Efficacy of chemotherapy combined hyperfractionated accelerated radiotherapy on limited small cell lung cancer

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1 [Chinese Journal of Cancer 27:10, ; October 2008]; 2008 Sun Yat-Sen University Cancer Center Clinical Research Paper Efficacy of chemotherapy combined hyperfractionated accelerated radiotherapy on limited small cell lung cancer Xiao Hu, 1,2 Yong Bao, 1,2 Yuan-Yuan Chen, 1,2 Jian-Ming Gao, 1,2 Wei-Hua Wang, 1,2 Yuan Liu, 1,2 Han He, 1,2 Zong-Wen Sun, 1,2 Shivaji Poudel, 1,2 Yan Wang, 1,2 Ting-Ting Zhuang, 1,2 Li Zhang 1,3 and Ming Chen 1,2, * 1 State Key Laboratory of Oncology in South China; Guangzhou, Guangdong P. R. China; 2 Department of Radiation Oncology; ;3Department of Medical Oncology; Cancer Center; Sun Yat-sen University; Guangzhou, Guangdong P. R. China Key words: lung neoplasm, limited stage, chemotherapy, hyperfractionated accelerated radiotherapy, combined therapy, efficacy Background and Objective: Limited small cell lung cancer (SCLC) is sensitive to both radiotherapy and chemotherapy. Radiotherapy can enhance survival rate and reduce the local/ regional recurrence rate of limited SCLC. This study was to analyze the efficacy of chemotherapy combined hyperfractionated accelerated radiotherapy (HART) on limited SCLC, observe treatment-related adverse events and summarize the treatment failure patterns. Methods: A total of 55 limited SCLC patients were treated with EP regimen as induction chemotherapy, then received radiotherapy, followed with EP regimen as consolidation chemotherapy. Prophylactic cranial irradiation (PCI) was given to those patients who had achieved complete remission (CR) after chemoradiotherapy. As treatment was completed, patients were followed up, the efficacy and toxicities were evaluated. Results: At the end of chemoradiotherapy, the overall response rate was 87.3%. The 1-, 3-, and 5-year overall survival rates were 79.1%, 40.3% and 16.1%, respectively, with the median survival time of 18.7 months. Grade III and IV hematologic toxicities were observed in 23 (41.8%) and 16 (29.1%) patients, respectively. Grade I and II radiation-induced pneumonitis occurred in 21 (38.2%) and 2 (3.6%) patients, respectively. Grade I and II radiation-induced esophagitis occurred in 29 (52.7%) and 12 (21.8%) patients, respectively. No grade III/IV non-hematologic toxicity was observed. Grade I and II pulmonary fibrosis occurred in 11 (20.0%) and 5 (9.1%) patients, respectively. Grade I esophageal stricture was observed in 2 (3.6%) patients. Of the 55 patients, 16 (29.1%) had local/regional recurrence, 21 (38.2%) suffered from distant metastasis. Conclusions: The toxicities of EP regimen chemotherapy combined with HART are mild *Correspondence to: Ming Chen; State Key Laboratory of Oncology in South China; and Department of Radiation Oncology; Cancer Center; Sun Yat-sen University; Guangzhou, Guangdong P. R. China Submitted: 01/08/08; Revised: 05/06/08; Accepted: 07/09/08 This paper was translated into English from its original publication in Chinese. Translated by: Wei Liu on 09/06/08. The original Chinese version of this paper is published in: Ai Zheng (Chinese Journal of Cancer), 27(10); Previously published online as a Chinese Journal of Cancer E-publication: to moderate and are tolerable by patients. Local/regional recurrence and distant metastasis are the main reasons of treatment failure. Lung cancer is a common malignancy of the thorax. In clinical practice, small cell lung cancer (SCLC) accounts for 20% of all lung cancers. Among all the diagnosed SCLCs, 40% are at limited stage. Despite the high sensitivity to both radiotherapy and chemotherapy, a 75 90% recurrence rate was observed in the patients treated with chemotherapy alone. 1 Thoracic irradiation reduced the recurrence rate to 50% and increased the long-term survival rate of limited SCLC patients by 5%. 2,3 Chemotherapy combined radiotherapy is the standard treatment modality for limited SCLC. To date, the standard chemotherapy regimen for limited SCLC is EP, 4-6 while wide controversies exist in the aspects of thoracic radiation doses, fractionation, target volume and the way and time points for thoracic irradiation to combine with chemotherapy. 7 Since June, 2002, the Thoracic Radiotherapy Group of Sun Yat-sen University Cancer Center started to treat limited SCLC patients by EP regimen chemotherapy combined thoracic hyperfractionated accelerated radiotherapy (HART). This study was initially designed as a prospective randomized clinical trial to compare different target volumes for irradiation. In control group, the prechemotherapy lesion was contoured for irradiation; in trial group, the post-chemotherapy lesion was contoured for irradiation. This article was to report the efficacy of chemotherapy combined HART on limited SCLC, as well as treatment-related adverse events and treatment failure patterns. The final results are pending for case accumulation and long-turn follow-up. Because of the limited case number, the two groups were analyzed as a whole, while the differences between these two groups were simply described. Materials and Methods Patients selection. Inclusive criteria. The inclusive criteria were as follow: the diagnosis of SCLC was confirmed by histology or cytology; limited SCLC, defined according to the Veteran s Administration Lung Study Group, 8 was confirmed by imaging examination [including brain computed tomography (CT)/magnetic resonance imaging (MRI), chest and abdomen contrasted CT and bone ECT); the patients aged of years, with no history of thoracic radiotherapy, chemotherapy and biotherapy; the tumor was evaluable; neutrophilic granulocyte /L, hemoglobin Chinese Journal of Cancer 2008; Vol. 27 Issue 10

2 g/l, platelet count /L; serum creatine and bilirubin < 1.5 times upper normal limit (UNL), aminotransferase < 2 times UNL; weight loss of 10% within six months before diagnosis. Written informed consent was required. Exclusive criteria. The exclusive criteria were as follow: a history of other malignant diseases except for non-melanoma skin cancer and carcinoma in situ of the cervix, with any contraindications for chemoradiotherapy, with malignant pleural and/or pericardial effusion. Treatment. Chemotherapy. EP regimen [venous administration of etoposide (VP-16) 120 mg/m 2 on d1 d3 and cisplatin (DDP) 60 mg/m 2 on d1] was used as induction chemotherapy every three weeks. Radiotherapy was administered within 1 2 weeks after 2 4 cycles of EP regimen. Another 2 4 cycles of EP regimen were administered within 1 2 weeks after radiotherapy with an interval of three weeks. Radiotherapy. Patients were fixed in vacuum bags and took supine position with their arms raised and hands held their heads. CT-simulation or 3-dimentional (3D) treatment planning system was applied to design radiotherapy plan. The targets were contoured in accordance with the ICRU 62 report. Gross tumor volume (GTV) included the primary tumor and positive lymph nodes (lymph nodes in the mediastinum with a short diameter 1.0 cm, lymph nodes with positive tumor cell sampling and 18 F-DG standard uptake value 2.5 on PET/CT). When contouring clinical target volume (CTV), patients were randomized into two arms: CTV of the trial arm involved post chemotherapy GTV with a margin of 0.8 cm, while CTV of the control arm included the pre-chemotherapy GTV with a margin of 0.8 cm. Planning target volume (PTV) involved CTV with a margin of cm. Chest irradiation was delivered by 1.5 Gy/fraction to a total dose of 45 Gy, two fractions/day with intervals of 6 h, 10 fractions/week for three weeks. Patients who achieved complete remission (CR) of tumor after the completion of chemoradiotherapy received prophylactic cranial irradiation (PCI) to the entire brain. Irradiation was delivered by two Gy/fraction to a total dose of 30 Gy, one fraction/day, five fractions/week for three weeks. Follow-up. The patients received chest X ray examination every two weeks since they received irradiation of 30 Gy. Patients were re-examined every three months in the first year after treatment and every six months thereafter. Physical examination and chest X ray examination were routinely took and CT scan was performed when necessary. Survival time was calculated from the beginning of chemotherapy. The cut-off time for follow-up was December 31 st Efficacy and toxicity evaluation. The curative efficacy was evaluated with thoracic CT scan after every two cycles of induction chemotherapy, immediately after radiotherapy and consolidation chemotherapy, and was classified as CR, partial response (PR), stable disease (SD) and progressive disease (PD) according to the WHO response criteria. During radiotherapy, KPS and acute radiationinduced pneumolitis and esophagitis were recorded in detail, routine blood test was done at least once a week. Acute adverse events were evaluated according to NCI CTC AE3.0 criteria; late adverse events were evaluated according to RTOG criteria. 8 Statistics. Statistical software package SPSS 13.0 was applied and the Kaplan-Meier method was used to estimate survival data. The distribution of survival time between groups was tested by log-rank method and the differences were regarded significant if p < Results Patient characteristics. From June 2002 to May 2007, a total of 55 limited SCLC patients were included in the study. Of the 55 patients, 47 were men and eight were women, with a median age of 56 (range, 40 75); one had stage IA disease, five had stage IIB disease, 17 had stage IIIA disease, and 32 had stage IIIB disease. KPS were 80 in all patients. Weight loss was 5% in seven patients, > 5% but < 10% in three patients. Treatment and acute adverse events. Induction chemotherapy. Of the 55 patients, 17 received two cycles of induction chemotherapy, 13 received three cycles, and 25 received four cycles. The main adverse events were hematological and gastrointestinal reactions (Table 1). Radiotherapy. When contouring CTVs, 26 patients were randomized into trial group, 29 into control group. Hematological adverse events and radiation esophagitis were the main adverse events (Table 2). The median duration of radiotherapy was 22 days (range, days). Ten (18.2%) patients suspended radiotherapy for 3 9 days: two suspended for Three days and nine days respectively because of grade IV hematological adverse events after two cycles of chemotherapy, while eight suspended for seven days because of holidays. Consolidation chemotherapy. Thirty-eight (69.1%) patients received consolidation chemotherapy. Thirty of them completed as planned and eight completed one cycle, with an average of 2.5 cycles. Thirteen patients received two cycles of consolidation chemotherapy, six received three cycles, and 11 received four cycles. Hematological adverse events were the main adverse events (Table 3). Late adverse events. Eleven patients developed grade I pulmonary fibrosis, five developed grade II pulmonary fibrosis. Two patients had grade I esophageal stricture. Eleven patients developed grade I neurotoxicity. No spinal cord injury was observed. Curative efficacy. Overall efficacy. After induction chemotherapy, five (9.1%) patients achieved CR of primary lesion and 39 (70.9%) achieved PR. After thoracic radiotherapy, 13 (23.6%) patients achieved CR and 33 (60%) achieved PR, but two (3.6%) developed supraclavicular lymph node and liver metastasis respectively and was evaluated as PD. After consolidation chemotherapy, 24 (43.6%) patients achieved CR, 24 (43.6%) achieved PR, three (5.5%) had PD (another one patient developed supraclavicular lymph node metastasis), and four (7.3%) had SD. Fifty-four patients completed radiotherapy as planned; one quitted radiotherapy because of supraclavicular lymph node metastasis. The overall response rate (CR+PR) was 87.3%. Among the 24 patients who achieved CR, 12 received PCI. Recurrence, metastasis and survival. The median follow-up time was 15.7 months (range, months). Sixteen (29.1%) patients had local/regional recurrence, including seven in trial group and nine in control group, two of them were alive. Twenty-seven patients died: 13 died of distant metastasis, seven died of local/regional recurrence, five died of both local/regional recurrence and distant metastasis, one died of second primary cancer of the pancreas without evidences of recurrence and/or distant metastasis of SCLC, one died with unknown reason. Twenty-one (38.2%) patients had distant metastasis, and three of them were still alive. The metastatic sites included the brain (14 patients, accounted for 66.7% of all patients suffered from metastatic disease), liver (four patients), bone (three patients), lung (one patient) and adrenal gland (one patient). One patient Chinese Journal of Cancer 354

3 Table 1 Acute adverse events caused by induction chemotherapy [cases (%)] Table 2 Acute adverse events caused by radiotherapy [cases (%)] Figure 1. Overall survival curve of limited small cell lung cancer (SCLC) patients treated with chemotherapy combined hyperfractionated accelerated radiotherapy (HART). Table 3 Acute adverse events caused by consolidation chemotherapy [cases (%)] Figure 2. Progression-free survival curve of limited SCLC patients treated with chemotherapy combined HART. developed second primary cancer of the rectum with right lung metastasis but no evidence of recurrence and/or metastasis of SCLC when was followed-up for 26 months (December 2007). The median survival time was 18.7 months (range, months). The 1-, 2-, 3-, 4- and 5-year overall survival rates were 79.1%, 51.2%, 40.3%, 32.2% and 16.1%, respectively (Fig. 1). The median progression-free survival time was 13.2 months (range, months). The 1-, 2-, 3- and 4-year progression-free survival rates were 62.5%, 47.4%, 41.5% and 31.1%, respectively (Fig. 2). The median survival time were (38.5 ± 5.9) months for trial group and (34.7 ± 5.1) months for control group (p = 0.679) (Fig. 3). Discussion At present, the combined treatment of chemoradiotherapy has been established as standard treatment modality for limited SCLC. The first-line chemotherapy for limited SCLC is EP regimen, 4-6 Figure 3. Overall survival curves of patients with target planning before or after chemotherapy. while wide controversies exist in the aspects of radiation dose, fractionation, target volume, the way and time points to combine thoracic radiotherapy with chemotherapy. 7 In a randomized prospective clinical trial conducted by Turrisi et al., 10 four cycles of concurrent EP regimen were combined with HART arm (1.5 Gy/fraction to a total dose of 45 Gy, 2 fractions/ 355 Chinese Journal of Cancer 2008; Vol. 27 Issue 10

4 day, 10 fractions/weeks for 3 weeks) and conventional fractionated radiotherapy arm (1.8 Gy/fraction to a total dose of 45Gy, 1 fraction/ day, five fractions/weeks for 5 weeks); the median survival time were 23 months in HART group and 19 months in conventional fractionated radiotherapy group, the 2- and 5-year survival rates of HART group were 47% and 26%, which were 6% and 10% higher than those of conventional fractionated radiotherapy group. This study applied the same dose/fraction pattern as Turrisi s, but the notion of concurrent chemoradiotherapy treatment modality for limited SCLC that implemented at that time has not yet been accepted by Chinese investigators, therefore, the study applied sequential treatment pattern that was more tolerable for the patients. Although several cycles of chemotherapy and HART were applied, intra-thoracic recurrence was observed in 16 (29.1%) patients in this study, higher than the recurrence rate (22.8%) observed in a prospective randomized phase II clinical study conducted by Chen et al. 11 As they also applied sequential chemotherapy and HART, the reason may lay in that a higher biological equivalent dose (BED) was applied in their study (1.4 Gy/fraction to a total dose of 56 Gy, two fractions/day, 10 fraction/week for four weeks). Schild et al. 12 summarized the relationship between long term survival and the BED applied in 8 clinical trials, the Pearson related coefficient was 0.81, indicating a close relationship. Moreover, with the results from more clinical studies, 13,14 higher irradiation doses may be suggested to enhance local control rate. The application of 4D CT positioning and 3D conformal radiotherapy could improve radiation doses while not obviously increase normal tissue injury. 15 This study randomized radiation targets into two arms, mainly to observe prospectively whether the local recurrent rates between the two arms are different or not and its impact on the overall survival time. Some clinical studies 16,17 indicated that local recurrent rate was not increased if post-chemotherapy lesion range was contoured for irradiation. In our study, this would be further discussed in a larger scale of cases. Brain metastasis is a major cause to death in SCLC patients. For those who have achieved CR after treatment, 15% failed in single brain metastasis. A meta analysis conducted by Auperin et al. 18 showed that in the patients achieved CR, the 3-year survival rate of PCI group was increased by 5.4% of control group (20.7% vs. 15.3%), and the risk to develop brain metastasis was decreased in PCI group by 54%, PCI also increased disease-free survival rate and decreased the cumulative occurrence rate of brain metastasis. For the 24 CR patients in this study, because of the refusal of patients, only 12 received PCI and three of them developed brain metastasis; brain metastasis was also observed in three of those didn t receive PCI. No obvious advantage was observed in PCI group, which may lie in the limited case number. Schild et al. 15 applied early intervention of PCI for the patients who had response to 3 cycles of chemotherapy, and found that only one (1.6%) of all 61 patients developed brain metastasis, but 75% of them developed grade IV hematological adverse events. The 2008 edition of NCCN guidelines 19 points out that PCI could be took into consideration as long as patients achieved PR. Therefore, we could take PCI into account for PR patients in the future, but it should only be given after all chemotherapy has been finished. SCLC cells are highly aggressive with a short potential doubling time and are inclined to develop early distant metastasis. Thus, prolonging treatment duration may have a negative impact on the curative efficacy. In this study, ten patients suspended radiotherapy for 3 9 days because of treatment-related adverse events and holidays, but the difference in median survival time was not significant (p = 0.718) as compared with those patients who did not suspend radiotherapy. The time point to combine thoracic radiotherapy with chemotherapy is still controversial. Erridge et al. 20 found that the start of any treatment and the end of radiotherapy (SER) may be a key factor to predict prognosis. Ruysscher et al. 21 argued that the 5-year survival rate of limited SCLC patients could be significantly increased if SER is < 30 days. In this study, the median SER was 89 days (range, days); the patients were divided into two groups using SER = 90 days as a cut-off, and the difference in median survival time was not significant (p = 0.697). These results may lay in the limited case number. Although no PD patients were observed after induction chemotherapy in this study, three patients developed supraclavicular lymph node and liver metastasis after thoracic radiotherapy and consolidate chemotherapy, indicating accelerated repopulation of cancer cells and proliferation of drug-resistant cell clones during treatment. 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