Use of thoracic radiotherapy in the treatment of limited stage small cell lung cancer

INTRODUCTION — The natural history of small cell lung cancer (SCLC) is one of rapid proliferation and early dissemination. This affects both the staging system and the therapeutic approach, which are different from those used for non-small cell lung cancer (NSCLC).

Patients with SCLC are divided into those with limited versus extensive stage disease. Limited stage disease is defined as disease confined to one hemithorax, ie, disease that can be included in a "tolerable" radiation field. Approximately one-third of patients present with clinically determined "limited disease"; however, many of these patients have subclinical metastatic disease.

Chemotherapy is the mainstay of treatment for patients with SCLC because of this proclivity for early dissemination. Considerable effort is being devoted to the development of more efficacious chemotherapy strategies to control systemic disease.

In addition to chemotherapy, there is a significant role for radiotherapy in the treatment of limited stage SCLC. Local tumor progression occurs in up to 80 percent of such patients treated with chemotherapy alone. The high recurrence rate can be significantly reduced by the addition of thoracic radiation therapy, and survival improved compared with chemotherapy alone. In addition, there may be a role for prophylactic cranial irradiation (PCI) in selected patients to prevent intracranial relapse.

This topic review will describe the role and optimal delivery of thoracic radiation therapy (TRT) for patients with limited stage SCLC. The efficacy of adding TRT to systemic chemotherapy and the use of PCI in the treatment of limited stage SCLC are addressed separately.

EFFICACY — Several randomized clinical trials have addressed the role of TRT for limited stage SCLC, but they have provided conflicting results regarding the benefit of adding TRT to chemotherapy. These discrepancies are partly due to differences in the details of treatment, including:

  bullet Total radiation dose
  bullet Dose fractionation
  bullet Timing of TRT
  bullet Radiation treatment fields
  bullet The agents and doses of chemotherapy

Meta-analysis has shown that the addition of TRT results in a small, statistically significant improvement in survival compared with the use of chemotherapy alone. A meta-analysis of 13 randomized trials found that the use of combined chemotherapy and TRT resulted in a statistically significant absolute survival benefit of 5.4 percent at three years, an effect that was greatest for patients less than 55 years old. The chemotherapy regimens differed among the studies, as did the TRT doses and delivery schedules.

A second meta-analysis of only 11 of these trials also evaluated the effect on local control. The addition of TRT was associated with an absolute overall improvement in local control of 23 percent (two year local control rates 47 versus 24 percent, 95% CI 16.5 to 34.1 percent). There was also a 5 percent absolute improvement in survival at two years (20 versus 15 percent).

In both analyses, the survival benefit with TRT was achieved at the cost of an increase in toxicity.

The survival benefit associated with the use of thoracic RT outside of clinical trials was illustrated in a review from the National Cancer Data Base. For patients with limited stage SCLC, the five-year survival rate for the 6752 patients diagnosed in 2000 was significantly higher in patients treated with TRT plus chemotherapy (13.3 versus 5.7 percent in those receiving chemotherapy alone).

METHOD OF DELIVERY — Treatment regimens vary according to dose, treatment volume, and fractionation schedule.

Dose — Several studies using conventional TRT for SCLC have provided evidence of a dose-response effect. As an example, a randomized trial compared the efficacy of a total dose of 25 versus 37.5 Gy. The treatments were given with daily fraction sizes of 2.5 Gy, which is higher than the conventional fraction size of 1.8 to 2.0 Gy. Actuarial local progression at two years was higher for the 25 Gy arm (80 versus 69 percent [p = 0.04]).

In a retrospective analysis of SCLC patients treated with standard fractionation, improved local control rates were observed as the total dose delivered increased from 30 Gy to 50 Gy. Reported 2.5 year local control rates were 16 percent for patients who received 30 Gy, compared with 63 percent for patients who received 50 Gy. A third study showed a local control rate of 96 percent for 26 patients with limited stage SCLC who received 60 Gy TRT.

Most standard TRT regimens that employ conventional fractionation (once daily treatment) involve doses on the order of 50 to 60 Gy, using daily fractions of 1.8 to 2.0 Gy. However, further dose escalation is under active study. As an example, a phase II study demonstrated the safety of 70 Gy in 35 once daily fractions over seven weeks concurrent with chemotherapy in patients with limited stage SCLC.

Treatment volume — Whether the appropriate TRT treatment fields should cover the original prechemotherapy tumor volume (with or without uninvolved nodal regions) or the postchemotherapy tumor volume is an unresolved issue. The Southwest Oncology Group (SWOG) performed a randomized trial in 191 patients with limited stage SCLC who had a partial response or stable disease following induction chemotherapy. Patients were randomized to TRT fields which included either the prechemotherapy or the postchemotherapy tumor volumes. This study failed to demonstrate a significant difference in failure patterns or median survival between the two regimens. However, this study was flawed because of a high patient attrition rate and the inclusion of patients who did not respond to chemotherapy, so that there was no difference between their prechemotherapy and postchemotherapy tumor volumes.

There were no apparent differences in severe drug-related toxicity or severe radiation pneumonitis between the TRT groups. However, severe complications related to myelosuppression were higher for patients treated with wide field TRT (17 of 93, 18 percent) than for those treated with reduced field TRT (8 of 98, 8 percent).

A retrospective review of 59 patients with limited stage SCLC treated at the Mayo Clinic also failed to show a significant difference in the rates of local recurrence, progression-free survival, or overall survival for patients treated with TRT fields which covered the prechemotherapy versus postchemotherapy tumor volumes. In this series, all local failures occurred within the TRT fields. There were no failures at the margin of a field, which would have implied that the treated volume was too small.

Thus, although the data are limited, the use of limited TRT fields appears reasonable. This approach may reduce the rate and severity of toxicity from combined modality therapy, without jeopardizing local control rates. Such toxicity issues will have increasing importance as both radiation and chemotherapy doses are intensified and agents with potential lung toxicity are added to chemotherapy regimens.

Fractionation schedule — Standard radiation fractionation schedules employ single daily treatments of 1.8 to 2.0 Gy, five times per week, over a continuous course for 5 to 6 weeks. Accelerated hyperfractionation schedules refer to delivery of a radiation course over a shorter total treatment time (acceleration), and with a greater number of treatment fractions (hyperfractionation). Radiation is delivered two or three times daily, and often the individual fraction sizes are reduced, eg, 1.5 Gy rather than 2.0 Gy per treatment.

  Accelerated fractionation — Several groups have investigated the use of accelerated hyperfractionation radiotherapy schedules in the treatment of SCLC. Accelerated hyperfractionated radiation therapy reduces the opportunity for tumor cell regeneration during treatment by shortening the overall treatment time. However, acute toxicities are greater to normal tissues. Late toxicities should be similar, given that late effects of radiation are more dependent on dose per fraction and total dose, than overall treatment time.

Uncontrolled trials comparing once daily to twice daily fractionation have produced conflicting results. Two separate series report 57 and 65 percent two-year survival rates, respectively , while a third, which used hyperfractionated TRT delivered late in the treatment course, reported only 19 percent two-year survival.

Unfortunately, two randomized trials have also failed to resolve this issue:

  bullet The Eastern Cooperative Oncology group randomly assigned 417 patients with limited stage SCLC to 45 Gy of concurrent TRT, either as once-daily treatments for 5 weeks, or twice-daily treatments over 3 weeks. In both groups, radiation was begun concurrent with cycle one of four planned 21-day cycles of cisplatin plus etoposide. After a median follow-up of nearly eight years, median survival was significantly longer in the group treated with twice-daily TRT (23 versus 19 months; two year survival rate, 47 versus 41 percent). However, esophagitis of such severity that patients could not swallow solids or required opiates or feeding tube placement was significantly more common the twice-daily TRT group (27 versus 11 percent). Worsened hematologic and pulmonary toxicities, reported in prior trials of hyperfractionation, did not differ significantly in this study.

This study showed that 45 Gy given twice daily was more efficacious than 45 Gy given once daily. It did not answer the questions of the relative efficacy of 45 Gy twice daily compared to the standard of once daily treatment to a higher dose (50 to 60 Gy). Nonetheless, it established 45 Gy given twice daily over three weeks as a standard regimen for the treatment of limited stage SCLC.

  bullet In a second trial by the North Central Cancer Treatment Group, 262 patients with limited stage SCLC were randomly assigned to once daily (50.4 Gy in 28 fractions) or twice daily (48 Gy in 32 fractions, with a two week break after 24 Gy) TRT beginning on cycle four of a planned six courses of etoposide and cisplatin. Neither local control nor survival (two-year survival rates 45 versus 47 percent) was better in the hyperfractionated group. Although it was postulated that the late delivery of TRT may have compromised the results, a later report documented very favorable five-year survival rates in both the hyperfractionation and conventional fractionation groups (22 and 21 percent, respectively).

Although severe treatment-related esophagitis was twice as frequent in the hyperfractionated group, a later quality of life analysis using Q-TWiST (Quality Time Without Symptoms or Toxicity) methodology demonstrated that the differences in the incidence and severity of toxicity between the two arms were inconsequential.

  Split course treatment — Hyperfractionated TRT has also been delivered as a split course treatment with alternating regimens of chemotherapy and TRT. In a pilot study by the Eastern Cooperative Oncology Group (ECOG), TRT consisting of 1.5 Gy given twice daily over five continuous days was delivered after the first, second, and third cycles of EP. The two-year progression-free survival for this series was 47 percent. The Groupe Lyonnais d'Oncologique Thoracique reported the results of a similar hyperfractionated TRT schedule alternating with chemotherapy in the treatment of 76 patients.. The median survival for this group was 14 months, and the one year disease-free survival was 42 percent.

The use of hyperfractionation regimens is considerably more complex, increases patient daily treatment time, and may be more expensive than standard fractionation. The ultimate role for such alternative fractionation schedules remains undefined.

INTEGRATION WITH CHEMOTHERAPY — The best method of integrating chemotherapy and TRT remains controversial. Sequential, concurrent, and alternating approaches have all been studied. Sequential therapy refers to treatment with one modality at a time, while concurrent therapy indicates that chemotherapy and TRT are delivered simultaneously. Alternating therapy refers to delivery of TRT on days when chemotherapy is not given, in such a fashion that the timing of the next chemotherapy cycle is not altered. In this treatment scheme, TRT is necessarily delivered as a split course.

The concurrent and alternating approaches are intuitively appealing because they enable delivery of multiple chemotherapy cycles without interruption. Insofar as SCLC is a systemic disease, the optimal delivery of systemic treatment is crucial. However, concurrent or alternating regimens have been associated with more toxicity (eg, myelosuppression, esophagitis, and pneumonitis) when compared with sequential treatment. This increased toxicity can be justified only if a beneficial impact on outcome is achieved. However, a survival benefit for concurrent or alternating as compared to sequential schedules has not been consistently supported by the clinical data:

  bullet Of the randomized trials that indicate a significant survival benefit for combined modality therapy compared to chemotherapy alone for limited stage disease, three used concurrent or alternating radiotherapy, while two used sequential therapy .

  bullet At least two randomized trials have directly addressed the issue of concurrent versus sequential or alternating chemotherapy and radiation IN SCLC. In one trial that randomly assigned 335 patients with limited stage disease to alternating or sequential schedules of chemotherapy (cyclophosphamide, doxorubicin, and etoposide) and irradiation, there was no survival benefit with alternating therapy (median survival 15 versus 14 months with sequential therapy).

In Japanese Clinical Oncology Group study 9104, 231 patients with limited stage SCLC were randomly assigned to four cycles of cisplatin plus etoposide every three or four weeks with either sequential or concurrent thoracic radiation therapy (45 Gy over three weeks in both groups). The concurrent group began radiation on day two of the first chemotherapy cycle. There was a trend towards improvement in median survival that favored concurrent radiation (27 versus 20 months, p = 0.097).

The two, three, and five year survival rates for the sequentially and concurrently treated patients were 35, 20, and 18 percent, and 54, 30, and 24 percent, respectively. Unfortunately, the study was statistically powered to detect a 50 percent improvement in survival with concurrent radiation therapy (12 to 18 months), when in fact, the median survival exceeded 18 months in both arms.

An early meta-analysis of 15 randomized trials evaluating the contribution of thoracic radiation therapy to outcomes in SCLC indirectly compared the method of treatment integration (sequential versus alternating or concurrent). There was no statistically significant difference in outcome between the two approaches.

The lack of consistently demonstrated benefit with these regimens may be in part due to the high frequency with which side effects diminished the total treatment given. However, in the previously discussed Japanese trial comparing sequential and concurrent radiation with cisplatin and etoposide, severe esophagitis was infrequent although more common in the concurrently treated group (9 versus 4 percent). Rates of pulmonary toxicity, and treatment-related death rates were similar. Furthermore, although the actual dose intensities for both cisplatin and etoposide were 1.3-fold higher in the sequential arm (because treatment cycles were administered every three rather than four weeks), the actual dose intensity as a proportion of the planned dose intensity was over 90 percent in both groups.

On the other hand, later studies suggest that early integration of TRT concurrent with chemotherapy as compared to delayed TRT is associated with a significant survival benefit.

EARLY VERSUS LATE TIMING IN COMBINED MODALITY TREATMENT — Treatment of SCLC generally begins with chemotherapy for several reasons:

  bullet There may be an advantage to early treatment of subclinical metastatic disease.
  bullet Initial treatment with chemotherapy enables evaluation of disease response to chemotherapy.
  bullet Treatment can often be initiated faster with chemotherapy than with TRT.

However, data are conflicting about whether to add TRT early or late in the treatment course. A Cancer and Leukemia Group B (CALGB) trial published in 1987 showed a small advantage for delayed delivery of TRT. This trial randomized patients with limited stage SCLC to one of the following three regimens:

  bullet TRT delivered concurrently with the first cycle of chemotherapy (early TRT)
  bullet TRT delivered concurrently with the fourth cycle of chemotherapy (late TRT)
  bullet Chemotherapy alone

Survival for patients treated with chemotherapy alone was significantly inferior to the two concurrent approaches. Although there was no statistically significant survival difference between the two concurrent arms, there was a trend favoring the regimen with late delivery of TRT (p = 0.08). However, the delivery of early TRT was associated with significant toxicity (primarily neutropenia), which resulted in subsequent chemotherapy dose reductions. Therefore the suggested survival benefit for the late TRT regimen in this older report may be related to the overall chemotherapy dose delivered rather than to the timing of the TRT delivery. Modern regimens (with the availability of growth factor support) more successfully deliver full dose chemotherapy together with RT.

A subsequent randomized trial from the National Cancer Institute of Canada published in 1993 compared two concurrent chemotherapy and TRT regimens for patients with limited stage SCLC.  In one arm, the TRT was delivered "early" (with the second cycle), and in the other arm TRT was delivered "late" (with the sixth cycle). In both arms, patients received six cycles of chemotherapy, consisting of cyclophosphamide, doxorubicin, and vincristine (CAV) alternating with etoposide and cisplatin (EP) every three weeks. TRT consisted of 40 Gy given in 15 fractions over three weeks.

Both progression-free survival (PFS) and overall survival (OS) were statistically significantly greater with early compared to late TRT: three-year PFS of 26 versus 19 percent; three-year OS of 29.7 versus 21.5 percent. Unlike the CALGB study in which patients in the early TRT group received lower total doses of chemotherapy, patients in both treatment arms of the NCI Canada study received similar chemotherapy doses.

A meta-analysis evaluated seven trials comparing early (beginning before nine weeks after the initiation of chemotherapy) to late RT (beginning later than nine weeks) in 1524 patients. The major finding was a small but significant improvement in two-year survival for early compared to late TRT (relative risk [RR] 1.17). This corresponded to an absolute survival benefit of 5 percent at two years.
Subset analyses revealed the following additional findings:

  bullet The survival benefit was seen only in patients treated with hyperfractionated RT (RR 1.44 and 1.39 at two and three years); there was no benefit from once-daily fractionation.
  bullet The survival benefit was seen only in patients treated with platinum-based chemotherapy (RR 1.30 and 1.35 at two and three years); there was no significant benefit with non-platinum-based regimens).

A Cochrane analysis showed a nonsignificant trend in favor of early TRT.

Overall, the data suggest that early delivery of TRT (concurrent with the first or second cycle of chemotherapy) is preferable to delivery later in the treatment course.

RECOMMENDATIONS — TRT should be part of the treatment strategy for limited stage small cell lung cancer in most patients. However, due to the modest survival benefit (approximately 5 to 7 percent)   and increased toxicity of combined modality treatment, it may be prudent to consider withholding TRT for certain patients deemed to be at high risk for treatment-related complications.

The optimal method of integrating chemotherapy and TRT is still uncertain, but concurrent or alternating regimens are appealing because the efficacy of TRT may be enhanced by the use of radiosensitizing chemotherapeutic agents. Furthermore, these delivery schedules do not interrupt the delivery of chemotherapy. There is a clear suggestion that delivery of TRT early in the treatment course is preferable.

The benefit of hyperfractionated TRT remains unproven, and is worthy of further investigation, such as that being conducted in the Intergroup randomized trial. Outside of a protocol setting, acceptable dose regimens include 45 Gy given twice daily in 1.5 Gy fractions, and 50 to 60 Gy given once daily in 1.8-2 Gy fractions. Limited treatment fields which include sites of known gross disease are probably sufficient.