American Journal of Clinical Oncology:
ACR Appropriateness Criteria® Radiation Therapy for Small-Cell Lung Cancer
Kong, Feng-Ming (Spring) MD, PhD, MPH*; Lally, Brian E. MD†; Chang, Joe Yujiao MD, PhD‡; Chetty, Indrin J. PhD§; Decker, Roy H. MD, PhD∥; Ginsburg, Mark E. MD¶; Kestin, Larry L. MD#; Langer, Corey J. MD**; Movsas, Benjamin MD§; Videtic, Gregory M. M. MD, CM††; Willers, Henning MD‡‡; Rosenzweig, Kenneth E. MD§§; Expert Panel on Radiation Oncology-Lung
*Ann Arbor Veteran Affairs Medical Center, University of Michigan, Ann Arbor, MI
§Henry Ford Health System, Detroit, MI
#21st Century Oncology of Michigan, A Division of Michigan Healthcare Professionals, Farmington Hills, MI
†Department of Radiation Oncology, University of Miami, Miami, FL
‡MD Anderson Cancer Center, Houston, TX
∥Yale University School of Medicine, New Haven, CT
¶Society of Thoracic Surgeons, Columbia University, New York, NY
§§Mount Sinai School of Medicine, New York, NY
**Department of Medicine, University of Pennsylvania, Philadelphia, PA
††Cleveland Clinic Foundation, Cleveland, OH
‡‡Massachusetts General Hospital, Boston, MA
The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply individual or society endorsement of the final document.
This article is a revised version of the American College of Radiology Appropriateness Criteria Radiation Therapy for Small-Cell Lung Cancer, excerpts of which are reprinted here with permission. Practitioners are encouraged to refer to the complete version at http://www.acr.org/ac.
B.M. provides research support to Henry Ford Health System Radiation Oncology Department from Varian Inc.; Philips Inc.; and Resonant Inc.
All other authors declare no conflicts of interest.
Reprints: Feng-Ming (Spring) Kong, MD, PhD, MPH, American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. E-mail: email@example.com.
The current standard of care for small cell lung cancer is combined-modality therapy, including the use of chemotherapy, surgery (in selected cases of limited stage of disease), and radiation therapy. This review will focus on the role, dose fractionation, technology and timing of thoracic radiation, and the role and dose regimen of prophylactic cranial irradiation for both limited and extensive stage of diseases. Consensus recommendation from experts is summarized in the tables for 2 typical case scenarios. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.
SUMMARY OF LITERATURE REVIEW
Small cell lung cancers (SCLC) make up approximately 15% to 20% of all newly diagnosed cases of lung cancer. In 2010, there were an estimated 33,380 new cases and 23,600 deaths.1 Compared with non-SCLC, SCLC can be a more aggressive malignancy secondary to an increased doubling time (faster proliferation). SCLC is considered a systemic disease at presentation. Because of its high rate of metastatic dissemination, the 5-year survival rate is only 5% to 6%.
In general, SCLC is classified as either limited-stage (LS-SCLC) or extensive stages (ES-SCLC). Only 30% of patients have LS-SCLC, which historically has been defined as disease confined within an ipsilateral hemithorax that can be safely encompassed in a “tolerable” radiation field.2 The standard of care for LS-SCLC involves the use of chemotherapy and early initiation of thoracic radiotherapy (TRT), followed by prophylactic cranial irradiation (PCI) for patients who have a good treatment response. In highly selected cases, patients will undergo surgical resection followed by chemotherapy with or without radiotherapy (RT). Patients with ES-SCLC have disease beyond the ipsilateral hemothorax, mediastinum, and ipsilateral supraclavicular fossa, which may include malignant pleural or pericardial effusions or contralateral lung or extrathoracic metastasis. The standard of care for ES-SCLC involves the use of chemotherapy and PCI for those who achieve a good response.
Treatment of LS-SCLC
Over 30 years ago, there was optimism that SCLC would prove to be a curable disease. A unique staging system had been devised, and the effectiveness of several chemotherapeutic agents and RT had been established. The central nervous system was identified as a sanctuary site for metastatic disease.3 During the last 30 years, landmarks in therapy have been provided by clinical trials of LS-SCLC. However, further research is still needed to improve the outcomes for patients with SCLC.
Before chemotherapy was implemented for treatment of SCLC, surgery alone was the standard of care for all lung cancer; long-term treatment outcome was dismal with 5-year survival rates close to 0%. A randomized trial from the Medical Research Council in the United Kingdom reported medial survival times of 28.5 weeks for surgery and 43 weeks for RT (P=0.04).4 Five-year overall survival (OS) rates were 1% for surgery and 4% for RT. Median OS times were 6 and 10 months, respectively, and 10-year OS rates were 0% and 4%, respectively.5 Surgery alone is not a treatment option for patients with SCLC. However, there is new interest in the use of surgery in patients with very early limited-stage disease (such as T1N0) in combination with chemotherapy. Currently, patients with clinical stage Ia (T1N0) after standard staging evaluation [including computed tomography (CT) of the chest and upper abdomen, bone scan, brain imaging, and positron emission tomography (PET) imaging] may be considered for surgical resection. Under such circumstance, all patients should undergo surgical mediastinoscopy to rule out occult nodal disease. Only those patients with pathologic negative nodes can be treated with radical surgical resection followed by chemotherapy alone. Concurrent chemotherapy and mediastinal radiation therapy is recommended when the nodes are positive on the surgical pathology (Table 1).
Chemotherapy alone is also not a standard option for LS-SCLC as local tumor progression occurs in up to 80% of such patients and survival is poor.6,7 As will be discussed shortly, multiple clinical investigations have demonstrated that TRT with chemotherapy results in only a modest improvement in survival. It should be noted that these clinical trials were carried out in a time when (1) staging was not used extensively; (2) effective, standardized chemotherapy regimens had not been established; (3) the trials utilized moderate RT doses; and (4) the combined therapy was predominantly sequential chemoradiotherapy. It is likely that the benefit from the addition of TRT is >5.4% reported in the literature.
A breakthrough occurred in the late 1960s with the recognition that SCLC patients were relatively more responsive to available chemotherapeutic agents when compared with an inert compound.8 Although encouraging results were achieved with chemoradiotherapy, the standard of care for LS-SCLC was chemotherapy alone for the better part of 2 decades.9 As a result, the 1980s saw a flurry of clinical trials investigating chemoradiotherapy versus chemotherapy alone in LS-SCLC.
The current standard of care for LS-SCLC is combined-modality therapy, including the use of chemotherapy, surgery (in selected cases), TRT, and PCI for those who achieve a good response.
Role of TRT in LS-SCLC
RT plays an important role in the treatment of patients with LS-SCLC. The addition of TRT has a small but clear survival advantage in this population. Although results from individual randomized trials were often inadequate to definitively determine the standard of care, at least 2 large meta-analyses have confirmed that TRT decreases thoracic recurrence and improves survival.10,11 Pignon et al10 reported that the relative risk of death in the combined therapy group, as compared with the chemotherapy-alone group, was 0.86 corresponding to a 14% reduction in the mortality rate. The benefit in terms of OS rates at 3 years was 5.4%. A meta-analysis by Warde and Payne,11 on the basis of 11 randomized trials, demonstrated that RT improved 2-year survival rates by 5.4%. In addition, a recent overview of prospective studies in LS-SCLC included 26 randomized clinical trials initiated by cooperative groups in North America between 1972 and 1992, and only 5 studies showed a statistically significant longer survival in the experimental arm compared with the control arm.12 All 5 positive trials studied some aspect of TRT.
The survival benefit associated with the use of TRT outside of clinical trials was also illustrated in a review from the National Cancer Data Base.7 For patients with LS-SCLC, the 5-year survival rate for the 6752 patients diagnosed in 2000 was significantly higher in patients treated with TRT plus chemotherapy (13.3% vs. 5.7% with chemotherapy alone). Furthermore, data for population databases demonstrate that improvement in outcomes for LS-SCLC has temporal association with the publication of these clinical results.13
RT Doses/Fractionations/Treatment Duration
Although a dose-response relationship has been demonstrated for many cancer types, there exists no adequate clinical trial addressing the impact of increasing radiation doses on local tumor control and OS in LS-SCLC. Prospective data indicate that doses of 45 to 50.4 Gy once daily (QD) are associated with high rates of locoregional failure (ie, ~50% or higher).14,15 Radiobiologically, the curve of tumor control probability as a function of radiation dose has its steepest incline at 50%, so that a relatively modest dose increase is expected to have a significant impact on local control rates. If hyperfractionation is not feasible, a dose of at least 60 Gy in 2 Gy daily fractions is recommended.16 The Cancer and Leukemia Group B (CALGB) has completed studies (CALGB 39808,17 30002,18 and 3020214) of 70 Gy of TRT with different chemotherapy combinations with acceptable toxicity. However, the local tumor control rate associated with this dose level has not yet been established. Retrospective data suggest improved local control with dose levels of 56 to 60 Gy, (ie, 60% to 78% at 3 y).16,19 It is important to note that local failure data are difficult to obtain and interpret because of problems associated with scoring local failure after high-dose TRT and competing risks. A Patterns of Care study in 2003 showed that the median RT dose used in the community was 50.4 Gy.15 The current National Comprehensive Cancer Network guidelines states that if daily fractionation is used, a dose of at least 66 to 70 Gy in 2 Gy fractions should be administered.20
The optimal dose fractionation of TRT is not known. Accelerated hyperfractionated RT [45 Gy in 1.5 Gy twice-daily (BID) fractions] is recommended based on the only phase III study on this topic.21 This dose regimen was studied by Intergroup 0096,21 which compared QD (45 Gy in 1.8 Gy daily fraction) versus BID RT (45 Gy given in BID 1.5 Gy fractions) in combination with concurrent etoposide and cisplatin (EP) therapy. An improved median survival time and 5-year survival rate was observed in the hyperfractionated arm compared with the QD group, 23 versus 19 months and 26% versus 16%, respectively (P=0.04). One must note that the accelerated hyperfractionated RT was associated with increased toxicities and that a dose of 45 Gy in 1.8 Gy daily fractions is not radiobiologically equivalent to 45 Gy given in BID 1.5 Gy fractions. Daily fractionation regimens such as 50.4 to 70 Gy in 1.8 to 2 Gy daily fractions may serve as reasonable alternatives. However, there are no trials that directly compare the efficacy and toxicity of 2 Gy fractions to those of 1.8 Gy fractions. Fractions of 2 Gy may be advantageous because of the associated reduction in overall treatment time (see below) and are commonly used in modern clinical protocols, although there may be concerns about esophageal toxicity due to increased dose intensity. Nevertheless, 45 Gy in 30 fractions over 3 weeks concurrent with EP therapy generated favorable results according to other published reports, and it is the recommended regimen for treating LS-SCLC until results of further phase III trials are available.
Treatment duration is an important factor associated with local control in several cancer types including lung cancer. It is widely accepted that accelerated fractionation (ie, shortening of overall treatment time) has the potential to reduce the negative impact of accelerated repopulation of tumor stem cells during the course of radiation treatment.22 It is unlikely that the typical delivery of BID fractions in accelerated treatment regimens contributes significantly to improved tumor cell kill, given the generally short repair half-times of rapidly proliferating tumor cells. The concept of treatment acceleration and repopulation can be applied to SCLC. In addition, because of the lack of a so-called shoulder observed for in vitro radiation survival curves, lowering the dose per fraction in BID regimens is not predicted to spare SCLC cells. In the findings of Intergroup 0096 mentioned earlier,21 45 Gy given in BID 1.5 Gy fractions that accelerated with a 3-week treatment duration was associated with improved local tumor control, median survival time, and 5-year OS. In contrast, the North Central Cancer Treatment Group used a similar regimen of hyperfractionated RT (45 Gy given in BID 1.5 Gy) with a treatment duration of 5.5 weeks (including a treatment break of 2.5 wk), failed to show a benefit of using hyperfractionated RT as compared with conventional 50.4 Gy at 1.8 Gy QD TRT in 5.5 weeks.23,24 These findings suggest that the favorable result from 45 Gy given in BID 1.5 Gy has most likely contributed to shortened duration of accelerated TRT when compared with hyperfractionation (Table 2).
Currently, 2 large-scale phase III randomized trials are underway to attempt to determine the optimum combination of dose, fractionation, and treatment duration. CALGB 30610, a US Intergroup trial, is a 3-arm study comparing standard TRT (45 Gy given in BID 1.5 Gy, based on Intergroup 0096) to 70 Gy in 2 Gy daily fractions (CALGB 39808 regimen) and 61.2 Gy concomitant boost TRT (RTOG® 97-12 regimen). After an interim analysis, the experimental arm with the highest rate of acute toxicity will be discontinued. In Europe and Canada, a 2-arm trial is comparing standard TRT to 66 Gy QD TRT. In Europe and Canada, a 2-arm trial (CONVERT) is comparing 45 Gy given in BID 1.5 Gy to 66 Gy at 2 Gy QD TRT with concurrent EP. Until the results of these trials are available, it is reasonable to consider a regimen of 60 to 70 Gy at 1.8 to 2 Gy QD as an alternative if 45 Gy at 1.5 Gy BID is not possible because of logistic considerations.
Timing of TRT Relative to Chemotherapy
TRT in LS-SCLC should be delivered early and concurrently with the chemotherapy rather than sequentially after the completion of chemotherapy. There have been 8 randomized trials and 3 meta-analyses25–27 that have attempted to address the timing of the delivery of TRT relative to chemotherapy. Studies that used standard cisplatin-based chemotherapy without significant dose reductions convincingly showed that early (with cycle 1 or 2 of chemotherapy) rather than late initiation of TRT is associated with a better outcome.
The National Cancer Institute of Canada performed a phase III prospective randomized trial to compare the outcomes of early versus late administration of RT.28 This trial enrolled 308 patients with LS-SCLC, all of whom received cyclophosphamide, doxorubicin, and vincristine alternating with EP chemotherapy for a total of 6 cycles. Patients were randomly assigned to TRT (40 Gy in 15 QD fractions over 3 wk) delivered during cycle 2 or cycle 6 concurrently with EP. Five-year survival rates showed a significant benefit for early TRT compared with late TRT (22% vs. 13%, respectively). Patients were randomized to initiate RT at the second cycle of chemotherapy (week 3) or during the last cycle of chemotherapy (week 15). The median progression-free survival time was 15.4 months in the early RT group versus 11.8 months in the late RT group (P=0.036); the median OS times were 21.2 and 16 months, respectively (P=0.008).
The Lung Cancer Study Group of the Japan Clinical Oncology Group (JCOG) conducted another phase III study in which patients were randomized to sequential chemoradiotherapy or concurrent chemoradiotherapy.29 A total of 231 patients received 4 cycles of EP and TRT consisting of 45 Gy given BID over 3 weeks. RT was initiated after the fourth cycle of chemotherapy on the sequential arm and on the first cycle of day 2 on the concurrent arm. The median survival time was 19.7 months in the sequential arm versus 27.2 months in the concurrent arm (P=0.097). The 5-year survival rate for patients who received sequential chemoradiotherapy was 18.3%, as compared with 23.7% for the patients who received concurrent chemoradiotherapy (P=0.097). This study also suggests that chemotherapy and concurrent RT is more effective than the sequential regimen. Thus, early concurrent chemoradiotherapy is the recommended treatment for LS-SCLC.
In a third trial, 107 patients with LS-SCLC were randomly assigned to TRT with carboplatin/etoposide, followed by 4 cycles of EP, or to 2 cycles of EP followed by TRT with carboplatin/etoposide and then 2 additional cycles of EP.30 TRT consisted of 54 Gy given in 1.5 Gy fractions BID. Five-year OS rates favored the early treatment arm compared with the late arm (30% vs. 15%, respectively). There were no chemotherapy dose reductions in either arm. Of note, there was no difference between the 2 groups in the rate of distant metastases, but there was a significantly better local control rate for those assigned to the early treatment arm.
Three meta-analyses have examined the optimal timing of TRT. One meta-analysis included 7 randomized trials published after 1985 and showed a significant improvement in 2-year OS rates for early TRT versus late TRT.26 Subset analysis showed that this benefit was more pronounced with the use of hyperfractionated RT and platinum-based chemotherapy. These results are consistent with the opinion that standard treatment for LS-SCLC should include the use of cisplatin-containing regimens and concurrent therapy with TRT delivered early. The Cochrane meta-analysis incorporated data from 7 randomized trials and was unable to determine the optimal strategy for integrating chemotherapy and TRT in patients with LS-SCLC, although several of the studies included did not use EP chemotherapy delivered at full doses.27 An additional meta-analysis from the same group indicated that the most important factor associated with improved 5-year survival was a short interval between the start of any treatment and the completion of TRT (relative risk, 0.62).25 This observation was attributed to the phenomenon of accelerated repopulation during treatment. The importance of a short interval between the start of treatment and the completion of RT can also be inferred from a report that analyzed outcome for 215 patients treated with concurrent chemotherapy and TRT during cycle 2 or 3.31 On multivariate analysis, RT treatment interruptions due to toxicity were the most important adverse prognostic factor for survival.
In all 3 of the studies that demonstrated a marked survival advantage for early TRT, patients received cisplatin-based chemotherapy, and both the early and late treatment arms had similar and high rates of patients receiving full doses of chemotherapy.28–30 In contrast, the randomized trials that did not demonstrate an advantage for early TRT either did not use cisplatin-based chemotherapy or had a lower percentage of patients in the early TRT arms who received full-dose chemotherapy compared with those in the late TRT arms.32–36 These deficits may suffice to explain the lack of an observed benefit for early TRT in those studies. The importance of receiving all planned chemotherapy was further supported in another meta-analysis of 8 trials.35
Practically, as treatment can often be initiated faster with chemotherapy than with TRT, delivery of TRT is often integrated early at the second cycle of chemotherapy. For patients with a good performance status and nonbulky disease, intensive therapy with RT early in the course of treatment is appropriate. However, delayed RT does have the advantage of avoiding the significant myelosuppression seen with full-dose chemotherapy and large-volume RT. Therefore, for patients with either a poor performance status or very bulky disease, delaying the initiation of RT until the third cycle of chemotherapy might be prudent. As the elderly comprise increasing portions of patients with SCLC, determining which patients will benefit from intensive therapy and which will benefit from delayed RT becomes critical. Available evidence does suggest that abbreviated therapy may still be of benefit to elderly and infirm patients.37
Radiation Treatment Volume
Several reports23,24 have demonstrated that the use of postchemotherapy volumes, with an associated smaller radiation field size does not increase the local recurrence rate after TRT. However, these fields still, in general, encompassed the primary tumor, ipsilateral hilum, mediastinum, and sometimes the supraclavicular region. Although the use of elective nodal irradiation has not been adequately studied, the Intergroup 0096 trial21 limited elective radiation by not allowing treatment with radiation to the contralateral hilum or to supraclavicular nodes, unless there was bulky superior mediastinal adenopathy. The use of even larger fields otherwise may increase the toxicity with a therapeutic benefit. Bulky SCLC tumors often require large radiation field size that can be reduced after effective chemotherapy shrinks the tumor, potentially reducing toxicity to the lungs and esophagus. The role of elective nodal irradiation has been summarized by a report from International Atomic Energy Agency on this issue.38
PET may have a role in designing radiation treatment volumes. In a prospective evaluation, the principal value of PET in LS-SCLC was the detection of additional sites of disease within the thorax. PET identified unsuspected regional nodal metastasis in 6 (25%) of 24 patients, and the RT plan was significantly altered to include the PET-positive/CT-negative nodes within the high-dose region in each of these patients.39 Selective nodal irradiation on the basis of fluorine-18-2-fluoro-2-deoxy-D-glucose-PET scans in LS-SCLC was also examined by a prospective study.40 PET-based involved nodal radiation resulted in a low rate of isolated nodal failures (3%), with a low percentage of acute esophagitis, whereas CT-based selective nodal irradiation resulted in an unexpectedly high percentage of isolated nodal failures (11%).
Prophylactic Cranial Radiation Therapy in LS-SCLC
Many clinical trials have been conducted to assess the role of PCI in SCLC treatment. Arriagada et al41 reported a prospective randomized study to evaluate the effects of PCI on SCLC. The rate of brain metastasis was significantly reduced by PCI, with a 2-year rate of brain metastasis decreasing from 67% to 40% with the use of PCI (P<10−13). The 2-year cumulative rate of brain metastasis as an isolated first site of relapse was 45% in the control group and 19% in the treatment group (P<10−6). The 2-year rate of OS was 29% in the PCI group and 21.5% in the control group (P=0.14). There were no significant differences between the 2 groups in terms of neuropsychological function or abnormalities indicated by CT brain scans. A multicenter randomized study reported by Gregor et al,42 showed similar results, with a significant decrease in brain metastasis. In 1999, Auperin et al43 performed a meta-analysis on 987 patients with SCLC (847 patients with limited disease and 140 patients with extensive disease) who were in complete remission from 7 trials that compared the use of PCI versus no PCI. PCI was associated with an absolute decrease of 25.3% in the cumulative incidence of brain metastasis at 3 years—from 58.6% in the control group to 33.3% in the PCI group. The relative risk of death in the treatment group as compared with the control group was 0.84 [95% confidence interval (CI), 0.73-0.97; P=0.01], which corresponded to an absolute increase in OS of 5.4% at 3 years—from 15.3% in the control group to 20.7% in the treatment group (P=0.01). As a result of this meta-analysis, PCI has become standard practice for patients with SCLC who have complete remission after chemoradiotherapy of the primary thoracic tumor.
Dose Fractionations for PCI
There have been multiple dose-fractionation schemes for PCI for LS-SCLC. A common one has been 25 Gy in 2.5 Gy daily fractions over 12 to 14 days.21,44 A review including 42 PCI trials with 4749 patients revealed the optimal total RT dose to be 30 to 35 Gy given in 2 Gy fractions.45 In a multinational phase III trial, 720 patients with LS-SCLC who had a complete response to their initial treatment were randomly assigned to PCI at a dose of either 25 Gy in 10 fractions or a dose of 36 Gy administered either as 18 fractions of 2 Gy each or 24 fractions given in BID 1.5 Gy fractions.46 Among the patients randomized to the 36 Gy treatment arm, 78% received QD therapy. The 2-year incidence rates of brain metastases were 23% with the higher radiation dose and 29% with the lower dose. This difference was not statistically significant (hazard ratio, 0.80; 95% CI, 0.57-1.11). However, the higher dose was associated with a significantly lower 2-year survival rate (37% vs. 42%; hazard ratio 1.20; 95% CI, 1.00-1.44). There was no obvious explanation for the increased mortality in the group treated with higher doses of PCI. Therefore, the standard dose of PCI should be 25 Gy in 10 fractions within 2 weeks. A dose of 30 Gy over 3 weeks may be an acceptable alternative, although it has not been directly compared with the 25 Gy dose.
Treatment of ES-SCLC
With improvements in staging through the use of CT, magnetic resonance imaging, and PET with fluorine-18-2-fluoro-2-deoxy-D-glucose tracer, more patients who previously were considered to have limited-stage disease are found to have ES-SCLC. The ratio of LS-SCLC to ES-SCLC was formerly 1:1 and is now 1:3. For ES-SCLC, the treatment of choice is chemotherapy with PCI, with or without TRT. Although many attempts have been made to develop newer therapies, cisplatin-based combination chemotherapy remains the mainstay of treatment.47 RT may also be used as a palliative therapy in some situations such as superior vena cava obstruction, brain metastasis, or bone metastasis. Concurrent chemotherapy in this setting is not recommended.
Chemotherapy for ES-SCLC
Several therapeutic agents and strategies have been tested during the last 3 decades in ES-SCLC. Response rates of 70% to 85%, with complete response rates of 20% to 30%, are encouraging, but virtually every patient relapses. The standard of care in the US has been to use the EP combination since the 1980s.48 Carboplatin may be substituted for cisplatin without an apparent loss of effect and is preferred in older patients or those with renal insufficiency.49
Newer agents do not appear to be more active than older agents. For example, epirubicin, ifosfamide, vinorelbine, carboplatin, gemcitabine, the taxanes, and the topoisomerase I inhibitors tested in the 1990s and 2000s are not more active than doxorubicin, cyclophosphamide, vincristine, cisplatin, and the topoisomerase II inhibitors tested in the 1970s and 1980s. Still, some promising results have been reported. Noda et al50 demonstrated the superiority of cisplatin plus irinotecan compared with cisplatin plus etoposide in a Japan Clinical Oncology Group trial. Hanna et al51 performed a comparative trial in the United States and did not demonstrate superiority with the use of irinotecan. In general, 2-agent regimens have been demonstrated to be more effective than single-agent regimens, even in elderly patients with a poor performance status.52–54 The addition of a third agent has produced higher response rates but at the cost of greater toxicity without an improvement in survival.55–58 Treatment beyond 4 to 6 cycles of any chemotherapy regimen is not beneficial. After 4 cycles of a standard EP regimen, treatment with either maintenance therapy or 4 cycles of topotecan failed to improve survival.59,60 A large challenge in the treatment of ES-SCLC remains the rapid development of drug resistance and the failure of second-line therapy to produce meaningful response rates and longer survival times.
TRT for ES-SCLC
The role of TRT in ES-SCLC is unclear, and it is typically not considered part of the standard of care. There is some preliminary evidence that adding TRT to chemotherapy improves the survival of patients with ES-SCLC. In 1 trial, there were patients who had a complete response outside the thorax to an initial 3 cycles of EP chemotherapy and an at least partial response in the thorax benefitted from subsequent concurrent chemotherapy and radiation.61 Median survival time (17 vs. 11 mo, P=0.041), 5-year survival rate (9.1% vs. 3.7%, P=0.041), and median time to local recurrence (30 vs. 22 mo, P=0.062) were all improved in the RT group. RTOG® 0937 is investigating the role of extracranial RT in addition to PCI following platinum-based chemotherapy in patients with extensive-disease small cell lung cancer. A similar trial is being performed within the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study (EORTC).
PCI for ES-SCLC
Although routine use of TRT to treat ES-SCLC should not yet be integrated into the standard care of patients, there is more convincing evidence for offering PCI to patients with ES-SCLC. In 2007, the EORTC published a landmark trial examining the role of PCI in ES-SCLC.62 It demonstrated that in patients with ES-SCLC who responded to chemotherapy, PCI reduced the risk of brain metastases at 1 year by 26% (40% brain metastases in the control group vs. 15% in the PCI group). Moreover, the 1-year survival rate was 27% in the irradiation group and was 13% in the control group. However, this gain may be associated with a negative impact on quality of life. In a correlative study for this trial,63 the mean global health status score was 8 points higher in the PCI group, a difference that is below the cutoff of a 10-point difference for clinical significance. The most significant side effects of PCI were fatigue and hair loss, whereas the impact on other health-related quality-of-life aspects, such as cognitive and emotional functioning, was limited. However, it is reasonable to offer PCI to all patients with ES-SCLC who respond to first-line chemotherapy.
A caveat of the EORTC trial is that brain imaging was not mandatory before PCI. Only 29% of patients had brain imaging studies done at diagnosis. As the incidence of asymptomatic brain metastases in SCLC is as high as ∼15%, it is likely that a sizeable fraction of these patients had clinically silent brain metastases for which PCI was therapeutic rather than prophylactic. Notably, in the observation arm, symptomatic brain metastases began to be diagnosed within only 1 to 2 months, which is consistent with the emergence of preexisting disease that would have been picked up, had a brain scan been performed. Therefore, the magnitude of the benefit of PCI in a clinical setting where all patients undergo brain imaging before PCI is not defined.
A balanced discussion between the patient and physician is necessary before making a decision to administer PCI. PCI is recommended for patients with either limited or extensive disease who obtain a complete or partial response. PCI is not recommended to patients with poor performance status (3 to 4) or impaired mental function. The recommended dose for PCI is 25 Gy in 10 fractions. PCI should not be given concurrently with systemic chemotherapy because of the increased risk of neurotoxicity but should be initiated within 3 to 6 weeks after the last chemotherapy cycle.
The treatment of patients with SCLC remains a clinical challenge. The Expert Panel on Radiation Oncology-Lung recommends the following.
* For patients with clinical stage T1N0, pathologic stage T1-T2N0, limited-stage disease after lobectomy and nodal dissection or nodal sampling, the treatment should be chemotherapy followed by PCI. TRT is not considered unless there is a concern of mediastinum nodal disease or surgical margins are suspicious or positive.
* For nodal-positive LS-SCLC (cT-1-4pN1-3M0), the consensus standard of care is chemotherapy with concurrent TRT. PCI should be recommended for patients with good treatment response to chemoradiation.
* For patients with ES-SCLC, TRT may be recommended in patients after 4 to 6 cycles of chemotherapy, particularly when PCI is planned, and local thoracic disease is remarkable, or causing local symptoms.
* TRT should start concurrently during the first or second cycle of chemotherapy in LS-SCLC, sequentially after completion of fourth or sixth cycle of chemotherapy in ES-SCLC.
* For TRT in LS-SCLC, 45 Gy given in BID 1.5 Gy fractions is the preferred regimen. When BID radiation is not possible because of logistical reasons, 60 to 70 Gy in 2 Gy daily fractions is an acceptable alternative. Radiation should cover involved primary tumor and nodal diseases with elective radiation of the first echelon nodal regions.
* When TRT is recommended for ES-SCLC, conventionally fractionated 30 to 54 Gy in 2 to 3 Gy daily is the preferred regimen. BID radiation is not recommended. Radiation can cover postchemotherapy volumes of involved primary tumor and nodal diseases without elective nodal radiation.
* PCI is to start after completion of TRT and systemic therapy and restaging workup showing a good treatment response.
* For PCI, 25 Gy in 2.5 Gy daily fractions for 10 treatments is the consensus recommendation. For younger patients with excellent performance status, 30 Gy in 15 daily fractions is an acceptable alternative.
1. Jemal A, Siegel R, Xu J, et al. Cancer statistics. CA Cancer J Clin. 2010;60:277–300
2. Zelen M. Keynote address on biostatistics and data retrieval. Cancer Chemother Rep 3. 1973;4:31–42
3. Einhorn LH, Bond WH, Hornback N, et al. Long-term results in combined-modality treatment of small cell carcinoma of the lung. Semin Oncol. 1978;5:309–313
4. Miller AB, Fox W, Tall R. Five-year follow-up of the Medical Research Council comparative trial of surgery and radiotherapy for the primary treatment of small-celled or oat-celled carcinoma of the bronchus. Lancet. 1969;2:501–505
5. Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up. Lancet. 1973;2:63–65
6. Cohen MH, Ihde DC, Bunn PA Jr, et al. Cyclic alternating combination chemotherapy for small cell bronchogenic carcinoma. Cancer Treat Rep. 1979;63:163–170
7. Gaspar LE, Gay EG, Crawford J, et al. Limited-stage small-cell lung cancer (stages I-III): observations from the National Cancer Data Base. Clin Lung Cancer. 2005;6:355–360
8. Green RA, Humphrey E, Close H, et al. Alkylating agents in bronchogenic carcinoma. Am J Med. 1969;46:516–525
9. Weiss RB. Small-cell carcinoma of the lung: therapeutic management. Ann Intern Med. 1978;88:522–531
10. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med. 1992;327:1618–1624
11. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol. 1992;10:890–895
12. Janne PA, Freidlin B, Saxman S, et al. Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer. 2002;95:1528–1538
13. Lally BE, Geiger AM, Urbanic JJ, et al. Trends in the outcomes for patients with limited stage small cell lung cancer: an analysis of the Surveillance, Epidemiology, and End Results database. Lung Cancer. 2009;64:226–231
14. Langer CJ, Swann S, Werner-Wasik M, et al. Phase I study of irinotecan (Ir) and cisplatin (DDP) in combination with thoracic radiotherapy (RT), either twice daily (45 Gy) or once daily (70 Gy), in patients with limited (Ltd) small cell lung carcinoma (SCLC): early analysis of RTOG 0241. ASCO Meeting Abstracts. 2006;24(suppl 18):7058
15. Movsas B, Moughan J, Komaki R, et al. Radiotherapy patterns of care study in lung carcinoma. J Clin Oncol. 2003;21:4553–4559
16. Miller KL, Marks LB, Sibley GS, et al. Routine use of approximately 60 Gy once-daily thoracic irradiation for patients with limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2003;56:355–359
17. Bogart JA, Herndon JE II, Lyss AP, et al. 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys. 2004;59:460–468
18. Miller AA, Wang XF, Bogart JA, et al. Phase II trial of paclitaxel-topotecan-etoposide followed by consolidation chemoradiotherapy for limited-stage small cell lung cancer: CALGB 30002. J Thorac Oncol. 2007;2:645–651
19. Roof KS, Fidias P, Lynch TJ, et al. Radiation dose escalation in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2003;57:701–708
21. Turrisi AT III, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340:265–271
22. Willers H, Held KD. Introduction to clinical radiation biology. Hematol Oncol Clin North Am. 2006;20:1–24
23. Bonner JA, Sloan JA, Shanahan TG, et al. Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma. J Clin Oncol. 1999;17:2681–2691
24. Schild SE, Bonner JA, Shanahan TG, et al. Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;59:943–951
25. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol. 2006;24:1057–1063
26. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol. 2004;22:4837–4845
27. Pijls-Johannesma MC, De Ruysscher D, Lambin P, et al. Early versus late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev. 2005:CD004700
28. Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1993;11:336–344
29. Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002;20:3054–3060
30. Jeremic B, Shibamoto Y, Acimovic L, et al. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study. J Clin Oncol. 1997;15:893–900
31. Videtic GM, Fung K, Tomiak AT, et al. Using treatment interruptions to palliate the toxicity from concurrent chemoradiation for limited small cell lung cancer decreases survival and disease control. Lung Cancer. 2001;33:249–258
32. Gregor A, Drings P, Burghouts J, et al. Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study. J Clin Oncol. 1997;15:2840–2849
33. Perry MC, Eaton WL, Propert KJ, et al. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med. 1987;316:912–918
34. Perry MC, Herndon JE III, Eaton WL, et al. Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: an update of Cancer and Leukemia Group B Study 8083. J Clin Oncol. 1998;16:2466–2467
35. Spiro SG, James LE, Rudd RM, et al. Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol. 2006;24:3823–3830
36. Work E, Nielsen OS, Bentzen SM, et al. Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer Group. J Clin Oncol. 1997;15:3030–3037
37. Murray N, Grafton C, Shah A, et al. Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol. 1998;16:3323–3328
38. Videtic GM, Belderbos JS, Spring Kong FM, et al. Report from the International Atomic Energy Agency (IAEA) consultants’ meeting on elective nodal irradiation in lung cancer: small-cell lung cancer (SCLC). Int J Radiat Oncol Biol Phys. 2008;72:327–334
39. Bradley JD, Dehdashti F, Mintun MA, et al. Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol. 2004;22:3248–3254
40. van Loon J, De Ruysscher D, Wanders R, et al. Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys. 2010;77:329–336
41. Arriagada R, Le Chevalier T, Borie F, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst. 1995;87:183–190
42. Gregor A, Cull A, Stephens RJ, et al. Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer. 1997;33:1752–1758
43. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341:476–484
44. Komaki R, Byhardt RW, Anderson T, et al. What is the lowest effective biologic dose for prophylactic cranial irradiation? Am J Clin Oncol. 1985;8:523–527
45. Sorensen JB. The role of prophylactic brain irradiation in small cell lung cancer treatment. Monaldi Arch Chest Dis. 2003;59:128–133
46. Le Pechoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol. 2009;10:467–474
47. Spira A, Ettinger DS. Extensive-stage small-cell lung cancer. Semin Surg Oncol. 2003;21:164–175
48. Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985;3:1471–1477
49. Okamoto H, Watanabe K, Kunikane H, et al. Randomized phase III trial of carboplatin(C) plus etoposide (E) versus split doses of cisplatin (P) plus etoposide (E) in elderly or poor-risk patients with extensive disease small cell lung cancer (ED-SCLC): JCOG9702. J Clin Oncol (Meeting Abstracts). 2005;23(suppl 16):LBA7010
50. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346:85–91
51. Hanna N, Bunn PA Jr, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006;24:2038–2043
52. Girling DJ. Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet. 1996;348:563–566
53. Lowenbraun S, Bartolucci A, Smalley RV, et al. The superiority of combination chemotherapy over single agent chemotherapy in small cell lung carcinoma. Cancer. 1979;44:406–413
54. Souhami RL, Spiro SG, Rudd RM, et al. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst. 1997;89:577–580
55. Loehrer PJ Sr, Ansari R, Gonin R, et al. Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: a Hoosier Oncology Group study. J Clin Oncol. 1995;13:2594–2599
56. Mavroudis D, Papadakis E, Veslemes M, et al. A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol. 2001;12:463–470
57. Niell HB, Herndon JE II, Miller AA, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol. 2005;23:3752–3759
58. Pujol JL, Daures JP, Riviere A, et al. Etoposide plus cisplatin with or without the combination of 4’-epidoxorubicin plus cyclophosphamide in treatment of extensive small-cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study. J Natl Cancer Inst. 2001;93:300–308
59. Schiller JH, Adak S, Cella D, et al. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593—a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:2114–2122
60. Sculier JP, Berghmans T, Castaigne C, et al. Maintenance chemotherapy for small cell lung cancer: a critical review of the literature. Lung Cancer. 1998;19:141–151
61. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol. 1999;17:2092–2099
62. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;357:664–672
63. Slotman BJ, Mauer ME, Bottomley A, et al. Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms: results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J Clin Oncol. 2009;27:78–84
small cell lung cancer; radiation therapy; appropriateness criteria
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