Radiotherapy in the Management of Small Cell Lung Cancer: Thoracic Radiotherapy, Prophylactic Cranial Irradiation

Summary of Key Points

In patients with clinically nonmetastatic small cell lung cancer (SCLC), positron emission tomography–computed tomography (PET–CT) as well as brain imaging is suggested to classify tumor stage.
To classify stage, it is recommended to use the Veterans Administration system (limited disease [LD] vs. extensive disease [ED]) as well as the International Union for International Cancer Control TNM Classification of Malignant Tumors seventh edition (2009), which recommended tumor, node, and metastasis (TNM) staging based on analysis of the International Association for the Study of Lung Cancer database. The prognostic value of clinical and pathologic T and N staging in patients with SCLC is confirmed in the eighth edition. For the M descriptors, more research is warranted.
In patients with nonmetastatic SCLC or LD, combined chemoradiation is the standard. Concomitant chemoradiotherapy gives the best results and is preferred to sequential chemoradiotherapy, but the latter can be an option in fragile patients. Compliance with alternating regimens may be difficult, but promising results have been published.
In fit, nonmetastatic SCLC patients, early chemoradiotherapy is recommended. In more fragile patients, for whom good compliance with early concomitant chemoradiotherapy cannot be expected, there is no survival advantage with early chemoradiation.
A randomized phase III trial showed no difference between once-daily (66 Gy/33 fractions per 6.6 weeks) and twice-daily radiation (45 Gy/30 fractions per 3 weeks) given along with chemotherapy for patients with LD-SCLC.
In patients with nonmetastatic SCLC who achieve a complete or partial response to initial therapy, prophylactic cranial irradiation (PCI) at the dose of 25 Gy in 10 daily fractions is recommended. It should not be administered concomitantly with chemotherapy.
In metastatic SCLC, PCI is also recommended among patients with any response to chemotherapy based on a randomized trial and the meta-analysis. The same regimen (25 Gy/10 fractions per 2 weeks) or a more hypofractionated regimen (20 Gy/5 fractions per 1 week) may be administered. A recent Japanese study showed a decrease in brain metastasis rate but failed to demonstrate survival advantage with PCI in patients with extensive stage SCLC, but mature data are awaited.
Patients should be informed of potential adverse effects on neurocognitive functioning that may be caused by PCI especially in elderly patients to balance the benefit of PCI on survival and risk of brain metastases.
In patients with ED-SCLC who have completed chemotherapy and achieved a response, a course of consolidative thoracic radiotherapy (TR) is suggested by the results of a randomized trial. A subgroup analysis has shown that among patients with partial response in the chest, but not complete response, consolidation TR had an impact on survival.

Small cell lung cancer (SCLC) represents less than 20% of all lung cancers. It is an aggressive tumor, and only a third of patients have limited stage disease at diagnosis. As SCLC has a high propensity for early metastatic dissemination, chemotherapy has been and still is the cornerstone of treatment, but SCLC is also very sensitive to radiotherapy (RT).

Patients often have bulky mediastinal disease at presentation. After staging procedures, SCLC was classically presented as LD or ED according to the Veterans Administration Lung Cancer Study Group Classification. LD was defined as confined to a hemithorax and the regional lymphatic nodes (mediastinum, ipsilateral, and contralateral hilar regions, and supraclavicular fossa), thus theoretically encompassable with an RT field. Although this classification has been used for many years, the International Association for the Study of Lung Cancer has recommended the use of the new TNM classification for nonsmall cell lung cancer (NSCLC) for SCLC as well. The seventh and the future eighth TNM classifications split patients into a larger number of prognostically homogeneous subgroups, which could better define those patients for whom thoracic RT (TR) might be beneficial. Recent advances in the management of SCLC are principally attributed to the improved knowledge of the indications for RT, both in nonmetastatic (or limited) and in metastatic (or extensive) diseases. By contrast, in the last two decades, chemotherapy progress has reached a plateau. The integration of TR with systemic chemotherapy in SCLC as well as PCI is really a “unique success story in the field of radiation oncology and highlights the potential for effective local therapy to impact overall outcomes.”

This relative “success story” started with the publication in the early 1990s of an individual patient data-based meta-analysis of randomized trials comparing combined chemoradiotherapy with chemotherapy alone, which demonstrated an absolute overall survival (OS) benefit of 5.4% in favor of combination therapy (3-year OS of 8.9% vs. 14.3% in the chemoradiation arm). Pignon and colleagues collected and analyzed individual data from 13 trials involving 2140 patients with LS-SCLC: the relative risk of death in the chemoradiation group, as compared with the chemotherapy alone group, was 0.86 (95% confidence interval [CI], 0.78–0.94; p = 0.001). This equated to a 14% reduction in death with the addition of radiation. Warde and Payne published similar findings in a literature-based analysis of 11 randomized trials. They showed that the addition of TR to chemotherapy led to an overall benefit of 5.4% on 2-year survival, and an improved 2-year intrathoracic tumor control (from 16.5% in the chemotherapy arm alone to 34.1% in the combined modality arm), resulting in a benefit in local control of about 25%. The combination of chemotherapy and RT became a standard in the early 1990s after the publication of these two meta-analyses. Subsequently, these benefits have been confirmed by other studies. The current state-of-the-art treatment for SCLC patients with nonmetastatic disease involves cisplatin (or carboplatin in more fragile patients)–etoposide chemotherapy combined with chest RT, as reported in guidelines worldwide.

It is possible, however, that the two reported meta-analyses underestimate the results that can be obtained with platinum-based chemotherapy and contemporary RT as only a few studies included in the meta-analyses used platinum-based chemotherapy and concurrent chemoradiation, which are considered nowadays as part of the optimal treatment approach.

There are indeed different ways of combining chemotherapy and TR: they can be administered concurrently, sequentially, or in an alternating fashion. Furthermore, the issue of timing of RT has also been addressed in randomized trials: whether radiation should be given early or late in the overall course of treatment has long been a subject of debate. Sequential schedules allow the delivery of full-dose chemotherapy followed by full-dose RT; tumor shrinkage can be observed after systemic therapy, but repopulation and selection of resistant cellular clones may lead to treatment failure. The alternating schedule has a good toxicity profile, although from a practical point of view, it may be a complicated approach; the good results obtained in a French Study group randomized trial could not be reproduced by a larger European Organization for Research and Treatment of Cancer (EORTC) study. The concomitant approach has the radiobiologic advantage of reducing the overall treatment time, which is a particularly relevant issue in SCLC treatment, although it is associated with an increased risk of acute toxicity, especially esophagitis. Even so, this latter approach has now become the standard of care.

Two phase III trials have studied alternating schedules: an EORTC study, which compared an alternating chemoradiation regimen with a sequential regimen, and the “Petites Cellules” study, which compared an alternating regimen with a concomitant chemoradiation approach. It should be noted that none of these trials used platinum-based chemotherapy. Results were poor in both trials, with no difference in terms of OS between the two arms (median 15 months vs. 14 months in the first study; 13.5 months vs. 14 months in the second one).

The Japan Clinical Oncology Group (JCOG) performed a phase III trial comparing a sequential and concurrent chemoradiation approach. A total of 231 patients with LD-SCLC were randomly assigned to receive four cycles of cisplatin plus etoposide every 3 weeks followed by accelerated hyperfractionated TR at the dose of 45 Gy in 3 weeks (sequential arm) or the same four cycles of chemotherapy administered every 4 weeks with the same modality of TR starting on day 2 of the first cycle of chemotherapy (concurrent arm). The results favored the concurrent schedule with a median survival of 27.2 months versus 19.7 months of the sequential arm, even if the difference was not significant ( p = 0.097).

Timing Question

Several phase III trials have examined the question of timing, that is, administration of early versus late RT during the course of combined chemotherapy and RT; however, the issue remains controversial. To try to clarify the issue, several meta-analyses were conducted between 2004 and 2007. The definition of early and late TR differs in these literature-based meta-analyses. The first two meta-analyses were published in 2004 by Fried et al. and Huncharek and McGarry on more than 1500 patients each. Both studies showed an advantage for early RT. In the first study, late TR was defined as beginning 9 weeks after initiation of chemotherapy or after completion of the third cycle of chemotherapy. This meta-analysis showed a statistically significant benefit of 5% of early TR over late TR in terms of 2-year OS (relative risk [RR], 1.17; p = 0.03). Moreover, both studies reported that the best results could be achieved if platinum and etoposide were administrated concomitantly with early RT. In a meta-analysis published by De Ruysscher et al., early RT was defined as beginning within 30 days after the start of chemotherapy. The 2-year and 5-year OS rates were not significantly different (odds ratio [OR], 0.84; 95% CI, 0.56–1.28 vs. OR, 80; 95% CI, 0.47–1.38). However, when the only trial that delivered concurrent nonplatinum-based chemotherapy was excluded, the results were significantly in favor of early RT, with a 5-year survival rate of 20.2% for early versus 13.8% for late RT (OR, 0.64; 95% CI, 0.44–0.92; p = 0.02). Based on the same published data of four randomized trials, De Ruysscher et al. hypothesized that the start of any treatment until the end of RT (SER) was important to consider in SCLC, taking into account both overall duration of RT and timing of TR. They concluded that a shorter time between the initiation of chemotherapy and the subsequent completion of RT was prognostic for survival. There was a significantly higher survival rate in the shorter SER arms; a 5-year OS rate of 20% was reached when the SER was less than 30 days (RR, 0.62; 95% CI, 0.49–0.80; p = 0.0003). Moreover, each additional week of the SER resulted in an overall absolute decrease in the 5-year survival rate of 1.8%. Acute toxicity, and particularly severe esophagitis, is related to timing and SER with a higher incidence in case of early RT and shorter time between start and end of therapy (OR, 0.63; 95% CI, 0.40–1.00; p = 0.05 and OR, 0.55; 95% CI, 0.42–0.73; p = 0.0001, respectively). This SER concept should certainly be further evaluated and considered in designing future studies as repopulation of cells seems to be a major cause of failure. As emphasized by Brade and Tannock in an editorial, repopulation of cells between dose fractions is important for recovery in normal tissue, but repopulation of surviving tumor cells also occurs and offsets tumor cell kill. Repopulation triggered by neoadjuvant chemotherapy may inhibit the effectiveness of subsequent RT.

The same team published an update of their literature-based meta-analysis including 11 trials; there was no difference in 2-year survival, but once again excluding the only nonplatinum-based trial, the benefit of early RT became statistically significant (OR, 0.73; 95% CI, 0.57–0.94; p < 0.05).

Another interesting observation that emerges from these studies is related to treatment compliance. Two studies with the same design and therapeutic regimen have been included in this meta-analysis: the NCI-C trial and the London trial. The survival advantage observed for the early RT group in comparison with the late one (21 months vs. 16 months; p < 0.05, respectively) reported by the NCI-C trial was not confirmed by the London trial (14 vs. 15 months, respectively). However, in the latter study, patients randomized to early chest radiation received significantly less chemotherapy than in the late arm (69% in the early group and 80% in the late one, p = 0.03). In the NCI-C study, the percentage of intended total dose completed was the same for the early and late groups (both 86%). Similar disappointing survival results have also been reported by the Hellenic trial; when analyzing compliance, a significant reduction in completion of planned chemotherapy was reported in patients who had early RT (71% in the early group and 90% in the late group, p = 0.01). Hence, it would seem that only patients who can receive early RT as planned according to the protocol benefit from it. This issue has been thoroughly addressed in an individual data-based meta-analysis that concluded that there was no difference in terms of OS between “earlier or shorter” versus “later or longer” TR when all trials were analyzed together. However, “earlier or shorter” delivery of TR with planned chemotherapy significantly improved 5-year OS at the expense of more acute toxicity, especially esophagitis. The authors highlight that the hazard ratio (HR) for OS is significantly in favor of “earlier or shorter” RT where there was a similar proportion of patients who were compliant with chemotherapy in both arms (HR, 0.79; 95% CI, 0.69–0.91) and in favor of “later or longer” RT among trials with different compliance to chemotherapy (HR, 1.19; 95% CI, 1.05–1.34; interaction test, p < 0.0001). Thereby, the absolute gain between “earlier or shorter” and “later or longer” TR in 5-year OS for similar compliance trials was 7.7% (95% CI, 2.6% to 12.8%) and was –2.2% (–5.8% to 1.4%) for different compliance trials. As expected, “earlier or shorter” TR was associated with a higher incidence of severe acute esophagitis.

Finally, a large retrospective study examined the National Cancer Database to assess practice patterns and survival for TR timing in relation to chemotherapy in 8391 nonmetastatic SCLC patients. This study suggested that early initiation of TR was associated with improved survival (5-year survival rate of 21.9%) compared with late initiation (5-year survival rate of 19.1%, p = 0.01), particularly when hyperfractionated radiation was utilized (28.2% vs. 21.2%, p = 0.004).

Sun et al. published a randomized trial of 219 patients, who were allocated to receive four cycles of cisplatin and etoposide with radiation beginning with the first cycle or the third cycle. It was not included in any of the meta-analyses. Patients received a total dose of 52.5 Gy in 25 daily fractions of 2.1 Gy over 5 weeks. Late RT was not inferior to early RT in terms of complete response rate, which was the main end point (early vs. late: 36.0% vs. 38.0%, respectively). After a median follow-up of 59 months, OS was similar in the two groups (rates at 2 years and 5 years after randomization in the early vs. late radiation arms were 50.7% vs. 56.0% and 24.3% vs. 24.0%, respectively). Thus as recommended by European and North American guidelines, patients with nonmetastatic disease, with good performance status (PS) and good compliance should be treated with concurrent chemoradiotherapy. TR should be administered early in the course of treatment, in fit patients, for whom a good compliance may be expected, preferably beginning with cycle one or two of chemotherapy. According to the study of Sun et al., TR could be administered concomitantly to the third cycle with equivalent results. Nevertheless, this observation should be confirmed in another study because one should be cautious when extrapolating results issued from Asian population studies to non-Asian patients in lung cancer. Chemotherapy should consist of four cycles of a platinum agent and etoposide.

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