908

Current Controversies in High-Dose-Rate versus Low-Dose-Rate Brachytherapy for Cervical Cancer

Alexandra J. Stewart, BM, MRCP Akila N. Viswanathan, MD, MPH
Department of Radiation Oncology, Brigham and Womens Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts. The use of brachytherapy in the treatment of cervical cancer has increased worldwide since its initial introduction over 100 years ago. However, certain aspects of the use of high-dose-rate (HDR) versus low-dose-rate (LDR) brachytherapy continue to be controversial, particularly the role of HDR in FIGO Stage III cervical cancer and the use of HDR with concurrent chemotherapy. This study represents a systematic literature review of prospective and retrospective series of patients with cervical carcinoma treated with external-beam radiation (EBRT) followed by either HDR or LDR radiation. The local control rates, survival rates, and treatment-related complications in patients with Stage III cervical cancer treated with HDR or LDR and those treated with concomitant chemotherapy are examined. Patients with Stage III cervical cancer treated with EBRT and brachytherapy have a local control rate of >50% in most series. Randomized prospective and retrospective studies show overall statistically equivalent local control, overall survival, and complication rates between HDR and LDR. However, LDR may be preferable for large, bulky tumors at the time of brachytherapy. Retrospective studies of HDR and concurrent chemotherapy are limited but have demonstrated toxicity rates similar to those with LDR. Selected patients with Stage III cervical carcinoma who have an adequate response to EBRT and concomitant chemotherapy may be treated with HDR brachytherapy. The existing literature shows no significant increase in complications in patients treated with HDR and concurrent chemotherapy; however, sufficient tumor shrinkage prior to HDR and careful monitoring of the dose to the normal tissues are imperative. Cancer 2006;107:90815. 2006 American Cancer Society.

KEYWORDS: Stage III cervical cancer, high-dose-rate (HDR) brachytherapy, lowdose-rate (LDR) brachytherapy, concomitant chemotherapy.

Dr. Stewarts current address: Royal Marsden Hospital, Surrey, England, UK. Address for reprints: Akila N. Viswanathan, MD, MPH, Department of Radiation Oncology, Brigham and Womens Hospital, Dana-Farber Cancer Institute, 75 Francis Street L2, Boston, MA 02115; E-mail: aviswanathan@partners.org Received December 19, 2005; revision received March 31, 2006; accepted April 5, 2006.

ocally advanced carcinoma of the cervix must be treated with a combination of external-beam radiotherapy (EBRT) and intracavitary radiotherapy. Studies show that the use of brachytherapy increases local control and survival in FIGO Stage III cervical cancer.1,2 Brachytherapy is a form of conformal dose escalation and decreases the risk of residual cancer and pelvic relapse.3,4 Since 1999, concurrent chemotherapy with radiation has been the standard of care in the treatment of cervical cancer.5 Intracavitary radiation in the form of low-dose-rate (LDR) brachytherapy has been in use for the treatment of cervical cancer for nearly a century, although the method has been greatly refined. High-dose-rate (HDR) brachytherapy for carcinoma of the cervix has been in use for over 30 years. LDR is defined as a dose of 0.42 Gray (Gy)/h, and HDR is defined as a dose of >12 Gy/h.6 HDR is widely used throughout Asia and Europe, and its use is steadily increasing in North America.7 The Patterns of Care Studies show

2006 American Cancer Society

DOI 10.1002/cncr.22054 Published online 27 July 2006 in Wiley InterScience (www.interscience.wiley.com).

Controversies in Brachytherapy for Cervical CA/Stewart and Viswanathan

909

that, in the United States, the use of HDR for treatment of cervical cancer increased from 9% during 19921994 to 16% during 19961999, although this increase did not reach significance (P .3).8 LDR uses fixed source positions and strengths to calculate the dose at the prescription point. Doses can be varied slightly by using sources of different activities. Tapering of the dose at the tandem tip results in a lower dose to the small bowel and sigmoid and decreases grade 35 late complications without affecting local control.9 Source dwell times can be optimized with HDR to customize the dose to the patients anatomy and tumor volume, thereby decreasing doses to normal tissues of the rectum, bladder, and vaginal mucosa.10 However, standard treatment parameters as derived from LDR must be considered. Specifically, the dose to the surface of the ovoids should be approximately twice the dose to point A, and the standard loading pattern (15-10-10) of LDR should be converted to HDR, with only slight modifications to consider normal tissue tolerance. Most commonly, a high dose to the sigmoid requires decreasing the top dwell times. LDR tolerance limits for the rectum and sigmoid (70 Gy) and vagina (130 Gy) must be maintained. HDR optimization to maintain a rectal biologically equivalent dose (BED) below tolerance is recommended to decrease late complications.19 HDR has several practical advantages over LDR and is therefore increasing in popularity, particularly in the developing world. These will be discussed in greater detail below. However, these benefits must be weighed against any potential risk of decreased tumor control or increased late complications (Table 1).

TABLE 1 The Advantages and Disadvantages of LDR and HDR Brachytherapy for Cervical Cancer
LDR ADVANTAGES @100 years of data Standardized doses Standardized treatment plan Standardized treatment time Maximum two insertions HDR

Outpatient treatment Short administration time Standard source strength Source easily available IV conscious sedation feasible Reassess tumor size with multiple fractions Dose optimization of normal tissues Minimal staff exposure Applicator stabilized by board during treatment High risk of errors:  Intense quality assurance  Intense maintenance  Intense physician/physicist time >Two fractions required Treatment required on day of insertion Expensive Caution with large tumors Caution with normal tissue dose

DISADVANTAGES Inpatient treatment Radiation exposure to staff Limited by source strength Limited sources available Spinal or general anesthesia Prolonged bedrest:  Need for anticoagulation  Constipating medication  Need for inpatient pain control

prohibits this repair during the actual irradiation. However, if an interval of more than 24 hours is maintained, normal tissues can undergo full repair.11 Therefore, LDR may allow recovery of more normal tissues during treatment, but HDR may offer the advantage of increased cytotoxicity to the tumor.

Radiobiologic Considerations
In carcinoma of the cervix, the response to radiotherapy is clearly dose-dependent; as the dose increases, so too does the probability of tumor control. However, the risk of damage and late complications in normal tissues also increases with the dose. This applies to both the overall dose from LDR and the dose per fraction for HDR treatment.

Repair The lower the dose rate of radiation a cell is exposed to, the greater the likelihood of repair. Late-reacting normal tissues seem more capable of repair than tumor; at a given therapeutic dose, the tumor is preferentially killed over normal tissue. The time course of LDR treatment (several days) allows for sublethal damage repair. The short treatment time of HDR

Repopulation Various studies have shown improved tumor control and increased patient survival in carcinoma of the cervix when radiotherapy is given in the shortest overall time.12,13 Shorter treatment times decrease the tumor cell repopulation time and shorten the time for accelerated repopulation. The continuous administration of LDR prevents repopulation during treatment. HDR at the end of a radiotherapy regimen may increase overall treatment time, decrease tumor control and disease-free survival, although not morbidity.14 The fractionated nature of HDR allows for the integration of brachytherapy within the EBRT schedule, permitting shorter overall treatment times. The American Brachytherapy Society (ABS) recommends starting HDR for small tumors after 2 weeks of pelvic EBRT at one fraction per week, continuing EBRT on the other 4 days of the week, or after the fourth week for patients with bulkier tumors, with all treatment completed within 56 days.15

910

CANCER

September 1, 2006 / Volume 107 / Number 5

TABLE 2 Randomized Trial Results of Toxicity, Overall and Disease-Free Survival Comparing HDR and LDR
Overall survival (%)* FIGO stage Patel et al.38 Stage I <3 cm Stage II <3 cm Stage I >3 cm Stage II >3 cm Stage III Stage I Stage II Stage III Stage II Stage III Stage IIB Stage IIIB HDR 100 82 87 74 71 66 61 47 89 69 65 71 LDR 100 82 88 78 76 89{ 73 45 100 70 74 63 Disease-free survival (%)* HDR 85 71 75 63 43 85 73 53 69 51 65 74 LDR 81 66 70 60 50 93 78 47 87 60 76 59 Toxicity (%)y HDR 0.4 LDR 2.4

Teshima et al.37

Hareyama et al.40 Lertsanguansinchai et al.39

10 9

13 4

* 5-year results unless otherwise stated. y Combined bowel and bladder grades 35 late complications, reported for all stages. { Statistically significant difference. 3-year results.

Reoxygenation The effect of hypoxia on tumor control in carcinoma of the cervix has been documented, with decreased survival in patients with a low initial hemoglobin level.1618 Because of the duration of administration of LDR, acute hypoxia may correct within the tumor during treatment. With HDR treatment, the tumor shrinks between insertions, allowing reoxygenation of areas of chronic hypoxia. The oxygen enhancement ratio is lower for LDR than for HDR.19 Reassortment During the overall treatment time of LDR, tumor cells may pass from the relatively radioresistant phases of late S and early G2 to the more radiosensitive phases of G2 and M. This might provide a theoretical advantage over HDR.

and rectal toxicity.22 With HDR the probability of late damage increases as the dose increases and the number of fractions decreases.20,21 This probability is also related to the percentage of dose received by normal tissue. If the normal tissue received 100% of the dose, 30 fractions would be needed for equivalent late complications with LDR.

Brachytherapy for Stage III Cervical Cancer

The use of HDR as an alternative to LDR for all stages of cervical carcinoma has been reported in a number of retrospective series2336 and four randomized prospective trials.3740 However, the data comparing HDR to LDR for cancer of the cervix are fraught with bias and may be difficult to compare because of a lack of detailed information on the radiation administered and a wide range of externalbeam and intracavitary dose and fractionation schedules. The prospective trials do not represent blinded clinical trials, and the retrospective series suffer from the potential bias of historic controls, stage migration over time, and improvement in radiotherapy techniques and dosimetry with modern imaging. The randomized trials of LDR versus HDR have generally comparable results for all stages of cervical cancer. No significant difference in disease-free survival is detected for any stage of cervical cancer; however, Teshima et al.37 demonstrated an increased overall survival for patients with Stage I disease treated with LDR (Table 2). However, the randomization techniques may be questioned. Patel et al.38 did

Dose and Fractionation

The dose and fractionation of HDR are closely correlated with local control and late complications.20,21 Lack of standardization of the conversion used complicates dose comparison between studies. The 1999 ABS survey on brachytherapy practice in the United States showed that physicians administering HDR gave an average dose of 4850 Gy to the pelvis in EBRT with an additional 30 Gy in five fractions of HDR brachytherapy.7 Sixty-seven percent of physician respondents used a midline shield after an average of 40 Gy. The use of a midline shield is controversial, with reports of both increased and decreased bladder

Controversies in Brachytherapy for Cervical CA/Stewart and Viswanathan TABLE 3 Stage III Overall Survival, Pelvic Control and Toxicity in Retrospective Series
Low-dose rate Overall survival{ (%) 38 46.5 45 46} 50.2 35.7 37.3} 47.3 42.6 58} 46 Pelvic control, (%) 61 72 58 4.8 3.7 16.8 0 53 75} 63 10.4 9.1 10.0 High-dose rate Overall survival (%) 54 52.2 33 36} 51.1 (6) 42.9 (4) 43.8 53.8} 31.6 47.2 33} 58 47.8 42 25 Pelvic control, (%) 64 83 50 3.5 2.5 25.6 (6) 11.0 (4) 1.4 9.0 2.4 22.7 2.5 7.0

911

No. Akine et al.30y{ Arai et al.31y{ Falkenberg et al.36y|| Ferrigno et al.32{ Hsu et al.29{# Kim et al.24** Kucera et al.26 Okkan et al.28y{ Orton et al.27{ Petereit et al.23y Sarkaria et al.25 Lorvidhaya et al.35y{ Sakata et al.33{ Souhami et al.41y Wong et al.34y{ 212 143 23 69 73 8 212 21 1464 50 57

Toxicity* (%)

No. 37 508 6 56 30 16 78 98 2721 50 12 675 48 77 51

Toxicity* (%)

45 44} 50 68.8 63 63.2

2.8

* Combined grades 35 late complications, reported for all stages. y FIGO Stage IIIB results. { 5-year results. 3-year results. || Cause-specific survival reported. } Statistically significant differences. # 6 and 4 fraction results. ** Adenocarcinoma only.

not state their randomization method but stratified 246 LDR patients and 236 HDR patients according to stage. Teshima et al.37 stated that they fully randomized before 1979, after which they selectively randomized, with older, more infirm patients being placed in the HDR arm. This gave 171 LDR patients and 258 HDR patients. Hareyama et al.40 randomized 71 patients to LDR and 61 patients to HDR by month of birth. Lertsanguansinchai et al.39 stratified by age and stage and then randomized 109 LDR patients and 112 HDR patients before starting EBRT. The role of HDR in Stage III cancer of the cervix is controversial, with two retrospective series23,32 showing a significant survival advantage for LDR, and one showing an advantage for HDR26 (Table 3). Although other retrospective series do not demonstrate a significant survival difference, none have a sufficient number of patients and resulting power to detect a difference between HDR and LDR if such a difference exists. Ferrigno et al.32 reported all Stage III results together and stated that the BED for the HDR patients was below that for the LDR patients, which may account for the survival advantage with LDR. In contrast, Kucera et al.26 showed a survival

advantage with HDR. The authors stated that the improvement in EBRT practice over the time of analysis must be considered in addition to a higher BED for the HDR patients. Petereit et al.23 showed equivalent 3-year survival and pelvic control rates with HDR or LDR brachytherapy for all stages of cervical cancer except Stage IIIB. Survival and local control rates were 58% and 75% for LDR versus 33% and 44% for HDR, respectively. Possible explanations for the disparity in survival include insufficient tumor shrinkage, higher than expected local control rates in the LDR patients, and significantly higher rates of hydronephrosis in the HDR group. The timing of HDR may have contributed to these results.23 HDR commenced at week one of pelvic EBRT, when tumor shrinkage would not yet have been adequate. This would give a volume advantage to LDR in these advanced cases with bulky tumors. Rates of pelvic control improved with the first brachytherapy insertion after most of the EBRT had been delivered, allowing for better dose distributions around a smaller tumor volume. With HDR, the outer margins may be missed if the implant is optimized to point A without 3D imaging and the tumor

912

CANCER

September 1, 2006 / Volume 107 / Number 5

TABLE 4 Fractionation and Toxicity of HDR and Concurrent Chemotherapy

HDR Dose (Gy) Tseng et al.59y Pearcey et al.52y{ Sood et al.57 Saibishkumar et al.58 Sood et al.56 Ozsaran et al.55|| Souhami et al.53|| Strauss et al.54|| 4.3 8 9 9 9 8.59 10 7 No. fractions 6 3 2 2 2 12 3 5 Toxicity (%)* No chemo 6.5 (GI) 3.2 (GU) 9 (GI) 7 (GU) 5 (GI) 1.1 (GI) 1.0 (GI) 10 0 Chemo 10 (GI) 3.3(GU) 5 (GI) 10 (GU) 5 (GI) 1.8 (GI) 0 (GU) 6 0 28 (GI) 6 (GU) 3.7 (GI) 3.7 (GU) Follow-up (months) 47 82 36 39 28 20 27 19

* Grades 35 late complications. y Prospective randomized trial. { Retrospective comparison of patients treated with and without chemotherapy. Retrospective review, all patients received chemotherapy. || Includes HDR, MDR, and LDR.

has not regressed sufficiently by the time of the implant. Use of CT or MR imaging with the brachytherapy applicator in place and optimization to the tumor volume as well as to the standard prescription points may obviate this discrepancy between HDR and LDR in large-volume cancers.4244 A metaanalysis of the primary data from 56 centers27 showed an overall survival advantage at 5 years for HDR over LDR for groups with advanced disease (47.2% vs. 42.6% for Stage III, P .05). However, patients with larger tumors have a significantly shorter disease-free survival than those with smaller tumors, independent of FIGO stage, when HDR brachytherapy is used.45 In Stage IIIB patients, the rate of local failure increases four-fold if HDR brachytherapy is administered before the 25th day of treatment.41 Therefore, individualized treatment is crucial; the amount of disease present at the time of brachytherapy is paramount in choosing between HDR and LDR brachytherapy, with consideration of the location and tolerance of normal tissues.

ment. In these situations, the use of interstitial needles may assist with the delivery of radiation dose. Interstitial implantation has conventionally been used with a template and LDR radiation. Local control rates for Stage III range from 44% to 88%.4648 With a median follow-up of 51 months, Syed et al. reported a 10% rate of Grade 3 or 4 late gastrointestinal and genitourinary complications for all stages of cervical cancer. Stage III patients had a 5-year diseasefree survival of 49%; Stage IIIB patients had a locoregional control rate of 61%.49 For interstitial implantation with HDR, Demanes et al. treated 62 patients with six fractions of HDR over two insertions; with a mean follow-up of 40 months, the 5-year disease-free survival rate for Stage III patients was 39%, but the regional pelvic control rate was 79%.50 A report of a combined tandem and ring with interstitial applicator using HDR on a fractionated basis was published, though longterm survival and toxicity data are not yet available.51

Chemotherapy Interstitial Implantation

Low survival rates for patients with Stage III cervical cancer may be due to inadequate radiation delivery. Conventional intracavitary brachytherapy may not be adequate to deliver a sufficient dose of radiation to an extensive and bulky tumor, such as those with lower vaginal involvement or pelvic sidewall involveSeveral randomized trials set the current standard of care for cervical cancer as radiotherapy with concomitant chemotherapy5; one of these studies allowed the use of HDR, MDR (medium-dose-rate), or LDR.52 A total of eight studies have used chemotherapy with HDR and reported toxicity. Three were single-arm retrospective analyses in which all patients received

Controversies in Brachytherapy for Cervical CA/Stewart and Viswanathan

913

chemo-radiation5355; 3 retrospectively compared patients treated with and without chemotherapy5658; 2 present prospectively collected data.52,59 None of these studies shows a significant difference in Grades 3 and 4 gastrointestinal and genitourinary late complications (Table 4). The single-arm series all administered weekly cisplatin. The comparative retrospective series administered cisplatin on days to 5 in weeks 1 and 456,57 or weekly cisplatin.58 One prospective trial administered weekly cisplatin,52 the other cisplatin, vincristine and bleomycin every 3 weeks.59 All trials administered daily external-beam radiation, with a range of doses from 4450.4 Gy. The HDR fractionation regimens are detailed in Table 4. Souhami et al.53 reported a high rate of rectal toxicity; however, the fraction size was larger than that used in the modern era. The randomized NCIC trial of weekly cisplatin chemotherapy with radiation versus radiation alone allowed HDR (15%), MDR (8%), or LDR (77%). Long-term toxicities were not significantly different between the 2 arms, although the type of brachytherapy in relation to the use of chemotherapy was not presented.52 A metaanalysis of concurrent cisplatin-based chemotherapy and radiotherapy with both HDR and LDR showed rates of grade 34 toxicity of 0%15% for gastrointestinal toxicity and 1%8% for genitourinary toxicity.60 The Radiation Therapy Oncology Group (RTOG) trial 90-01 required insertion of LDR brachytherapy; with a median follow-up of 6.6 years, the incidence of Grade 3 or higher late complications was 14% in both arms. No review with HDR and chemotherapy has such long follow-up. However, the RTOG 90-01 initially published, and their results with a median follow-up of 43 months, which had a 12% versus 11% rate of grade 34 late toxicity for those treated with and without chemotherapy. These are very similar to the follow-up time and toxicity rates presented in the HDR retrospective reviews (Table 4). Current clinical trials allow the use of HDR brachytherapy and require that chemotherapy not be administered on the same day as brachytherapy treatment.

The anterior rectal wall adjacent to the posterior often receives the highest dose of radiation. With 3D imaging, the recommended dose limit for HDR to a 2-cc volume of rectum is 70 Gy3 and 90 Gy3 for a 2cc volume of bladder.43 Most series show comparable rates of Grades 35 late complications with LDR and HDR therapy. Toxicity rates in the randomized trials with LDR and HDR are listed in Table 2 and for the Stage III retrospective series in Table 3. Table 4 lists the toxicity with HDR and chemotherapy already described. An analysis of the primary data from 56 centers27 showed a significant decrease in all major complications (grades 15) when HDR brachytherapy was used (9% vs. 21% with LDR, P < .001). This corresponded to a significant decrease in the bladder and rectal maximum dose point of 13%.

CONCLUSIONS
HDR may be an acceptable alternative to LDR brachytherapy in carefully selected patients with carcinoma of the cervix. To individualize treatment, it is useful to have both HDR and LDR available. Ideal candidates for HDR will have a small volume of disease, a vagina large enough to hold packing, and an inability to complete treatment in less than 56 days, or the ability to tolerate an inpatient stay. Ideal candidates for LDR are patients who cannot tolerate outpatient treatment or who have bulky residual disease at the time of implantation. In the setting of Stage III carcinoma of the cervix, patients must have sufficient tumor shrinkage to ensure adequate coverage of the target with radiation when an optimized HDR treatment plan is used. Patients with persistent large bulky tumors and/or vaginal disease who do not respond to EBRT may require interstitial therapy. HDR may be used with chemotherapy, although doses to the bladder and rectum must be monitored to prevent increased normal-tissue toxicity. As data mature, additional information regarding late toxicities resulting from HDR and concomitant chemotherapy will become available. Imaging with 3D techniques such as CT and MRI during brachytherapy will allow for optimization of dose away from normal tissues. Future studies comparing LDR and HDR with CT or MR imaging will be necessary to determine if visualization of critical structures will reduce long term morbidity and increase local control for cervical cancer patients.

Morbidity
The risk of late normal-tissue complications depends on a number of factors: whole-pelvic EBRT dose, total dose of brachytherapy, number of fractions of brachytherapy, normal-tissue proximity and dose, intercurrent illnesses, and the use of chemotherapy or other radiation sensitization. The rate of late normal-tissue toxicity of brachytherapy ranges between 5% and 35% for all grades of complications.11,27,28

REFERENCES
1. Lanciano RM, Martz K, Coia LR, Hanks GE. Tumor and treatment factors improving outcome in stage III-B cervix cancer. Int J Radiat Oncol Biol Phys. 1991;20:95100.

914
2.

CANCER

September 1, 2006 / Volume 107 / Number 5

platin and radiotherapy: A Gynecologic Oncology Group Study. Gynecol Oncol. 2004;94:495501. Lee SW, Suh CO, Chung EJ, et al. Dose optimization of fractionated external radiation and high dose rate intracavitary brachytherapy for FIGO stage IB uterine cervical carcinoma. Int J Radiat Oncol Biol Phys. 2002;52:13381344. Stitt JA, Fowler JF, Thomadsen BR, et al. High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system: I. Clinical and radiobiological consideration. Int J Radiat Oncol Biol Phys. 1992;24:335348. Hama Y, Uematsu M, Nagata I, et al. Carcinoma of the uterine cervix: Twice versus once-weekly high dose rate brachytherapy. Radiology. 2001;219:207212. Chao KSC, Williamson JF, Grigsby PW, et al. Uterosacral space involvement in locally advanced carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys. 1998;40:397403. Petereit DG, Sarkaria JN, Potter DM, et al. High dose rate versus low dose rate brachytherapy in the treatment of cervical cancer: Analysis of tumor recurrencethe University of Wisconsin experience. Int J Radiat Oncol Biol Phys. 1999;45:12671274. Kim WC, Kim GE, Suh CO, et al. High versus low dose rate intracavitary irradiation for adenocarcinoma of the uterine cervix. Jpn J Clin Oncol. 2001;31:432437. Sarkaria JN, Petereit DG, Stitt JA, et al. A comparison of the efficacy and complication rates of low dose rate versus high dose rate brachytherapy in the treatment of uterine cervical carcinoma. Int J Radiat Oncol Biol Phys. 1994;30:7582. Kucera H, Potter R, Knocke TH, et al. High dose versus low dose rate brachytherapy in definitive radiotherapy of cervical cancer. Wien Klin Wochenschr. 2001;113:5862. Orton CG, Seyedsadr M, Somnay A. Comparison of high and low dose rate remote afterloading for cervix cancer and the importance of fractionation. Int J Radiat Oncol Biol Phys. 1991;21:14251434. Okkan S, Atkovar G, Sahinler I, et al. Results and complications of high dose rate and low dose rate brachytherapy in carcinoma of the cervix: Cerrahpasa experience. Radiother Oncol. 2003;67:97105. Hsu WL, Wu CJ, Jen YM, Yen SH, Lin KT, Ger LP et al. , Twice-per-day fractionated high versus continuous low dose rate intracavitary therapy in the radical treatment of cervical cancer: A nonrandomised comparison of treatment results. Int J Radiat Oncol Biol Phys. 1995;32:14251431. Akine Y, Arimoto H, Ogino T, Kajiura Y, Tsukiyama I, Egawa S, et al. High dose rate intracavitary irradiation in the treatment of carcinoma of the uterine cervix: Early experience with 84 patients. Int J Radiat Oncol Biol Phys. 1988;17:893898. Arai T, Nakano T, Morita S, Sakashita K, Nakamura YK, Fukuhisa K. High dose rate remote afterloading intracavitary radiation therapy for cancer of the uterine cervix. Cancer. 1992;69:175180. Ferrigno R, Nishimotot IN, Novaes PER, Pellizzon ACA, Maia MAC, Fogarolli RC, et al. Comparison of low and high dose rate brachytherapy in the treatment of uterine cervix cancer. Retrospective analysis of two sequential series. Int J Radiat Oncol Biol Phys. 2005;62:11081116. Sakata KI, Nagakura H, Oouchi A, et al. High dose rate intracavitary brachytherapy: Results of analyses of late rectal complications. Int J Radiat Oncol Biol Phys. 2002;54:13691376. Wong FCS, Tung SY, Leung TW, et al. Treatment results of high dose rate remote afterloading brachytherapy for cervical cancer and retrospective comparison of two regimes. Int J Radiat Oncol Biol Phys. 2003;55:12541264.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

Montana GS, Fowler WC, Varia MA, Walton LA, Mack Y, Shemanski L. Carcinoma of the cervix, stage III results of radiation therapy. Cancer. 1986;57:148154. Paley PJ, Goff BA, Minudri R, Greer BE, Tamimi HK, Koh WJ. The prognostic significance of radiation dose and residual tumor in the treatment of barrel-shaped endophytic cervical carcinoma. Gynecol Oncol. 2000;76:373379. Eifel PJ, Thoms WW Jr, Smith TL, Morris M, Oswald MJ. The relationship between brachytherapy dose and outcome in patients with bulky endocervical tumors treated with radiation alone. Int J Radiat Oncol Biol Phys. 1994;28:113118. Green J, Kirwan J, Tierney J, et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix (Review). Cochrane Database Syst Rev. 2005;4:CD002225. International Commission on Radiation Units and Measurements (ICRU), Dose and volume specifications for reporting intracavitary therapy in gynecology. Bethesda, MD: ICRU, 1985. ICRU Report no. 38. Nag S, Orton C, Young D, et al. The American Brachytherapy Society Survey of brachytherapy practice for carcinoma of the cervix in the United States. Gyn Oncol. 1999;73:111118. Eifel PJ, Moughan J, Erickson B, Iarocci T, Grant D, Owen J. Patterns of radiotherapy practice for patients with carcinoma of the uterine cervix: A patterns of care study. Int J Radiat Oncol Biol Phys. 2004;60:11441153. Foroudi F, Bull CA, Gebski V. Radiation therapy for cervix carcinoma: Benefits of individualized dosimetry. Clin Oncol. 2002;14:4349. Mai J, Erickson B, Rownd J, et al. Comparison of four different dose specification methods for high dose rate intracavitary radiation for treatment of cervical cancer. Int J Radiat Oncol Biol Phys. 2001;51:11311141. Orton C. High dose rate brachytherapy may be radiobiologically superior to low dose rate due to slow repair of late responding normal tissue cells. Int J Radiat Oncol Biol Phys. 2001;49:183189. Perez CA, Grigsby PW, Castro-Vita H, et al. Carcinoma of the uterine cervix. Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy. Int J Radiat Oncol Biol Phys. 1995;32: 12751288. Petereit DG, Sarkaria JN, Chappell R, et al. The adverse effect of treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol Phys. 1995;32:13011307. Chen SW, Liang JA, Yang SN, et al. The adverse effect of treatment prolongation in cervical cancer by high dose rate intracavitary brachytherapy. Radiother Oncol. 2003;67:69 76. Nag S, Erickson B, Thomadsen B, et al. The American Brachytherapy Society recommendations for high dose rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 2000;48:201211. Fyles AW, Pintilie M, Kirkbride P, et al. Prognostic factors in patients with cervix cancer treated by radiation therapy: Results of a multiple regression analysis. Radiother Oncol. 1995;35:107117. Kapp DS, Fischer D, Gutierrez, et al. Pretreatment prognostic factors in carcinoma of the uterine cervix: A multivariate analysis of the effect of age, stage, histology and blood counts on survival. Int J Radiat Oncol Biol Phys. 1983;9:445 455. Winter WE III, Maxwell GL, Tian C, Sobel E, Rose GS, Thomas G, et al. Association of hemoglobin level with survival in cervical carcinoma patients treated with concurrent cis-

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

Controversies in Brachytherapy for Cervical CA/Stewart and Viswanathan

35. Lorvidhaya V, Tonusin A, Changwiwit W, et al. High dose rate afterloading brachytherapy in carcinoma of the cervix: An experience of 1992 patients. Int J Radiat Oncol Biol Phys. 2000;46:11851191. 36. Falkenberg E, Kim RY, Meleth S, De Los Santos J, Spencer S. Low-dose-rate vs. high-dose-rate intracavitary brachytherapy for carcinoma of the cervix: The University of Alabama at Birmingham (UAB) experience. Brachytherapy. 2006;5:4955. 37. Teshima T, Inoue T, Ikeda H, et al. High dose rate and low dose rate intracavitary therapy for carcinoma of the uterine cervix. Final results of Osaka University Hospital. Cancer. 1993;72:24092414. 38. Patel FD, Sharma SC, Negi PS, et al. Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: A clinical trial. Int J Radiat Oncol Biol Phys. 1993;28:335341. 39. Lertsanguansinchai P, Lertbutsayanukul C, Shotelersuk K, Khorprasert C, Rojpornpradit P, Chottetanaprasith T, et al. Phase III randomized trial comparing LDR and HDR brachytherapy in treatment of cervical carcinoma. Int J Radiat Oncol Biol Phys. 2004;59:14241431. 40. Hareyama M, Sakata K, Oouchi A, et al. High dose rate versus low dose rate intracavitary therapy for carcinoma of the uterine cervix. Cancer. 2002;94:117124. 41. Souhami L, Corns R, Duclos M, Portelance L, Bahoric B, Stanimir G. Long-term results of high-dose rate brachytherapy in cervix cancer using a small number of fractions. Gyn Oncol. 2005;97:508513. 42. Haie-Meder C, Potter R, Van Limbergen E, Briot E, De Brabandere M, Dimopoulos J, et al. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): Concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol. 2005;74:235 245. 43. Potter R, Haie-Meder C, Van Limbergen E, Barillot I, De Brabandere M, Dimopoulos J, et al. Recommendations from Gynaecological (GYN) GEC ESTRO Working Group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol. 2006;78: 6777. 44. Kirisits C, Potter R, Lang S, Dimopoulos J, Wachter-Gerstner N, Georg D. Dose and volume parameters for MRIbased treatment planning in intracavitary brachytherapy for cervical cancer. Int J Radiat Oncol Biol Phys. 2005;62: 901911. 45. Kapp KS, Stuecklschweiger GF, Kapp DS, Poschauko J, Pickel H, Lahousen M, et al. Prognostic factors in patients with carcinoma of the uterine cervix treated with external beam irradiation and IR-192 high-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys. 1998;42:531540. 46. Aristizabal SA, Surwit EA, Hevezi JM, Heusinkveld RS. Treatment of advanced cancer of the cervix with transperineal interstitial irradiation. Int J Radiat Oncol Biol Phys. 1983;9:10131017.

915

47. Hughes-Davies L, Silver B, Kapp D. Parametrial interstitial brachytherapy for advanced or recurrent pelvic malignancy: The Harvard/Stanford experience. Gynecol Oncol. 1995;58: 2427. 48. Fontanesi J, Dylewski G, Photopulos G, Tai DL, Eddy T, Kun LE. Impact of dose on local control and development of complications in patients with advanced gynecological malignancies treated by interstitial template boost technique. Endocuriether Hyperther Oncol. 1993;9:115119. 49. Syed AMN, Puthawala AA, Abdelaziz NN, et al. Long term results of low dose rate interstitial intracavitary brachytherapy in the treatment of carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 2002;54:6778. 50. Demanes DJ, Rodriguez RR, Bendre DD, et al. High dose rate transperineal interstitial brachytherapy for cervical cancer: High pelvic control and low complication rates. Int J Radiat Oncol Biol Phys. 1999;45:105112. 51. Kirisits C, Lang S, Dimopoulos J, Berger D, Georg D, Potter R. The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: Desgin, application, treatment planning and dosimetric results. Int J Radiat Oncol Biol Phys. 2006;65:624630. 52. Pearcey R, Brundage M, Drouin P, Jeffrey J, Johnston D, Lukka H, et al. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol. 2002;20:966972. 53. Souhami L, Seymour R, Roman TN, et al. Weekly cisplatin plus external beam radiotherapy and high dose rate brachytherapy in patients with locally advanced carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 1993;27:871878. 54. Strauss HG, Kuhnt T, Laban C, et al. Chemoradiation in cervical cancer with cisplatin and high dose rate brachytherapy combined with external beam radiotherapy. Results of a phase II study. Strahlenther Onkol. 2002;178:378385. 55. Ozsaran Z, Yalman D, Yurut V, Aras A, Ozsaran A, Hanhan M, et al. Radiochemotherapy for patients with locally advanced cervical cancer: Early results. Eur J Gynaecol Oncol. 2003;24: 191194. 56. Sood BM, Gorla GR, Garg M, et al. Extended field radiotherapy and high dose rate brachytherapy in carcinoma of the uterine cervix: Clinical experience with and without concomitant chemotherapy. Cancer. 2003;9:17911798. 57. Sood BM, Gorla G, Gupta S, et al. Two fractions of high dose rate brachytherapy in the management of cervix cancer: Clinical experience with and without chemotherapy. Int J Radiat Oncol Biol Phys. 2002;53:702706. 58. Saibishkumar EP Patel FD, Sharma SC. Results of a phase , II trial of concurrent chemoradiation in the treatment of locally advanced carcinoma of uterine cervix: An experience from India. Bull Cancer. 2005;92:E7E12. 59. Tseng CJ, Chang CT, Lai CH, Soong YK, Hong JH, Tang SG, et al. A randomized trial of concurrent chemoradiotherapy versus radiotherapy in advanced carcinoma of the uterine cervix. Gynecol Oncol. 1997;66:5258. 60. Lukka H, Hirte H, Fyles A, et al. Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer-a metaanalysis. Clin Oncol. 2002;14:203212.