1 University Hospital Groningen, 2 Radiotherapeutic Institute Zwolle, 3 Martini Hospital Groningen, 4 Radiotherapeutic Institute and Medical Center Leeuwarden, 5 Department of Statistics, Leiden, and 6 Comprehensive Cancer Center North-Netherlands, The Netherlands
Received 20 May 2003; revised 4 November 2003; accepted 17 December 2003
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ABSTRACT |
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To determine the radiosensitizing effect of prolonged exposure of carboplatin in patients with locally unresectable non-small-cell lung cancer (NSCLC).
Patients and methods:
Patients with histologically proven NSCLC, performance score <2, weight loss <10%, and normal organ functions were randomized between carboplatin 840 mg/m2 administered continuously during 6 weeks of radiotherapy or thoracic radiotherapy alone (both 60 Gy). Toxicity was evaluated with National Cancer Institute Common Toxicity Criteria (NCI CTC) and the Radiation Therapy Oncology Group (RTOG) criteria. Quality of life was measured with European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30/LC13 questionnaires.
Results:
One-hundred and sixty patients were included. Pathologically confirmed persistent tumor was present in 53% of patients in the combination arm versus 58% in the radiotherapy alone arm (P = 0.5). Median survival in the combination arm was 11.8 [95% confidence interval (CI) 9.314.2] months and in the radiotherapy alone arm 11.7 (95% CI 8.115.5) months; progression-free survival was not different between arms [6.8 and 7.5 months, respectively (P = 0.28)]. Acute toxicity was mild, late toxicity was radiation-induced cardiomyopathy (three patients) and pulmonary fibrosis (five patients). Quality of life was not different between arms, but in all measured patients cough and dyspnea improved, pain became less, and slight paresthesia developed 3 months after treatment.
Conclusion:
Addition of continuously administered carboplatin as radiosensitizer for locally unresectable NSCLC does not improve local tumor control or overall survival.
Key words: carboplatin, NSCLC, radiosensitization, radiotherapy, stage III
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Introduction |
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Patients and methods |
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Study design
Patients were stratified according to stage, performance status and hospital. Block randomization was used and treatment allocation was performed by telephone into either carboplatin and radiation, or radiation alone.
Treatment schedules
Radiotherapy was delivered on the primary tumor with a 2 cm margin around the tumor volume and ipsilateral hilum and to the mediastinum with a 2 cm margin around the involved mediastinum as estimated on CT scan. Treatment was performed by the two isocentric parallel opposed field technique (anteriorposterior and posterioranterior) during the first 20 fractions up to 40 Gy, followed by a boost of 20 Gy with a CT-treatment plan for the last 2 weeks up to a total of 60 Gy, using 625 MV photons. The original tumor volume was treated with 2 Gy per day in five fractions per week. The planned dose of the first 40 Gy was calculated without correction for the lung inhomogeneity, the boost dose was 20 Gy in 10 fractions without correction for lung homogeneity or 22 Gy with correction for lung inhomogeneity. The dose specifications were in accordance with the ICRU-29 report. The dose to the spinal cord did not exceed 50 Gy in 25 fractions (/ß = 2).
Carboplatin was delivered in a dose of 20 mg/m2/day continuously during 6 weeks of radiotherapy. A 20 ml syringe with carboplatin in 5% glucose was supplied to each patient every 48 h, also during the weekends. The syringe was connected to a venous access port, which was implanted subcutaneously under local anaesthesia before treatment and connected to the subclavian vein. The needle and extension tube were renewed in the third treatment week.
Assessments
Pretreatment assessment included staging procedures, medical history and physical examination, complete blood count, platelets, electrolytes, renal and liver function tests, lung function tests and quality of life. During treatment, once every 2 weeks a complete blood count was performed and twice during the 6-week treatment renal and liver functions were tested. After treatment, tumor response was measured with CT-scan according to World Health Organization (WHO) criteria and by endobronchial evaluation. Bronchoscopical findings were defined as presence or absence of endobronchial tumor and a description of other mucosal abnormalities from which biopsies had been taken. In case biopsies were negative or not available, macroscopic mucosal evaluation prevailed in the bronchoscopical evaluation. Overall tumor response was assessed with both CT and bronchoscopical measurements.
Follow-up assessments were every 3 months in the first year, thereafter every 6 months for 2 years and then yearly with history, physical examination, blood tests, chest X-ray and appropiate imaging tests or biopsies in case of suspected metastases.
Toxicity was scored with the National Cancer Institute Common Toxicity Criteria (NCI CTC) and for acute and late radiation toxicity Radiation Therapy Oncology Group (RTOG) criteria were used. Pulmonary function was measured before and 3 months after treatment. Quality of life was assessed with European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30/LC13 questionnaires before, after and 3 months after treatment.
Statistics
In NSCLC the 2-year survival after thoracic radiation is 15% [4]. The study was designed to have 85% power to detect 15% difference in the 2-year survival. The accrual goal was 265 randomized patients. During the study the independent Data Monitoring Committee (DMC) periodically reviewed safety and efficacy data. Survival was calculated from the date of randomization to the date of death or last follow-up. Progression-free survival was defined as the time from randomization to the first date of progressive disease, relapse or death. KaplanMeier method with two-sided log-rank test was used for analyzing survival data. For patient characteristics, response rates and toxicity chi-square square tests were used. Quality of life data for both treatment groups were analyzed with ANOVA and changes of the last assessment from baseline was compared with paired t-test. P <0.05 was considered as statistically significant.
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Results |
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Endobronchial antitumor efficacy
Bronchoscopical evaluation before treatment was performed in 150 patients. Ten patients had their diagnosis by other diagnostic routes. One-hundred and seventeen patients had centrally located and therefore bronchoscopically evaluable tumors and in 33 patients bronchoscopical findings were normal.
After treatment 117 patients had a repeat bronchoscopy. Normal endobronchial findings were observed in 32 patients and 85 patients had visible tumor and/or strongly inflammed mucosa at the site of the original tumor. There was no difference in pathologically confirmed endobronchial tumor response between both treatment arms: 32 of 60 (53%) bronchoscopically evaluable patients had endobronchial tumor in the combination arm and 33 of 57 (58%) in the radiotherapy alone arm (P = 0.5). In 31 of 117 patients endobronchial biopsies revealed no or inadequate tissue procurement and in these patients only endobronchial evaluation was taken for overall bronchoscopical response measurement.
Combining CT and bronchoscopy results revealed an overall tumor response of 40% (95% CI 3149) in the combination arm and 45% (95% CI 3654) in the radiotherapy arm (not significant; 117 patients).
Survival
The median survival in the combination arm was 11.8 (95% CI 9.314.2) months and in the radiotherapy alone arm 11.7 (95% CI 8.115.5) months (Figure 1). The 2-year overall survival was 20 and 28%, respectively. Progression-free survival was 6.8 (95% CI 5.78.0) and 7.5 (95% CI 3.611.3) months, respectively (P = 0.28). Local control in the combination arm and radiotherapy alone arm at 1 and 2 years was 60 and 72% and 35 and 38%, respectively. Second-line chemotherapy was administered to 14 patients in the combination arm and to 19 patients in the radiotherapy arm. Censoring for second-line chemotherapy did not change these results significantly. The median survival of overall tumor responders was 16.0 (95% CI 12.319.7) months; that of the non-responders was 10.0 (95% CI 8.411.7) months (P <0.001).
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Discussion |
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The principal disadvantage of concomitant therapy remains the enhancement of normal tissue toxicity, both hematological and esophageal, resulting in unnecessary patient morbidity and attenuation of radiotherapy and/or chemotherapy delivery. The present study shows that low-dose carboplatin gives little hematological toxicity and adds mild non-hematological toxicity to radiation toxicity. At 3 months after treatment slight paresthesia of hand and feet was reported by patients in this study but even after longer follow-up no symptoms of radiation myelitis were observed. Radiation myelitis was also not observed in 158 patients who received 50.4 Gy on their spine and who lived more than 1 year [16].
Many studies have looked into the problem of carboplatin scheduling in relation to radiation [17]. Different scheduling of carboplatin either weekly or every other week together with hyperfractionated radiotherapy did not change the toxicity profile or local antitumor effect [18]. However, one study showed that median time to local recurrence with 5 months difference was significantly longer in patients treated with concurrent hyperfractionated radiotherapy and low-dose carboplatin and etoposide, but the distant metastasis-free survival rate did not differ as compared with hyperfractionated radiotherapy alone [10]. A Japanese phase II study performed in elderly NSCLC patients with stage III showed that daily low-dose carboplatin using 30 mg/m2/day during 4 weeks added to 5060 Gy radiotherapy gave a response rate of 50% and 2-year actuarial survival rate of 20% [19]. In the present study the median survival was slightly lower than in the study of Clamon et al., where patients also received induction chemotherapy [5]. The radiosensitizing effect of low-dose continuous carboplatin schedule used in this study is clinically not relevant. Low-dose continuous chemotherapy may have effects on endothelial cells, preventing their recovery and effectively starving tumors of their blood supply [20]. However, 6 weeks is clearly too short a period to show an interaction of radiation and carboplatin on endothelial level in terms of survival. Longer periods of continuous low-dose chemotherapy may be necessary [21]. We conclude that addition of continuous carboplatin to thoracic radiotherapy is not beneficial for patients with locally unresectable NSCLC and that in more than half of the NSCLC patients histologically confirmed endobronchial tumor remained present after treatment.
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Acknowledgements |
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FOOTNOTES |
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