An Accelerated Radiotherapy Scheme Using a Concomitant Boost Technique for the Treatment of Unresectable Stage III Non-small Cell Lung Cancer

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1 Original Article Japanese Journal of Clinical Oncology Advance Access published May 1, 25 Jpn J Clin Oncol doi:193/jjco/hyi75 An Accelerated Radiotherapy Scheme Using a Concomitant Boost Technique for the Treatment of Unresectable Stage III Non-small Cell Lung Cancer Mustafa Izmirli 1, Fuat Yaman 2, M. Yakup Buyukpolat 2, Adnan Yoney 2 and Mustafa Unsal 2 1 Yuzuncu Yil University, Faculty of Medicine, Department of Radiation Oncology, Van and 2 SSK Okmeydani Hospital, Department of Radiation Oncology, Istanbul, Turkey Received March 14, 25; accepted March 21, 25 Background: We designed a phase II trial for evaluation of the efficacy and tolerability of an accelerated concomitant boost radiotherapy scheme for the treatment of the patients with non-small cell lung cancer (NSCLC). Methods: Thirty patients with unresectable stage IIIA/IIIB NSCLC were prospectively enrolled in this protocol. All patients were scheduled to receive 15 fractions of conventional radiotherapy in dosesof1.8gy,toatotalof27gy.forthelast1treatmentdays,anacceleratedconcomitantboost schedule was started that was composed of 1.8 Gy/fraction/day, 5 days/week to the large field and 1.8 Gy/fraction/day to the boost field 6 h apart, to a total dose of 63 Gy/35 fractions/5 weeks. Results: Median follow-up time was 13 months (range, 5 5 months; 3-year overall, disease-free, loco-regional disease-free and metastasis-free survivals were 23%, 19%, 19% and 23%, respectively). The most common acute toxicity was esophagitis in 31% of patients with the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria grade 1, and in 54% with grade 2. Radiation pneumonitis developed in 16% of patients with RTOG/EORTC grade 1. Three-year actuarial rate of late pulmonary and skinsubcutaneous toxicity were % and 16%, respectively. No late radiotherapy complications of spinal cord or esophagus were recorded. Conclusion: Overall survival, local control and freedom from local progression were comparable with the results reported with pure hyperfractionated radiotherapy. The overall rate of acute and late toxicity was acceptable. Key words: concomitant boost non-small cell lung cancer radiation therapy INTRODUCTION Non-small cell lung carcinoma (NSCLC) accounts for 75% of all lung cancers. More than one-third of patients with NSCLC are stage IIIA or IIIB at presentation. The majority of these patients are not candidates for surgical resection, but are suitable for radiotherapy. However, in spite of all efforts, radiotherapy alone or in combination with chemotherapy has not significantly improved the 5-year survival rates of 5 1% (1,2). Although distant metastases account for the majority of deaths, some of them occur at this stage due to loco-regional failures in the thorax (3). Therefore, improvement of For reprints and all correspondence: Mustafa Izmirli, Yuzuncu Yil University, Faculty of Medicine, Department of Radiation Oncology, Arastirma Hastanesi Maras caddesi, Van, Turkey. izmirlimustafa@hotmail.com loco-regional control can still play a role in prolonging patient survival. NSCLC is thought to be a rapidly proliferating tumor, its potential doubling time being 5 7 days (4). It has also been recognized that tumor cells proliferate during irradiation and, furthermore, that proliferation after irradiation is more rapid than before. Thus, it is called accelerated proliferation (5). It is one of the reasons why very high radiation doses are required to sterilize NSCLC. According to Fletcher s estimation (6), the dose should be 8 9 Gy, or even as high as 1 Gy. Unfortunately, the conventional technique of radiation therapy cannot deliver such high doses to tumors because of the poor tolerance of normal lung tissue. Another way is to amplify the biological dose by radiobiological means. It has been demonstrated that a short course of irradiation, which still retains a high dose, would produce a much stronger effect # 25 Foundation for Promotion of Cancer Research

2 Page 2 of 6 ACBRT treatment for unresectable NSCLC in killing tumor cells, because it will provide less opportunity for tumor cells to proliferate (7). Based on this knowledge, we designed an altered fractionation radiotherapy scheme. An intensive dose of 63 Gy was delivered in 5 weeks, which was one and a half weeks shorter than the usual course of conventional fractionation. SUBJECTS AND METHODS Pretreatment evaluations included complete history, physical examination, diagnostic imaging and laboratory studies. All patients had to go through the following workup procedures: chest radiography; computerized tomography (CT) for chest and brain; radionuclide bone scan; ultrasonographic examination of abdomen; blood biochemistry and complete blood count. CT scans of abdomen or pelvis and bone marrow aspiration were performed according to the patient s complaints. Patients who met the following requirements were eligible for this study: informed consent, histologically or cytologically proven NSCLC at stage IIIA or IIIB (American Joint Committee on Cancer 1997) (except malignant pleural effusion); Karnofski performance status (KPS) >7; age between 18 and 7 years; no chemotherapy, radiotherapy or surgery before enrollment; no severe heart or pulmonary disease; normal functions of liver, kidney and bone marrow; no history of other malignancy except non-melanomatous skin cancer. Criteria for patient withdrawal from the trial were: disease progression in thorax or distant metastases during treatment; accelerated concomitant boost radiotherapy (ACBRT) interrupted for more than 7 days due to severe acute complications or intercurrent diseases. Two dimensional (2D) planning techniques were used for radiation treatment simulation. Radiotherapy (RT) was administred through large and boost fields, both consisting of a pair of anterior-posterior and posterior-anterior opposed parallel fields. The large field included the primary tumor and involved nodes >1 cm in their shorter axis, ipsilateral hilium, superior mediastinum and subcarinal nodes, and a 2 cm margin was added to the initial target volume. The paraesophageal and inferior pulmonary ligament nodal regions were included if the tumor was in the lower lobe. Ipsilateral or bilateral supraclavicular lymph node irradiation was reserved for patients with upper lobe lesions or for those with superior mediastinal node involvement. The boost fields included only the primary tumor and its involved nodes with 1.5 cm margins. Direct radiation of the spinal cord was avoided on the boost field, with a maximum spinal cord dose of 45 Gy. All doses were calculated with heterogeneity corrections for lung density. The patients received conventional radiotherapy for the first 3 weeks consisting of 15 fractions at a dose of 1.8 Gy/fraction to a total dose of 27 Gy and then continued with the accelerated schema. ACBRT was composed of 1.8 Gy/fraction/day, 5 days/ week to the large field Gy/fraction/day to the boost field given 6 h apart for the last 1 treatment days to a total dose of 63 Gy/35 fractions/5 weeks. Radiotherapy was delivered with 18 MeV photons by either a linear accelerator or a cobalt-6 machine over 5 weeks, which was one and a half weeks shorter than the usual course of conventional fractionation. Treatment time and expense were therefore also reduced. Simulation films and beam verification port films were required for each treatment field. The patients were followed up weekly during the course of irradiation. Afterwards, the follow-up was scheduled to be done every three months for the first two years, every six months between 3 and 5 years and yearly thereafter. The following examinations and tests were performed: clinical examination; chest CT/magnetic resonance imaging (MRI); ultrasound examination for abdomen; whole blood biochemical profiles at 2 4 weeks, 6 months and months after radiotherapy. When patients had symptoms suggestive of distant metastases, appropriate tests and measurements were carried out to rule out or confirm them. Acute side effects and toxicity as well as late complications were evaluated by the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria (8). Late pulmonary fibrosis was evaluated by clinical symptoms and imaging studies. The immediate tumor responses were evaluated 2 4 weeks after the completion of ACBRT with CT scan by Union Internationale Contre le Cancer response criteria. Loco-regional disease-free survival was defined as complete or partial elimination of the tumor, but in the latter case the size should be stable after treatment. Once the tumor reappeared, or the residual lesion enlarged on CT or MRI, it was considered as locoregional progression. Actuarial survival, disease-free survival, loco-regional disease-free survival, and distant metastasis-free survival were observed as end-points, and were estimated by Kaplan Meier models. The principle of intent to treat was applied in estimation of all endpoints. The first day of irradiation was taken as the initial date to begin observation for all events. RESULTS From June 2 to December 21, 3 eligible patients were registered for this study. One patient with brain metastases, one patient with intercurrent disease (myocardial infarction) and two patients with disease progression were withdrawn from the trial. Thus, four cases among 3 patients dropped out from the trial during the irradiation. The clinical characteristics of the remaining 26 patients are shown in Table 1. There were 25 males and one female with a median age of 59 years (range, 49 7 years). Three patients were in stages IIIA and 23 in stage IIIB. Histologically, squamous cell carcinoma was predominant (69%), followed by adenocarcinoma (%), and undifferentiated carcinoma accounted for 19% of cases. Eighty-one percent of the patients underwent bronchoscopic biopsy, while the remaining 19% were assessed by cytological examination. Twelve of 26 patients had weight loss of >5% 6 months before diagnosis. Nodal stages of the patients were as follows: 46% N, 8% N1 and 46% N2 by radiological examination. Most of the patients (88%) presented with T4 and % with T3 disease.

3 Jpn J Clin Oncol Page 3 of 6 Table 1. Clinical characteristics of 26 patients with NSCLC Table 2. Results of statistical analysis for 26 patients Variables n (%) Age Median (range) 59 (49 7) Sex Male 25 (96) Female 1 (4) Median 1 year (%) 2 years (%) Overall survival Disease-free survival Loco-regional disease-free survival Metastasis-free survival years (%) Histological type Squamous cell carcinoma 18 (69) Adenocarcinoma 3 () Undifferentiated carcinoma 5 (19) Clinical stage Stage IIIA 3 () Stage IIIB 23 (88) Clinical tumor status T3 3 () T4 23 (88) Clinical nodal status N (46) N1 2 (8) N2 (46) Weight loss Present (46) Absent 14 (54) Treatment machines Linear accelerator (Elekta) (46) Co-6 (Theratron 78) 14 (54) Primary tumor was localized to: left upper lobe in 42%, left lower lobe in 4%, right upper lobe in 38%, right middle lobe in 8%, right lower lobe in 8%. For the 26 patients who completed the treatment, a total of 63 Gy in 35 fractions was delivered within a median duration of 36 days (range, 33 4 days). There was no treatment delay due to acute radiotherapy-related toxicities, but treatment was interrupted for traditional and religious holidays. Immediate tumor responses were evaluated 2 4 weeks (median 3.6 weeks) after completion of radiotherapy. It was observed that 8% of patients achieved complete response, 5% partial response and 42% stable disease after ACBRT. At the last follow-up, five patients were still alive. Among these survivors, four patients were alive with no evidence of disease and one patient was alive with bone metastases. Twenty-one patients died due to disease progression: nine with distant metastases, nine with loco-regional progression and three with both distant and loco-regional failure. The median survival time was 13 months for the entire group (Table 2). The 1-, 2- and 3-year overall survival rates were 58%, 27% and 23%, and disease free survival rates for the same time points were 42%, 19% and 19%, respectively Overall survival Figure 1. Overall survival for 26 patients with non-small cell lung cancer treated by accelerated concomitant boost radiotherapy. Disease-free survival Figure 2. Disease-free survival for 26 patients with non-small cell lung cancer treated by accelerated concomitant boost radiotherapy. (Figs 1 and 2). The 1-, 2- and 3-year loco-regional diseasefree survivals were 46%, 19% and 19%, and 1-, 2- and 3-year distant metastasis-free survivals were 54%, 23% and 23%, respectively (Figs 3 and 4). 6 6

4 Page 4 of 6 ACBRT treatment for unresectable NSCLC Locoregional disease-free survival Figure 3. Loco-regional disease-free survival for 26 patients of non-small cell lung cancer treated by accelerated concomitant boost radiotherapy. Distant metastasis-free survival Figure 4. Distant metastasis-free survival for 26 patients of non-small cell lung cancer treated by accelerated concomitant boost radiotherapy. All of the patients tolerated the treatment well. The incidents of acute toxicity are shown in Table 3. The most common acute complication was radiation esophagitis, which occurred in 22 cases (85%), of which eight cases (31%) were grade 1 and 14 cases (54%) were grade 2. All esophagitis occurred 3 4 weeks after the beginning of ACBRT. Topical anesthesia and parenteral nutritional support were administered to the patients with esophagitis, and all patients could continue ACBRT without interruption. The radiation-induced acute pulmonary toxicity was observed within a median time of 4 weeks (range, 3 5 weeks) after beginning ACBRT. Four patients (16%) developed grade 1 acute pulmonary toxicity. Symptoms resolved after corticosteroid treatment. Anemia was observed in four cases (16%), with grade 1 in two cases (8%) and grade 2 in twocases(8%).acuteskinreactions(13withgrade1,sevenwith 6 6 Table 3. The incidences of acute toxicity Toxicity Grade 1 Grade 2 Grade 3 Grade 4 Anemia 2 2 Neutropenia Thrombocytopenia Skin reactions Esophagitis 8 14 Pnomonitis 4 grade 2, one with grade 3) were seen after the 1th day of radiotherapy; grade 4 toxicity was not observed in any patient. Skin reactions were significantly higher in patients treated with the cobalt-6 teletherapy machine compared with linear accelerators (P = 1). No other serious acute toxicity was recorded. Three-year actuarial rates of late pulmonary and skinsubcutaneous toxicity were % and 16%, respectively. A total of three cases (%) were found to have pulmonary fibrosis (grade 1 in two cases, grade 2 in one case). No late radiotherapy complications of spinal cord or esophagus were recorded. DISCUSSION Although some new treatment schedules such as hyperfractionated accelerated irradiation or combination of irradiation and chemotherapy have shown promising results, the outcome is still far from satisfactory for locally advanced NSCLC. Therefore, there is a need for new treatment strategies for NSCLC. The predominant cause of death for locally advanced NSCLC has been distant metastases (9). However, as the effectiveness of systemic chemotherapy has been enhanced in recent years, distant metastases rates have been found to be declining. Therefore, improvement of thoracic tumor control has become quite important. For locally advanced NSCLC, loco-regional control is one of the requisites for cure. Moreover, several studies have shown that improvement of locoregional control could decrease distant metastases, and thus improve survival (1 14). By conventional irradiation techniques, a maximum tumor dose of 6 66 Gy can be delivered, but results in poor local control in 2% of cases (15). To further increase the local control rate for NSCLC, shortened overall irradiation time has been tried and resulted in an improved outcome by using Continuous Hyperfractionated Accelerated Radiation Therapy (CHART) (16), Continuously Hyperfractionated Accelerated Radiation Therapy Weekendless (CHARTWEL) (17) and Hyperfractionated Accelerated Radiation Therapy (HART) (18). This clinical trial was therefore designed to further improve loco-regional control for locally advanced NSCLC. In the CHART trial implemented by Saunders et al. (16), 563 patients with NSCLC (the majority with stage III disease) were randomly assigned to conventional RT (3 once daily 2 Gy fractions, 5 days/week) or CHART (1.5 Gy three times

5 Jpn J Clin Oncol Page 5 of 6 daily for consecutive days). CHART was associated with a significantly better 2-year survival and local tumor control (29% versus 2% and 23% versus 16%, respectively) but with more frequent dysphagia during the first three treatment months (19% versus 3%). The CHART trial showed that acceleration of the radiotherapy schema yielded better tumor control and survival, but with a higher risk of complications. We designed in our trial a mild acceleration in order to keep side effects low. Concomitant chemoradiation may provide better control of both distant and loco-regional diseases. A few randomized trials have compared concomitant full dose cisplatin-based chemotherapy and thoracic RT with sequential therapy (19 21). Among them, two studies showed statistically significant benefit for concomitant therapy (19,2). One phase III study was conducted by a West Japanese group: 32 patients with unresectable stage III NSCLC were randomly assigned to concurrent chemotherapy that was composed of cisplatin, mitomycin and vindesine plus thoracic RT (two courses of 28 Gy in 2 Gy daily fraction, with a 1-day interval between courses) or sequential chemoradiotherapy (the same chemotherapy regimen) (19). Concurrent therapy was associated with a significantly higher response rate (84% versus 66%), median survival (16.5 versus 13.3 months, P = 39), and 2- and 3-year survival (34.6% versus 27.4% at 2 years and 22.3% versus 14.7% at 3 years). In a follow-up report, the local relapse-free survival also significantly favored concurrent therapy (33.9% versus 19.6% at 5 years) (22). In a recent phase III trial by the Radiation Therapy Oncology Group (RTOG 941), comparison was made among sequential vinblastine/cisplatin followed by conventional fractionation RT (6 Gy), concurrent chemotherapy including the same chemotherapeutic agents with conventional fractionation RT (6 Gy) and concurrent chemoradiation with hyperfractionated RT (administered twice daily to a total dose of 69.6 Gy) (2). In the latest update, median survival was significantly better in the concurrent standard RT arm (17 versus 14.6 and 15.2 months in the sequential and twice daily RT arms, P = 38 for the comparison with sequential therapy) as was 4-year survival (21% versus % and 17%, respectively) (2). Although hematological and organ-based toxicities were greater in the concurrent approach, treatment-related death rates were not increased. In our study, the median survival time was 13 months and 2-year overall survival and disease-free survival were 27% and 19%, respectively, which is comparable with the findings of the CHART trial, but is apparently poorer than those of the concurrent chemoradiotherapy trials with survival results of 35% at 2 years. All of the patients in this trial tolerated the ACBRT therapy. Complications were handled easily without interruption of treatments. As to late complications, the 3-year actuarial rates of late-pulmonary and skin-subcutaneous toxicity were % and 16%, respectively, but limited to a maximum of RTOG/ EORTC grade 2, and no other severe late complications have been found. The acute and late complications were comparable with those in conventional radiotherapy. After ACBRT, the loco-regional control was expected to be improved. In general, local control rates were in the range of 2% for locally advanced NSCLC (15). In this trial ACBRT yielded a 3-year loco-regional progression-free interval of 31%, which seemed to be improved. However, 13 patients still failed in thorax despite intensive irradiation. All of them failed inside the radiation fields, which implies that the dose to the tumor is still not large enough. Our experience from this study concurs with the current postulation that there is accelerated proliferation of NSCLC cells during irradiation, and hence a short course of ACBRT produced stronger effects in sterilization of NSCLC loco-regionally. CONCLUSIONS In this trial, overall irradiation time was shortened by the ACBRT technique, thus the biological dose was increased. Therapeutic results of this radiotherapy schedule are comparable with those in the literature. Further clinical trials using ACBRT fractionation schedules are warranted for NSCLC, in combination with new chemotherapy drugs and 3D conformal radiotherapy. References 1. Perez CA, Stanley K, Rubin P, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Cancer 198;45: Perez CA, Pajak TF, Rubin P, et al. Long-term observation of the patterns of failure in patients with unresectable non-oat cell carcinoma of lung treated with definitive radiotherapy: report by the Radiation Oncology Group. Cancer 1987;59: Perez CA, Stanley K, Grundy G, et al. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung. Cancer 1982;5: Wilson GD, Mcnally NJ, Dische S, et al. Measurement of cell kinetics in human tumors in vivo using bromodeoxyuridine incorporation and flow cytometry. Br J Cancer 1988;58: Withers HR, Taylor JMG, Maciewjewski B, et al. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncologica 1988;27: Fletcher GH. Clinical dose response curves of human malignant epithelial tumors. Br J Radiol 1973;46:1. 7. Chen M, Jiang GL, Fu XL, et al. The impact of overall treatment time on outcomes in radiation therapy for non-small cell lung cancer. Lung Cancer 2;28: Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31: Moore DF, Lee JS. Staging and prognostic factors: non-small cell lung cancer. In: Pass HI, Mitchell JB, Johnson DH, editors. Lung cancer: principles and practice, first edition. Philadelphia, PA: Lippincott 1996; Dosoretz DE, Galmarini D, Rubenstein JH, et al. Local control in medically inoperable lung cancer: an analysis of its importance in outcome and factors determining the probability of tumor eradication. Int J Radiat Oncol Biol Phys 1993;27: Perez CA, Bauer M, Edelstein S, et al. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 1986;: Saunders MI, Barltrop MA, Rassa P, et al. The relationship between tumor response and survival following radiotherapy for carcinoma of the bronchus. Int J Radiat Oncol Biol Phys 1984;1:53 8.

6 Page 6 of 6 ACBRT treatment for unresectable NSCLC 13. Graham MV, James A, Purdy P, et al. Preliminary results of a prospective trial using three dimensional radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 1995;33: Sibley GS, Jamieson TA, Marks LB, et al. Radiotherapy alone for medically inoperable stage I non small-cell lung cancer: the Duke experience. Int J Radiat Oncol Biol Phys 1998;4: Arriagada R, LeChevalier T, Quoix E, et al. ASTRO plenary: effects of chemotherapy on locally advanced non-small cell lung cancer: a randomized study of 353 patients. Int J Radiat Biol Phys 1991;2: Saunders M, Dische S, Barrett A, et al. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial (CHART steering committee). Radiother Oncol 1999;52: Saunders M, Rojas A, Lyn B, et al. Experience with dose escalation using CHARTWEL (continuous hyperfractionated accelerated radiotherapy weekend less) in non-small cell lung cancer. Br J Cancer 1998;78: Fu XL, Jiang GL, Wang LJ, et al. Hyperfractionated accelerated radiation therapy for non-small cell lung cancer: clinical phase I/II trial. Int J Radiat Oncol Biol Phys 1997;39: Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17: Curran WJ, Scott C, Langer C, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III non small cell lung cancer: RTOG 941 (abstract). Proc Am Soc Clin Oncol 23;22:621a. 21. Pierre F, Maurice P, Gilles R, et al. A randomized phase III trial of sequential chemo-radiotherapy versus concurrent chemo-radiotherapy in locally advanced non small cell lung cancer (GLOT-GFPC-NPC 95-1 study) (abstract). Proc Am Soc Clin Oncol 21;2:3a. 22. Furuse K, Hosoe S, Masuda N, et al. Impact of tumor control on survival in unresectable stage III non-small cell lung cancer (NSCLC) treated with concurrent thoracic radiotherapy and chemotherapy (abstract). Proc Am Soc Clin Oncol 2;19:4a.