Twice-Daily Compared with Once-Daily Thoracic Radiotherapy in Limited Small-Cell Lung Cancer Treated Concurrently with Cisplatin and Etoposide.

Turrisi. The New England Journal of Medicine -- January 28, 1999 -- Volume 340, Number 4

We studied 417 patients with limited small-cell lung cancer. All the patients received four 21-day cycles of cisplatin plus etoposide. We randomly assigned these patients to receive a total of 45 Gy of concurrent thoracic radiotherapy, given either twice daily over a three-week period or once daily over a period of five weeks. Twice-daily treatment beginning with the first cycle of chemotherapy significantly improved survival as compared with concurrent once-daily radiotherapy (P=0.04 by the log-rank test). After a median follow-up of almost 8 years, the median survival was 19 months for the once-daily group and 23 months for the twice-daily group. The survival rates for patients receiving once-daily radiotherapy were 41 percent at two years and 16 percent at five years. For patients receiving twice-daily radiotherapy, the survival rates were 47 percent at two years and 26 percent at five years. Grade 3 esophagitis was significantly more frequent with twice-daily thoracic radiotherapy, occurring in 27 percent of patients, as compared with 11 percent in the once-daily group (P<0.001). Four cycles of cisplatin plus etoposide and a course of radiotherapy (45 Gy, given either once or twice daily) beginning with cycle 1 of the chemotherapy resulted in overall two- and five-year survival rates of 44 percent and 23 percent, a considerable improvement in survival rates over previous results in patients with limited small-cell lung cancer.

More From the Paper

Cisplatin plus etoposide has largely supplanted the older regimens of cyclophosphamide, doxorubicin, and vincristine. Advantages of the cisplatin-etoposide regimen over the older regimen include the absence of toxic effects on intrathoracic organs and the ability to use thoracic radiotherapy concurrently. A meta-analysis of trials comparing chemotherapy alone with combined chemotherapy and thoracic radiotherapy found that combined treatment improved survival among patients with limited small-cell lung cancer, but the best method of integrating thoracic radiotherapy with chemotherapy remained undefined. The optimal total dose, volume, duration, and timing of thoracic radiotherapy have not been tested in prospective trials. Fractionation of the customary once-daily radiotherapy dose into two treatments each day has biologic advantages and has been successful in pilot studies. In vitro, small-cell lung-cancer cell lines have marked radiosensitivity even to small doses of radiation. The dose-response curves for small-cell lung-cancer cell lines lack a shoulder, which means that even at relatively low doses per fraction, small cells are killed exponentially; by contrast, radiation spares cell populations that have a shoulder. For these reasons, multiple small fractions of radiotherapy can kill small-cell cancer while reducing permanent damage to normal tissues. In addition, the use of small fractions may diminish the risks of late effects of radiation.

Pilot studies of twice-daily thoracic radiotherapy suggested that this therapy might have excellent results when combined with cisplatin and etoposide. The two-year survival rate was approximately 40 percent, and the rates of myelosuppression and esophagitis were tolerable: grade 3 granulocytopenia occurred in 70 to 80 percent of the treated patients and grade 3 esophagitis in 35 to 40 percent.

Cisplatin-etoposide combined with once-daily radiotherapy was also examined in pilot studies. The Southwest Oncology Group, using daily fractionated thoracic radiotherapy at a total dose of 45 Gy, reported a two-year survival rate of 40 percent.  Toxic effects were equally reversible in pilot studies of twice-daily or once-daily thoracic radiotherapy.

In this study of limited small-cell lung cancer, we compared once-daily and twice-daily thoracic radiotherapy while holding other variables constant.

Methods

Patients

We enrolled 419 patients in the study, which began in May 1989 and ended in July 1992. Two patients were found to have been enrolled twice. The primary analysis thus included 417 patients and was conducted on an intention-to-treat basis. Of the 417 patients, 36 (21 receiving once-daily radiation and 15 receiving twice-daily radiation) were excluded from the analysis of eligible patients: 7 withdrew from treatment and never received any therapy according to the protocol, and 29 were found to be ineligible. The reasons for ineligibility were the absence of pretreatment tumor measurements (eight patients), extensive disease (six), histologic findings of non-small-cell cancer (six), incomplete staging studies (five), elevated serum aspartate aminotransferase level (one), incorrect diagnosis (one), inadequate performance status(see below; one), and absence of on-study data (one). Thus, 381 patients (185 receiving once-daily treatment and 196 receiving twice-daily treatment) were eligible for a secondary analysis.

For patients to be eligible the small-cell lung cancer had to be confined to one hemithorax, the ipsilateral supraclavicular fossa, or both. Patients with pleural effusions found on chest films were excluded, regardless of cytologic findings, as were patients with contralateral hilar or supraclavicular adenopathy. Staging was done by computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and brain; radionuclide bone scanning; and bilateral iliac-crest bone marrow aspiration and biopsy. Adequate organ function was defined as a white-cell count of at least 4000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a serum creatinine level of less than 1.5 mg per deciliter (130 µmol per liter), serum aspartate aminotransferase and alanine aminotransferase levels less than two times the upper limit of normal, a serum bilirubin level of less than 0.5 mg per deciliter (8.6 µmol per liter), and a forced expiratory volume in one second of at least 1.0 liter. Symptomatic cardiac disease or a myocardial infarction within the previous six months was cause for exclusion. Patients had to be available for follow-up. In all cases, histologic or cytologic findings confirmed the diagnosis of small-cell lung cancer. Patients with prior cancer or prior treatment with either chemotherapy or radiotherapy were ineligible. All patients enrolled in the study gave informed consent.

Chemotherapy

The patients received four cycles of chemotherapy. Each three-week cycle consisted of 60 mg of cisplatin per square meter of body-surface area on day 1 and 120 mg of etoposide per square meter on days 1, 2, and 3. No dose adjustments were permitted for the first two cycles. During cycles 3 and 4, the dose of etoposide was reduced for patients with grade 4 toxic effects, febrile neutropenia or documented infection, or thrombocytopenia associated with bleeding. The dose of cisplatin was reduced during cycles 3 and 4 for patients with serum creatinine levels of 1.6 to 2.5 mg per deciliter (140 to 220 µmol per liter) and was further reduced if the levels were 2.6 mg per deciliter (230 µmol per liter) or higher.

Thoracic Radiotherapy

In both groups, the total dose of thoracic radiotherapy was 45 Gy for each patient. Patients receiving once-daily therapy received 1.8 Gy daily in 25 treatments over a period of five weeks. Accelerated twice-daily thoracic radiotherapy involved the administration of 1.5 Gy in 30 treatments over a period of three weeks. In both groups, thoracic radiotherapy began concurrently with the first cycle of chemotherapy.

The target volume for thoracic radiotherapy, which was similar in both groups, included the gross tumor, as defined by the chest CT scan, and the bilateral mediastinal and ipsilateral hilar lymph nodes. Irradiation of uninvolved supraclavicular fossae was forbidden. The inferior border extended 5 cm below the carina or to a level including ipsilateral hilar structures, whichever was lower. The clinically determined volume was expanded by a margin of 1 to 1.5 cm.

Radiotherapy treatment used linear accelerators; no cobalt-60 machines were allowed. Patients underwent treatment setup with radiotherapy simulators to mark field borders before treatment. Reduction of the field to conform to a smaller target volume after treatment was not allowed.

Interruptions of thoracic radiotherapy were discouraged, but it was interrupted when patients had platelet counts under 50,000 per cubic millimeter, weight loss of 4.5 kg (10 lb) or more (grade 2), or hospitalization for neutropenic fever or sepsis, but not when patients had difficulty swallowing or fever with low white-cell counts.

Prophylactic Cranial Irradiation

Systemic therapy was scheduled to last 12 weeks. The stage of disease was then determined again according to the results of chest radiography and head and chest CT. Because of the high frequency of brain metastases (50 percent), patients with a complete response were offered prophylactic cranial irradiation, despite reports of neurotoxicity. This treatment consisted of 10 doses of 2.5 Gy to the midplane of the brain over a two-week period, for a total of 25 Gy.

Survival

As of this writing, the median follow-up was almost eight years, and the minimal potential follow-up was approaching five years. Of the 417 patients, 335 had died: 175 patients who received once-daily therapy (85 percent) and 160 patients who received twice-daily therapy (76 percent). The median survival was 20 months for all patients, 19 months for those receiving once-daily therapy, and 23 months for those receiving twice-daily therapy. The two-year survival rate was 44 percent for all patients, 41 percent for those receiving once-daily therapy, and 47 percent for those receiving twice-daily therapy (standard error for both groups, 3 percent). The five-year survival rate was 23 percent for all patients, 16 percent for those receiving once-daily therapy, and 26 percent for those receiving twice-daily therapy (standard error for both groups, 3 percent).

Discussion

In this trial of chemoradiotherapy for small-cell lung cancer, we gave four cycles of cisplatin-etoposide chemotherapy concurrently with 45 Gy of thoracic radiation administered twice daily or once daily. The survival rate among the 417 patients exceeded that in any previously reported large, randomized trial of chemotherapy and radiotherapy for this disease. After five years of follow-up, only 335 deaths have been reported, even though 353 deaths were anticipated at two years. Survival was significantly better in the group receiving twice-daily radiotherapy than in the group receiving once-daily radiotherapy (P=0.04). The magnitude of the difference between the groups at two years was quite small and clinically insignificant, but with further follow-up to five years, the difference between the treatments favored the twice-daily treatment group by 10 percent (standard error, 4 percent).

Many assert that adding thoracic radiotherapy to chemotherapy increases toxicity without improving survival. A meta-analysis of chemotherapy alone as compared with chemotherapy and radiotherapy found that the addition of radiotherapy improved the survival rate at three years only slightly. The trials included in the meta-analysis all used cyclophosphamide-based or doxorubicin-based regimens; in none did initial treatment include cisplatin and etoposide.

Although it was introduced in the late 1970s, the combination of cisplatin and etoposide emerged as primary therapy only in the early 1980s. A clear advantage of cisplatin plus etoposide is that the combination can be given concurrently with relatively full doses of thoracic radiotherapy, with less morbidity than occurs with doxorubicin-based  or cyclophosphamide-based  regimens. The meta-analysis identified no differences regarding the timing of thoracic radiotherapy and chemotherapy.

The best method of integrating chemotherapy and thoracic radiotherapy remains unknown. Because small-cell lung cancer responds well to thoracic radiotherapy, only moderate doses of radiation (40 to 50 Gy) have been used in most trials. Choi et al. (reported that esophagitis limited treatment when the total dose from twice-daily treatment exceeded 45 Gy, and that a total dose of 70 Gy could be tolerated with once-daily treatments. Papac and colleagues reported a rate of local failure of only 3 percent with 60 Gy fractionated once daily, but with only a small gain in median survival. Without radiotherapy, local failure occurs in 90 percent of patients.Our study verifies that local failure remains an important problem, but we found that improved local therapy contributes to both local control and survival.

The timing of concurrent radiotherapy and chemotherapy may be an important therapeutic variable. We initiated therapy at the same time as the first cycle of cisplatin plus etoposide. Others have begun radiotherapy at the time of later cycles of chemotherapy. Murray et al. reported that cisplatin-etoposide therapy in combination with radiotherapy beginning with cycle 2 was superior to concurrent radiotherapy beginning with cycle 6. Recently, Takada and colleagues verified that beginning radiotherapy concurrently with etoposide was superior to beginning radiotherapy after the completion of four cycles of chemotherapy. The Cancer and Leukemia Group B trial compared radiotherapy starting with cycle 1 of chemotherapy and radiotherapy starting with cycle 4. This 1987 trial used cyclophosphamide-based chemotherapy. It found the best survival when the radiotherapy began with cycle 4. Others, particularly in Europe, found that sequential strategies were superior to concurrent treatment, which was associated with excess toxicity. Cyclophosphamide-based or doxorubicin-based chemotherapy continues to be used in these studies, which may explain the inability to integrate concurrent thoracic radiotherapy successfully. The two-year survival in these trials is about half the rate in our study.