a prognostic factor in sarcoma and carcinoma patients.
Int J Oncol 1997; 10:333-7
28. van Hensbergen Y, Broxterman HJ, Elderkamp YW, et al. A doxorubicin-CNGRC-
peptide conjugate with prodrug properties. Biochem Pharmacol 2002; 63:897-08
29. van Hensbergen Y, Broxterman HJ, Hanemaaijer R, Jorna AS, Verheul HM, Pinedo HM,
Hoekman K. Soluble aminopeptidase N/CD13 in malignant and nonmalignant effusions
and intratumoral fluid. Clin Cancer Res 2002; 8:3747-54
30. Heymach JV. Angiogenesis and antiangiogenesis approaches to sarcomas. Current
Opinion in Oncol 2001; 13:261-9
31. Holmgren L, Jackson G, Arbiser J. P53 induces angiogenesis-restricted dormancy in a
mouse fibrosarcoma. Oncogene 1998; 17:819-24
32. Hornick JL, Fletcher CDM. Immunohistochemical staining for KIT (CD117) in soft
tissue sarcomas is very limited in distribution. Am J Clin Pathol 117:188-93
33. Hu M, Nicolson GL, Trent JC, et al. Characterization of 11 human sarcoma cell strains:
evaluation of cytogenetics, tumorogenicity, metastasis, and production of angiogenic
factors. Cancer 2000; 95:1569-76
34. Huang J, Frischer JS, Serur A, et al. Regression of established tumors and metastases by
potent vascular endothelial growth factor blockade. PNAS 2003; 100:7785-90
35. Indraccolo S, Morini M, Gola E, et al. Effects of angiostatin gene transfer on functional
properties of in vivo growth of Kaposis sarcoma cells. Cancer Res 2001; 61:5441-6
36. Jain RK. Understanding barriers to drug delivery: high resolution in vivo imaging is key.
Clin Cancer Res 1999; 5:1605-6
37. Kandel J, Bossy-Wetzel E, Radvanyi F, Klagsbrun M, Folkman J, and Hanahan D.
Neovascularization is associated with a switch to the export of bFGF in the multislep
development of fibrosarcoma. Cell 1991; 66:1095-1104
38. Kawauchi S, Fukuda T, Tsuneyoshi M. Angiogenesis does not correlate with prognosis
or expression of vascular endothelial growth factor in synovial sarcomas. Oncol Rep
1999; 6:959-64
39. Kuenen BC, Taberno J, Baselga J, et al. Efficacy and toxicity of the angiogenesis
inhibitor SU5416 as a single agent in patients with advanced renal cell carcinoma,
melanoma, and soft tissue sarcoma. Clin Cancer Res 2003; 9:1648-55
40. Lejeune FJ, Pujol N, Lienard D, et al. Limb salvage by neoadjuvant isolated perfusion
with TNFa and melphalan for non-resectable soft tissue sarcoma of the extremeties. Eur J
Surg Oncol 2000; 26:669-78
179
ET-743 (Trabectedin), 7, 10
Ewings sarcoma, 105106, 152 Idiosyncratic toxicity, 74
Exon 9 mutations, 133 Ifosfamide, 2, 11, 48, 152
Exon 11 mutations, 133 dose-response curve of, 3
External beam radiotherapy (EBRT), 2122, 36 Imatinib
Extracellular domain clinical efficacy of, 121
mutations in, 131132 dose-escalation of, 137
Extracompartmental sarcoma, 19 mesylate, 119f
Extremity sarcomas metabolism, 120
chemoradiation for, 4849 oncogene kinase targeting with, 136137
multimodal therapy for, 4849 pharmocokinetics of, 120
preoperative radiation therapy for, 4647 phase II studies of, 121
response, 138141
False-positive trials, 11 Immunohistochemistry, 93
Farnesyl transferase inhibitors (FTI), 109 for classification, 9395
ras protein targeting by, 9 for drug targeting, 95
Fibro-histiocytic differentiation, 94 limitations of, 9596
Fibrosarcoma, 107108 for monomorphic spindle cell tumors, 94t
Fluorescence in situ hybridization (FISH), 101 for undifferentiated round cell tumors, 95t
Fusion genes Induction therapy
protein products of, 155156 postoperative chemotherapy, 4748
preoperative radiation therapy, 4647
Gastrointestinal stromal tumors (GIST), 5, 91, rationale for, 4445
95, 108 for sarcomas, 45
diagnosis of, 138 for solid tumors, 4445
gastric, 136 Integral doses, 35
genotyping of, 140 Intensity modulated radiotherapy (IMRT), 18,
imatinib treatment of, 121 30
KIT-driven, 120123 dose constraints for, 28t
KIT mutations in, 130, 132136 elements of, 2425
molecular classifications of, 141t, 142 five field, 31f
neo-adjuvant treatment of, 122 inverse planning, 2629
other sarcomas and, 142143 mechanisms of, 25
PDGFRA and, 135 Interferon-gamma, 73
risk assessment for, 92t Isodose lines
variants of, 136 distribution of, 27f
Gene expression Isolated limb perfusion, 6667
histological subtypes of sarcomas and, chemotherapy and, 67
156157 with cytostatic drugs, 67t
in synovial sarcoma, 155 duration of, 73
Geometric uncertainty in histologies, 7071
margins for, 2021 TNF-based, 6769
reduction of, 34
Gross tumor volume (GTV), 19, 24f Juxtamembrane domain
mutations of, 130131
Hematological disorders
kinases in, 143t Kaplan-Meier estimates, 11
HER1 protein, 157 of progression-free rates, 12f
Histamine, 74 Kaposi sarcoma, 173, 176
Histologies Karyorrhexis, 92
TNF-based ILP in, 7071 Kinase 1 domain
Histopathological grading, 8792 mutations in, 132
FNCLCC system for, 8890 Kinase mutations
limitations of, 9092 imatinib response and, 138141
NCI system for, 8890 use of, 138
systems for, 8890 Kinases
Histopathological typing, 6267 in hematological/mesenchymal disorders,
HPLC 143t
denaturing, 131 inhibitors, 143
Hyperthemia KIT
mild, 73 activated, 108
Hypoxia, 73, 171 activation loop of, 132
Index 183