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Combined Chemoradiation Therapy for Limited-Stage Small-Cell Lung Cancer

Combined Chemoradiation Therapy for Limited-Stage Small-Cell Lung Cancer

ABSTRACT: After nearly 4 decades of use in treating small-cell lung cancer (SCLC), thoracic radiation has become integral to the management of limited-stage disease. Many prospective randomized trials have demonstrated that adding thoracic radiation therapy to chemotherapy improves locoregional control and survival at 3 and 5 years. This has resulted in a greater appreciation of the role of thoracic radiation in the treatment of SCLC. Currently, the most commonly used regimens incorporate concurrent administration of cisplatin (Platinol) and etoposide (VePesid) chemotherapy and radiation doses of 45 Gy given over 5 weeks. However, issues concerning timing, volume, and dose fractionation remain to be resolved. [ONCOLOGY 13(Suppl 5):107-115, 1999]


Introduction

Approximately 20% of new lung cancer cases are
small-cell lung cancer,[1] composed of cells with small, round or spindle-shaped,
darkly staining nuclei and scant cytoplasm. Small-cell lung cancer
manifests as a central tumor with early dissemination to the regional
lymph nodes and distant sites. It has a large growth fraction, grows
rapidly, is associated with paraneoplastic syndromes (syndrome of
inappropriate secretion of antidiuretic hormone, Cushing’s
syndrome, and Eaton-Lambert syndrome), develops almost exclusively in
smokers, and is sensitive to chemotherapy.[2] Even when the disease
is extensive, approximately 60% of patients will respond to intensive
chemotherapy. The results of initial chemotherapy trials showed
median survival of patients with limited-stage disease treated with
combination chemotherapy to be approximately 12 months, compared with
3 months for those receiving best supportive care.[3] Long-term
survival is rare, however, with fewer than 10% of patients alive at
10 years.

The American Joint Committee on Cancer’s TNM staging system has
been used to stage non–small-cell lung cancer with reasonable
prognostic predictive value. The system has not been universally
adopted for small-cell lung cancer because the majority of small-cell
lung cancer patients present with stages beyond IIIA, and because
small-cell lung cancer is considered a systemic disease characterized
by rapid proliferation and early distant dissemination. Thus,
clinicians have adopted the simple two-stage system of the Veterans
Administration Lung Cancer Study Group, limited and extensive
disease. Limited stage is defined as tumor confined to one hemithorax
and the regional nodes, and is based on whether all detectable
disease can be encompassed by a tolerable, single continuous
therapeutic radiation port. Extensive-stage disease encompasses
demonstrable extra-thoracic disease. A better understanding of the
biology of small-cell lung cancer and of its patterns of failure has
provided the principles for its management.[2,4] Since small-cell
lung cancer is a systemic disease, current treatment of limited
disease consists of chemotherapy to manage undetected micrometastases
present at diagnosis and thoracic radiation therapy to improve
locoregional tumor control. The presence of pleural effusions or
involved supraclavicular or contralateral hilar nodes has been
considered limited disease in some trials and extensive disease in
others; such differences must be kept in mind when results from
different institutions and cooperative groups are compared.

Impact of Thoracic Radiation on Local Control
and Survival

Thoracic radiation therapy has been used to treat small-cell lung
cancer since the 1960s, but surgery was the treatment of choice for
patients with all types of lung cancer until approximately 25 years
ago. It was abandoned following the results of a randomized trial
conducted in the United Kingdom by the Medical Research Council that
compared radiation therapy alone with surgery alone in patients who
had limited-stage disease.[5] None of the patients were alive at 10
years in the surgery group compared with 5% alive in the radiation
group. Additionally, a review of the outcome of a large number of
small-cell lung cancer patients treated in the United States whose
disease was thought to be surgically resectable revealed absolutely
no difference in survival whether or not surgery was performed.[6]

Just as the discovery of the radiosensitivity of small-cell lung
cancer shifted local management of limited disease from surgery to
radiation,[5] realization of the propensity of small-cell lung cancer
for early systemic metastases also led to the assessment of
chemotherapy. The observation of high overall and complete response
rates in limited-disease patients who received only chemotherapy
initially led some to question the value of local therapy with
thoracic radiation. In 1969, the Veterans Administration Lung Cancer
Study Group demonstrated that cyclophosphamide (Cytoxan) treatment
could double median survival in patients with extensive-stage
disease—to 6 months.[7] However, the high frequency of
locoregional recurrence (up to 80% of limited-stage patients) and the
poor survival of patients who received only chemotherapy led to
investigations of the role of thoracic radiation therapy in the
management of small-cell lung cancer.

Several single-institution and cooperative group randomized trials
were initiated in the United States to test the role of thoracic
radiation therapy in the treatment of limited-stage small-cell lung
cancer (Table 1).[8-20] The cooperative group randomized trials
include those conducted by the Southeast Cancer Study Group
(SECSG),[19] the National Cancer Institute,[10] the Cancer and
Leukemia Group B (CALGB),[8] the Eastern Cooperative Oncology Group
(ECOG),[13] and the Southwest Oncology Group (SWOG).[14] In each,
patients with limited disease were randomized to chemotherapy with or
without thoracic radiation. All results showed that chest radiation
improved local control, and all but Osterlind,[11] LeBeau,[18] and
the SWOG trial[14] reported borderline improvement or significantly
improved survival with combined-modality treatment.

Two meta-analyses have also shown a small but significant improvement
in survival for patients treated with chemotherapy and thoracic
radiation vs those treated with chemotherapy alone.[21,22] Pignon et
al obtained data on 1,862 individual patients from the American,
European, and Japanese investigators who had conducted 13 randomized
studies.[21] They then updated the survival rates and performed an
intent-to-treat analysis that included all patients; they found that
treatment with thoracic radiation was associated with a 14% reduction
in the risk of death (P = .001). In addition, the 3-year survival
rate improved for patients treated with chemotherapy and radiation
therapy to 14.3% compared with 8.9% for patients who received
chemotherapy alone. No significant survival differences emerged,
however, when the timing of thoracic radiation (early vs late) and
the schedule of chemotherapy and radiation (sequential vs concurrent)
were evaluated.

Moreover, this intent-to-treat analysis may have underestimated the
impact of radiation on improving survival. Warde and Payne analyzed
11 published trials and discovered significantly better survival for
patients who received chemotherapy and radiation therapy.[22] The
odds ratio was 1.56 for patients treated with chemoradiotherapy (P
< .001). Comparison of the 2-year survival rates showed a 5.4%
improvement for patients who received radiation therapy. The 5%
increase in absolute survival in patients receiving thoracic
radiation represents a more than 50% relative improvement in the
survival rate observed with chemotherapy alone. Local control rates
were doubled from approximately 25% with chemotherapy alone to
approximately 50% with the addition of thoracic radiation. Neither
study reported the “best” chemotherapy and radiation
regimen. However, the use of cisplatin (Platinol) and etoposide
(VePesid) (PE) and concurrent thoracic radiation has been associated
with the best survival results observed thus far.

Despite these findings demonstrating the benefits of thoracic
radiation on local control and survival in limited-stage small-cell
lung cancer, the chest relapse rate remains unacceptably high, with a
60% actuarial risk of local recurrence by 3 years. Further
enhancement of locoregional control may increase the proportion of
long-term survivors. Issues like the optimal integration of thoracic
radiation with chemotherapy (sequential vs concurrent vs
alternating), the appropriate volume, and dose/fractionation need to
be explored further.

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