Hematol Oncol Clin N Am

18 (2004) 297 – 307

Radiation therapy in small cell lung cancer

Branislav Jeremic, MD, PhD
Department of Radiation Oncology, Klinikum rechts der Isar, Technical University Munich,
Ismaninger Strasse 22, D-81675 Munich, Germany

The modern history of radiation therapy (RT) and, in general, treatment of

small cell lung cancer (SCLC) started in the early 1970s when distinct behavior
patterns of SCLC (early and widespread dissemination) led to clear differentia-
tion from non– small cell lung cancer (NSCLC). SCLC was divided between
limited disease (LD) and extensive disease (ED) [1]. Before the 1970s, patients
with SCLC were treated similarly to those harboring other lung cancer subtypes.
This treatment included mostly surgery and RT. In the late 1960s, the British
Medical Research Council published the results of the randomized trial compar-
ing surgery to RT in SCLC [2], with RT achieving a better 5-year survival rate
(5% versus 1%). This finding, however, did not unequivocally establish RT as the
standard treatment at that time because chemotherapy (CHT) had been increas-
ingly used to combat this seemingly chemosensitive disease, both intra- and ex-
trathoracically [3]. CHT became the leading treatment approach, particularly due
to the encouraging results obtained with it. It was recognized early, however,
that despite good initial responses, the vast majority of SCLC patients continued
to fail locally and distantly with the passage of time [4]. Although the latter may
call for improvements in CHT, the former (on a locoregional level) clearly called
for more and better RT to combat chemoresistant tumor clonogens present from
the outset of treatment. A special issue was the high frequency of brain relapses
that also called for consideration of prophylactic cranial irradiation (PCI) to
address the issue of brain being the sanctuary site in SCLC. These clinical obser-
vations led to attempts to address improvements in the treatment by offering
thoracic RT (TRT) and PCI.

Thoracic radiation therapy in limited-disease small cell lung cancer

Despite frequent use in SCLC during the 1970s and 1980s, it took at least
20 years to establish TRT as an indispensable part of a combined modality ap-

E-mail address: bjeremic@lrz.tu-muenchen.de

0889-8588/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.hoc.2003.12.002
298 B. Jeremic / Hematol Oncol Clin N Am 18 (2004) 297–307

roach in this disease. Owing to the two meta-analyses [5,6] that showed a small
but significant improvement in 2- and 3-year survival rates averaging 5% to 7%
and an improvement in local control rates in 25% of cases with the addition of
TRT, combined TRT/CHT is now widely (but not unequivocally) accepted as the
standard treatment approach in LD SCLC. It is noteworthy that the CHT regi-
mens in the studies included in the two meta-analyses did not include cisplatin/
etoposide, which is considered a standard regimen nowadays. TRT characteristics
also were not demystified, particularly regarding time/dose/fractionation and the
timing of TRT and CHT.
Regarding total dose and fractionation, early studies used either conven-
tional fractionation (eg, 2.0 Gy per fraction) or somewhat hypofractionated TRT
(eg, 40 Gy in 15 daily fractions or 45 Gy in 20 daily fractions). A recent ret-
rospective analysis showed no difference between these two fractionation
regimens in an institutional setting [7]. With the appreciation that SCLC is
extremely radiosensitive and that the cell survival curve has an extremely small
‘‘shoulder’’ [8], it was expected that more twice-daily fractionation should be
more effective. Early studies with twice-daily fractionation were very encourag-
ing [9] and they have led to testing accelerated hyperfractionation versus conven-
tional fractionation [10]. Accelerated hyperfractionation to a dose of 45 Gy,
1.5 Gy twice-daily, was superior to conventional, once-daily fractionation using
the same total dose, although the toxicity also was more pronounced in the twice-
daily group. In addition to a somewhat lower therapeutic ration in that study,
critics indicated an insufficient total dose in the once-daily arm that may have not
been optimal. Indeed, a recent study from the Cancer and Leukemia Group B
showed that 70 Gy given as a once-daily regimen may successfully be combined
with CHT [11]. Confirmation that this may be feasible in ordinary clinical
practice comes from two retrospective studies that recently confirmed that ap-
proximately 60 Gy of once-daily TRT may be given in unselected patients with
LD SCLC [12] and that a total dose of 50 Gy produces better results than
historical controls (lower TRT doses) [13]. This question also was addressed in a
randomized study that compared two concurrent cycles of PE with twice-daily,
split-course TRT or with once-daily TRT, both given after three cycles of PE
[14,15]. There was no difference in 3- and 5-year overall and locoregional
control. Possible explanations for the similarity of results of this and the inter-
group study [10] may lie in the inferiority of the split-course regimen (which
undermined the effect of hyperfractionation) or in the effects of acceleration
outweighing those of hyperfractionation. Extending overall treatment time,
therefore, which allows tumor cell regeneration, may have been the reason for
this finding due to a delay in TRT by long-lasting induction CHT or by split-
course protocol for TRT. Also, in the split-course study [14,15], the combination
was actually a sequential one, contrasting early concurrent TRT/CHT in the
intergroup study [10].
Timing in combined TRT/CHT relates to the concurrent part of a combined
regimen, usually being divided between ‘‘early’’ and ‘‘late.’’ Although early and
late should imply a considerable time difference in administration of TRT/CHT
 B. Jeremic / Hematol Oncol Clin N Am 18 (2004) 297–307 299

(versus time zero or the start of the treatment), data from the literature are in-
consistent regarding this issue: in absolute terms, what was early for one study
was late for another [16 – 21], including the fact that some of these studies did not
include concurrent TRT/CHT but rather a sequential approach [20]. Although
overall data supported the early administration of TRT/CHT (ie, up to cycle 3 of
CHT), no firm conclusions can be drawn from the literature. In an attempt to
solve this problem, a recent meta-analysis was performed that investigated the
optimal timing of TRT/CHT in LD SCLC by comparing early (<9 weeks after
initiation of CHT) with late (9 weeks after initiation of CHT) [22]. Seven trials
with 1524 patients were included. The 2-, 3-, and 5-year overall survival risk
ratios and risk differences indicated a significantly increased survival at 2 years,
with a similar trend at 3 and 5 years. The risk difference favored early TRT/
CHT for 5.2% at 2 years. Particularly good results were obtained for the
hyperfractionated TRT and platinum-based CHT studies in which a strong as-
sociation was seen between early TRT and improved survival, with risk differ-
ences at 2, 3, and 5 years being 16.7% (P<0.001), 9.2% (P = 0.03), and 8.3%
(P = 0.07), respectively. When once-daily and doxorubicin-based CHT were
considered, no difference between early and late TRT was seen. Effect of early
TRT was more pronounced in platinum-based CHT, in contrast to doxorubicin-
based CHT.
The issue of optimal treatment volume is of no importance if a clinician
uses early (cycle 1) concurrent TRT/CHT but becomes progressively more im-
portant when concurrent TRT/CHT follows one or more initial CHT cycles. The
clinician is faced with the question of what to treat: pre-CHT or post-CHT visible
volumes? Another question is, What should be the safety margin around the
visible tumor and which, if any, elective nodal coverage should be used? No
consensus exists, so far. One prospective study showed no difference between
large-field TRT and limited-field TRT [14], whereas other retrospective studies
showed the opposite [23,24]. This issue cannot be discussed separately from
other TRT issues such as dose or fractionation and must also take into account
toxicity and quality of life.
It took even more time for PCI to become a standard of treatment in LD
SCLC. Although it was frequently practiced in complete response (CR) and
occasionally in good partial response (PR) patients, it was not unequivocally
proved to produce superior survival. Of additional importance is the fact that
numerous thoracic oncologists were frequently raising the question of toxicity of
PCI, mostly indicating a decline in neurocognitive functions after PCI. Recent
years, fortunately, brought a sobering picture. First, a meta-analysis [25] showed
that PCI reduced the relative risk of death, with a relative risk of 0.84 cor-
responding to a 5.4% absolute increase in the 3-year survival rate. Also observed
was an absolute increase of 8.8% in the disease-free survival rate and an absolute
decrease in the cumulative rate of central nervous system (CNS) metastases
(25.3% at 3 years). This meta-analysis firmly established PCI as an indispensable
part of a general treatment plan in LD SCLC. Second, the issue of PCI toxicity
was clearly discarded [26,27], with both studies evaluating the occurrence of
300 B. Jeremic / Hematol Oncol Clin N Am 18 (2004) 297–307

neurocognitive impairment with neuropsychologic assessments and one of the

studies using CT scans to document any morphologic changes [26]. A recent
prospective study initiated by the Institut Gustave-Roussy should clarify the issue
of optimal dose/fractionation of PCI [28]. The current approach is to administer
PCI at the time of achieving CR, but its timing becomes important to avoid ad-
ministration concurrently with CHT, and thus more CNS toxicity. Another issue
regarding the administration of PCI is its use in patients experiencing a good PR
(eg, 80% – 90% tumor shrinkage), which seems to be the next issue to be
addressed, not only because of an intention to decrease CNS failures and prolong
the life but also to improve quality of life with PCI.

Thoracic radiation therapy in extensive-disease small cell lung cancer

Various active drugs have been used to treat patients with ED SCLC, offering
improvement in survival from 1.5 to 3 months to 9 to 12 months in the last
2 decades [29,30]. The prognosis for patients with ED SCLC remains poor, how-
ever, despite the fact that up to 90% of patients experience objective response
following initial CHT. Most of them eventually relapse, making the 5-year
survival rate only 1%. TRT was occasionally practiced in ED SCLC. Almost
20 years ago, a large retrospective review of literature showed that RT in ED
SCLC reduced the frequency of initial chest failure, but CR rates, overall re-
sponse rates, median survival, and 2-year disease-free survival times were iden-
tical for patients treated with CHT alone and those treated with CHT and TRT
[31]. It is unfortunate that most of the studies from this report originated in the
1960s and 1970s and included TRT characteristics that are not considered optimal
today. Clinicians must also take into account the systemic character of ED SCLC
that may have obscured possible effects of RT on survival (established on a local
level), especially in adequately chosen subgroups of patients suitable for the
‘‘curative’’ role of RT. Other issues concerning RT, such as irradiation to sites
of systemic tumor or the role of PCI were also controversial.
Those few studies in which TRT was employed were inconclusive. The
Cancer and Leukemia Group B performed a prospective randomized study in
ED SCLC comparing two CHT regimens with or without TRT [32], with no
difference in either response rates or survival. The Southwest Oncology Group
performed two consecutive studies in ED SCLC with (study 7415) or without
(study 7828) TRT, again with no seemingly different outcome between patients
in these two studies [33]. Attempts to include not only intrathoracic tumor bur-
den but also the sites of the distant spread did not bring anticipated improvement
in the treatment outcome [34 – 36].
In ED SCLC, TRT was mostly used palliatively to ameliorate symptoms at
the local or distant level, and only rarely was it employed in the initial combined
modality approach with curative intent [37]. The rationale for this was that ED
SCLC is a systemic disease and that local/regional therapy such as TRT does
not have a curative role in its treatment. Even patients that were experiencing CR
 B. Jeremic / Hematol Oncol Clin N Am 18 (2004) 297–307 301

after a few cycles of CHT, however, subsequently relapsed locoregionally, alone

or accompanied by distant metastasis. It is possible, therefore, that this tempo-
rary benefit of induction CHT may be fortified and improved by introducing
TRT, provided that these patients live long enough to verify this hypothesis.
These patients should be those with the least burden of tumor cells—mostly those
with either clinical CR/CR or PR/CR.
To investigate the role of TRT in ED SCLC, the author and colleagues [38]
designed a study with the primary aim of identifying the subgroup of patients
most likely to benefit from this treatment modality. These patients should have
been in the best prognostic subgroup, having a CR at distant sites, whereas their
status on the local level could have been either CR or PR (combined, CR/CR and
PR/CR). With this approach, it was ensured that this subgroup of patients would
have had reasonable outcome, even if treated with CHT alone. With the use of
TRT, the author and colleagues were able to investigate whether TRT could fortify
the effect of CHT (CR) or improve it (PR) by eradicating CHT-resistant tumor
cells that were likely to predominate in cases of PR (after three cycles of platinum/
etoposide). In brief, the goal was to ‘‘convert’’ ED SCLC into LD SCLC with
initial CHT and then to administer TRT/CHT as if it was LD SCLC, comparing it
to CHT only. It seems that this treatment plan worked well in patients with ED
SCLC when achieving not just CR/CR but also PR/CR. In the TRT group, the
median time to local recurrence was 30 months and the 5-year local recurrence –
free survival rate was 20% (the corresponding figures for patients treated with
CHT only were 22 months and 8.1%, respectively), which led to the improve-
ment in survival, with the median survival time of 17 months and a 5-year sur-
vival of 9.1% (the corresponding figures for patients treated with CHT only were
11 months and 3.7%, respectively). The study proved that RT given as acceler-
ated hyperfractionated TRT (54 Gy, 1.5 Gy twice daily) is capable of eradicating
drug-resistant tumor cells, showing again that there is no complete cross-resist-
ance between these two treatment modalities in SCLC [21,39]. Results of this
study indicated that TRT may play an important role in the treatment of ED
SCLC. The small sample size and single-institutional environment clearly call
for verification of these results in the multi-institutional setting with large pa-
tient numbers.

Radiation therapy for relapsing small cell lung cancer

TRT is considered standard treatment in LD SCLC. Therefore, repeat RT is not
frequently offered to patients with LD SCLC who were initially treated with TRT/
CHT due to a fear of excessive toxicity from TRT. Its role in relapsing ED SCLC
should be clearer because ED SCLC traditionally is treated with CHT alone.
It is unfortunate that data are scarce. The data that clearly indicated an impact
of TRT were published before TRT became widely accepted as part of the stan-
dard treatment in LD SCLC. These retrospective studies were published years
ago, included small patient numbers, and consisted of LD and ED SCLC pa-
302 B. Jeremic / Hematol Oncol Clin N Am 18 (2004) 297–307

tients [40 –42]. Furthermore, a wide range of total doses were used (20 – 60 Gy).
Regardless, response rates in the TRT fields ranged from 52% to 77%, with
better outcome for patients treated with 40 Gy. The studies also indicated the
effectiveness of TRT in this setting and indicated no cross-resistance between
CHT and TRT. The median survival times were short (range 3 – 4 months), how-
ever, due to numerous patients dying of distant progression not addressed by the
TRT. Although the short median survival times obscured the true results ob-
tainable by TRT, these studies clearly showed that TRT is capable of substantially
improving locoregional tumor control, which was later manifested by the facts
that TRT was incorporated from the outset in a combined modality approach
in SCLC and that it can also be practiced in cases of ED SCLC, after CR or PR
is obtained.
In addition to TRT, intraluminal RT was also practiced in cases of relapsing
SCLC, although not as frequently as it was practiced for relapsing NSCLC to
prolong the survival and to offer symptom control [43,44]—goals that were suc-
cessfully achieved. The use of intraluminal RT may be especially important in
cases when previous high-dose external beam TRT has been employed.

Radiation therapy for metastatic small cell lung cancer

Another use of RT in SCLC is in patients presenting with distant metasta-
sis, mostly those occurring in the brain and bones. RT has been successfully prac-
ticed for a number of decades, and accumulated knowledge has enabled better
insight into TRT characteristics such as total dose, fractionation, and the pos-
sibility of combining it with surgery in cases of CNS metastases [45 –49]. It has
been shown that RT cannot only prolong survival of such patients (those with
CNS metastases) but also enable a substantial symptom-free period of time.
RT is an important aspect that can bring better quality of life to patients in whom
only palliation is sought. Similar applies to RT in bone metastasis, where
numerous prospective randomized studies clearly showed that single-fraction
RT is not only an effective treatment approach in this disease but also equal to
multifraction regimens [50 –54], the former having an advantage for both patients
and hospitals [55,56]. Furthermore, single-fraction RT carries a possibility of suc-
cessful retreatment, once or more, in cases of treatment failure [57,58].
Also, with somewhat lesser frequency, RT is used in metastatic lesions
occurring in subcutaneous tissues, liver, or lung. In particular, with the wide-
spread use of high-precision RT (stereotactic radiosurgery or stereotactic frac-
tionated RT), metastatic lesions located in the liver [59,60] or lung will become
easier to treat [61,62].

Radiation therapy for medical emergencies in small cell lung cancer

Here, the most common of all medical emergencies occurring in SCLC, namely
metastatic spinal cord compression and superior vena cava syndrome (SVCS)
 B. Jeremic / Hematol Oncol Clin N Am 18 (2004) 297–307 303

are discussed. Most patients will require RT for metastatic spinal cord compres-
sion during the course of the disease, either alone or in combination with steroids,
analgesics, CHT, hormones, or surgery. Various RT dose/fractionation regimens
have been used, from multifraction regimens to single-fraction RT [63 –66]. RT is
capable of producing substantial improvement in motor, sensory, and autonomic
function and of having strong analgesic effects.
The presence of SVCS does not preclude a curative treatment strategy. Al-
though RT is frequently used, other treatment options such as CHT or stenting
are often appropriate. In fact, CHT is even more frequently used initially in
SVCS, although RT has been used in selected cases. It seems, however, that there
is no difference between these two modalities [67,68]. One study randomized
SVCS patients to initial CHT followed by further CHT or RT and found no dif-
ference [69]. In cases of SVCS, RT usually has included all locoregional disease
and employed somewhat larger doses per fraction (on the order of 300 – 400 cGy)
[67,70], with fraction size increasing with decreasing performance status of pa-
tients [71].

Summary
RT in SCLC plays an important role in virtually all cases. Although RT is
considered standard treatment, this treatment modality is under active investiga-
tion in LD SCLC regarding numerous issues such as total dose, fractionation,
and combination with newer drugs. The issues of optimal fractionation and total
dose of PCI are the subject of an ongoing international trial. TRT/PCI awaits
further investigation in ED SCLC that is aimed at the best prognostic subgroup of
patients. In addition to curative attempts, RT as external beam RT or intraluminal
brachytherapy is a valuable tool in the treatment of metastatic disease and of
medical emergencies.

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