Hyperfractionated Radiation Therapy with and without Concurrent Chemotherapy for Advanced Non-Small Cell Lung Cancer

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1 3732 Hyperfractionated Radiation Therapy with and without Concurrent Chemotherapy for Advanced Non-Small Cell Lung Cancer Branislav Jeremic, M.D.,* Stanisa Jevremovic, M.D.,* Ljiljana Mijatovic, M.D.,* and Slobodan Milisavljevic, M.D.7 Background. Locally advanced non-small cell lung cancer (NSCLC) continues to be a frustrating challenge for oncologists. In this group of patients, the overall 5- year survival rates have been 34% in prospective randomized trials with radiation therapy (RT) alone. Methods. One hundred sixty-nine patients, 18 years of age or older, with histologically or cytologically proven, advanced, nonresectable NSCLC; a Karnofsky performance status score of 50 or greater; and no previous therapy were treated as follows: treatment arm 1: hyperfractionated radiation therapy (HFX RT) to a total tumor dose of Gy (61 patients); treatment arm 2: HFX RT to the same tumor dose with chemotherapy (CT) consisting of 100 mg of carboplatin, days 1 and 2, and 100 mg of etoposide (VP-16), days 1-3, given every week during the RT course (52 patients); and treatment arm 3: HFX RT to the same tumor dose with CT consisting of 200 mg of CBCDA, days 1 and 2, and 100 mg of VP-16, days 1-5, during the first, third, and fifth weeks of the RT course (56 patients). Acute and late toxic effects were scored from 0 (none) to 5 (fatal), according to the Radiation Therapy Oncology Group classification. Results. The authors observed acute overall Grade 3 toxic effects in 11.5 /~ of patients in treatment arm 1, 13.4% of patients in treatment arm 2, and 16.1% of patients in treatment arm 3. Acute overall Grade 4 toxic effects were observed in 1.6% of patients in treatment arm 1,3.8% of patients in treatment arm 2, and 10.7% of patients in treatment arm 3. Regarding late toxic effects, we observed late overall Grade 3 toxic effects in 3.3% of patients in treatment arm 1, 11.6% of patients in treatment arm 2, and 15.4% of patients in treatment arm 3. Presented at the 74th Annual Meeting of the American Radium Society, Orlando, Florida, April 11-15, From the Departments of *Oncology and tthoracic Surgery, University Hospital, Kragujevac, Yugoslavia. Address for reprints: Branislav Jeremic, M.D., KBC Kragujevac, Department of Oncology, Zmaj Jovina b.b., Kragujevac, Yugoslavia. Accepted for publication December 14, Late overall Grade 4 toxic effects were observed in treatment arms 2 and 3 only: 3.8% in treatment arm 2 and 8.9% in treatment arm 3. No Grade 5 toxic effects were observed during this study. Conclusions. The acute toxic effects observed during this study in treatment arms 1 and 2 are at least comparable to those previously published in other studies of this type, but a high incidence of acute overall toxic effects was observed in treatment arm 3. Regarding late toxic effects, the authors observed a higher incidence of Grade 3 overall late toxic effects in treatment arm 2 and a high incidence of Grade 4 overall late toxic effects in treatment arm 3. Results of this study show that the addition of CT to HFX RT carries a risk of increased high-grade toxic effects, both acute and late. Cancer 1993; 71: Key words: hyperfractionation, radiation therapy, chemotherapy, non-small cell lung cancer. Non-small cell lung cancer (NSCLC) represents a significant proportion of the daily workload of radiation therapists and radiation therapy departments in Europe and the United States. Locally advanced NSCLC accounts for approximately one-third of all cases of bronchopulmonary cancer. Expanded use of surgical procedures proved to carry certain benefits in localized disease, leaving radiation therapy (RT) as the best therapy available for advanced disease. RT alone, however, provided an overall 5-year survival rate of only 3-6% in prospective randomized trials.'-6 Analysis of the patterns of failure in numerous retrospective and prospective randomized studies shows that both local and systemic failure play an important role in the poor survival of these patients. This observation justifies the use of combined RT and chemotherapy (CT) because the addition of CT could increase the probability of control of primary tumor and systemic One of the possible ways of increasing local tumor control is the use of hyperfraction-

2 HFX RT for Advanced NSCLClJeremic et al ated radiation therapy (HFX RT). A Phase 1/11 study by the Radiation Therapy Oncology Group showed improved survival for patients treated with HFX RT compared with that obtained with tumor doses considered to be standard (60 Gy in 30 fractions of 2.0 Gy, 5 days per week for 6 weeks), although the benefit was shown only for the 69.6-Gy treatment arm and only for patients in subgroups with a favorable prognosis, a high Karnofsky performance status, and no significant weight loss." Induction CT combined with RT has been reported to provide increased survival in a Cancer and Leukemia Group B (84-33) study." There is also increasing interest in concurrent use of RT and CT. Platinating agents proved to be particularly effective in various tumor types treated with concurrent RT and CT,'',l9 including NSCLC.20 Synergistic activity of platinating agents and epipodophyllotoxin etoposide (VP-16) also was ob- ~erved*l-'~; it also was found that VP-16 can enhance the radiation effect.25 Therefore, our aim was to conduct a Phase 1 study on the use of HFX RT with and without concurrent CT in patients with locally advanced NSCLC to explore feasibility and toxic effects of the addition of CT. Because the newer platinum analogue carboplatin (CBDCA) has more limited toxicity, we have designed a study with HFX RT with and without concurrent CBDCA and VP-16. Materials and Methods Eligibility criteria included the following: patient age of 18 years or older; histologically or cytologically proven, advanced NSCLC classified as Stage IIIA or IIIB by the International System; a Karnofsky performance status score of at least 50%; and no previous therapy. Patients were excluded if they had postoperative thoracic recurrence or a history of any prior or concurrent cancer (except that of the skin), unless the patient had no evidence of disease for more than 5 years. The pretreatment evaluation included medical history, physical examination, complete blood count, biochemical screening tests, postero-anterior (PA), and lateral chest radiographs. Computed tomography scans of the thorax and brain and pulmonary function tests were recommended. For 6 months, patients were examined every month after the completion of therapy, every 2 months for 2 years, and every 4 months thereafter. An interval medical history was obtained and physical examination, complete biochemical tests, and chest radiographs were performed before each visit. Systemic biopsies were not performed routinely but were used if signs of tumor persistence or recurrence were suspected. RT was administered with 6-10-MV photons from linear accelerators. The primary tumor was encom- passed with a minimum 2-cm margin, as was the entire mediastinum from the suprasternal notch to a level 6 cm below the carina (upper and middle lobe lesions) or to the diaphragm (lower lobe lesions); the ipsilateral hilum was encompassed with a 2-cm margin and the contralateral hilum with a l-cm margin. The ipsilateral supraclavicular fossa was included in the treatment field only if the primary tumor was located in the upper or middle lobe. The initial target volume was treated to a minimum tumor dose of 50.4 Gy, after which reduced fields included all detectable tumor, treated to doses as high as 64.8 Gy. Doses were specified at middepth at the central axis for parallel-opposed fields or at the intersection of the central axes for other techniques. The maximum dose to the spinal cord was 50.4 Gy. A maximum dose of 21.6 Gy was recommended for the contralateral lung, 45.6 Gy for the entire heart, and 60 Gy for the esophagus. Two daily fractions of 1.2 Gy were administered five times a week with an interval of hours. CT was introduced for patients in treatment arms 2 and 3. In treatment arm 2, CT consisted of 100 mg of CBDCA, days 1 and 2, and 100 mg of VP-16, days 1-3. In treatment arm 3, CT consisted of 200 mg of CBDCA, days 1 and 2, and 100 mg of VP-16, days 1-5. CT was administered every week during the RT course in treatment arm 2 and during the first, third, and fifth weeks during the RT course in treatment arm 3. CT was administered between the two daily fractions: 3-4 hours after the first one, and 1-2 hours before the second one. Radiation-induced effects on normal tissue were assessed as either acute or late phenomena, according to the Radiation Therapy Oncology Group.16 A toxic effect related to treatment was considered to be acute if it occurred within the first 90 days after the start of treatment. A toxic effect was considered to be late if it occurred after 90 days or an acute toxic effect persisted beyond day 90. Toxic effects were scored from 0 (none) to 5 (fatal). Results All 169 patients were assessable for toxic effects. The treatment groups were balanced by pretreatment characteristics (Table 1). Assessment of acute Grade 3 toxic effects showed bronchopulmonary, hematologic, and esophageal toxic effects as the most common (Table 2). There is no significant difference between the treatment groups, although there is a trend for patients receiving concurrent CT to have a higher incidence of toxic effects, especially hematologic effects. Regarding acute overall Grade 4 toxic effects, a large proportion of patients in treatment arm 3 have experienced toxic effects,

3 3734 CANCER ]me 1, 2993, Volume 71, No. 11 Table 1. Pretreatment Characteristics of Patients and Tumors According to Treatment Group Characteristic Total no. of patients Male/female 46/15 40/12 43/13 Median age in yr (range) 61 (38-70) 62 (44-65) 59 (41-68) KPS International System stage IlIA IIIB Weight loss > 5% KPS: Karnofskv performance status leading to a significant difference between treatment arms 1 and 2 and treatment arm 3 (1.6% and 3.8% versus 10.7%, respectively; treatment arm 1 versus treatment arm 3, P = 0.021; and treatment arm 2 versus treatment arm 3, P = 0.035). If we exclude hematologic toxic effects, which were apparent during the addition of CT and contributed significantly to the total toxic effects, the incidence of overall Grade 3 and 4 acute toxic effects is lowered, thus making the difference insignificant; however, there is a trend for CT-treated patients (especially those experiencing Grade 4 toxic effects) to have an increased incidence of such toxic effects (P = 0.106). Regarding overall Grade 3 late toxic effects, we have observed a difference between treatment arms 1 and 3 and treatment arm 2 (P = 0.031) (Table 3). The difference between treatment arms 1 and 3 is not significant (P = 0.125), although there is a trend for CTtreated patients (treatment arm 3) to have a higher inci- Table 2. Acute Toxicity Toxicity Grade Bronchopulmonary Hematologic Esophageal Gastric Cutaneous Grade 3 in a patient 11.5% 13.5% (9.6%)* 16.1% (8.9S)" Grade 4 in a patient 1.6% 3.8% (1.9%)* 10.7% (5.3%)* * Percentages in parentheses in Groups 2 and 3 exclude hematologic toxicity. Table 3. Late Toxicity Toxicity Grade Bronchopulmonary Esophageal Osseous Heart Grade 3 in a patient (%) 3.3% 11.6% 5.4% Grade 4 in a patient (%) 0 3.8% 8.9% dence of late toxic effects. Regarding overall Grade 4 late toxic effects, we have observed a difference between treatment arms 1 and 2 and treatment arm 3 (P = 0.039), but the difference between treatment arms 1 and 2 is not significant (P = 0.143). Because of acute toxic effects, treatment was interrupted in treatment arm 1 in 4 of 61 (6.5%) patients for 5-12 days, in treatment arm 2 in 5 of 52 (9.6%) patients for 9-14 days, and in treatment arm 3 in 8 of 56 (14.3%) patients for days. No patient refused to complete therapy. Dose modifications were not made. We have observed neither Grade 5 toxic effects nor treatment-related deaths during this study. Discussion Advanced NSCLC represents a frustrating therapeutic challenge for oncologists. The survival figures from several prospective randomized trials that used RT alone are similar, with a median duration of survival of approximately 9-10 months and a 5-year survival rate of approximately Most prospective randomized trials comparing RT alone with RT plus CT did not show an improvement in survival with the addition of CT,I Recently, the Cancer and Leukemia Group B reported on a statistically significant difference in the median duration of survival and 1-year survival rate for patients treated with two cycles of induction CT (vinblastine and cisplatin) followed by radical RT (60 Gy) versus patients treated with the same RT a10ne.i~ Robinow et al., from the Mayo Clinic, reported on an improvement in the median survival and 5-year survival rate for patients with Stage disease treated with two cycles of VP-16, cyclophosphamide, doxorubicin, and cisplatin and thoracic split-course RT administered concurrently with the third and fourth cycles of CT.25 More recently, Cox et al. reported encouraging results with HFX RT alone in Stage I11 NSCLC by the Radiation Therapy Oncology Group classification, but

4 HFX RT for Advanced NSCLClJeremic et al benefits were shown only in the group receiving 69.6 Gy and patients in a subgroup with a favorable prognosis, a high Karnofsky performance status, and no significant weight loss.'6 Incorporated in a general treatment plan, CT could increase local tumor control and decrease development of distant metastases. There is increasing evidence that platinating agents can potentiate RT effect^'^,^^; it also was shown that VP-16 can enhance the radiation effe~t.~~ A recent report by Schwachofer et al. confirmed observations about platinating agents as RT potentiators.28 When administered 3 hours after completion of irradiation procedures, the growth-delay single and split doses were enhanced to the same extent (although the drug-enhancement ratio for cisplatin was larger than for CBDCA). When these agents were present in the target cells at the time of irradiation, the split-dose RT response was especially strongly enhanced. Recovery from sublethal damage was repressed totally. These laboratory findings already were tested in clinic, where various human squamous cell carcinomas were treated with RT and concurrent CT,'8,'9 including that of the lung," with promising results. These observations (both laboratory and clinical) led us to the current study design: timing of CT between the two daily fractions of irradiation, 3-4 hours after the first one and 1-2 hours before the second one. Regarding acute Grade 3 and 4 overall toxic effects, those observed in treatment arms 1 and 2 appeared to be comparable to those observed in other studies of that type. Those observed in treatment arm 3, however, were more prevalent, with a statistically significant difference for acute Grade 4 overall toxic effects but not for acute Grade 3 overall toxic effects. There is a trend, however, for patients treated with CT in that treatment arm to have a higher incidence of toxic effects. Hematologic toxic effects contributed significantly to overall toxic effects, especially in patients in treatment arm 3. Regarding late Grade 3 and 4 overall toxic effects, treatment arms 2 and 3 carried a risk of increased toxic effects, which is significant for late Grade 3 overall toxic effects (treatment arm 2) and late Grade 4 overall toxic effects (treatment arm 3). The increased incidence of acute and late Grade 4 overall toxic effects shows that the design of this treatment arm carries a significant risk for high-grade toxic effects. This is consistent with previous observations that large doses of platinating agents given concurrently with RT produce more severe damage than small although it is limited to acute toxic effects. Despite the fact that there are different mechanisms of acute and late normal tissue damage, it would be interesting to speculate about drug-enhanced late normal tissue damage. Time-dose patterns of RT and concurrent CT are likely to cause this occurrence, which we observed in treatment arm 3. During this study we have not observed Grade 5 toxic effects, and none of the patients died of treatment-related toxic effects. Treatment-related toxic effects were well-documented in this study, especially increased high-grade acute and late overall toxic effects that could be attributed to the addition of CT. A longer follow-up and more patients are needed for additional evaluation of concurrent RT and CT, and studies measuring survival as an endpoint will show us more about the risk-benefit ratio of using the RT and CT concurrently in patients with advanced NSCLC. References 1. Holsti LR, Mattson K. A randomized study of split-course radiotherapy of lung cancer: long term results. Znt / Radiat Oiicol Biol Phys 1980; 6: Lee RE, Carr DT, Childs DS Jr, Comparison of split-course radiation therapy and continuous radiation therapy for unresectable bronchogenic carcinoma: 5 year results. AIR 1976; 126: Perez CA, Pajak TF, Rubin P. Long term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy: report by the Radiation Therapy Oncology Group. Caiicer 1987; 59~ Petrowich Z, Stanley K, Cox JD, Paig C. Radiotherapy in the management of locally advanced lung cancer of all cell types: final report of randomized trial. Cancer 1981; 48: Roswit B, Patno ME, Rapp R. The survival of patients with inoperable lung cancer: a large scale randomized study of radiation therapy versus placebo. Raifiology 1968; 90: Sealy R, Lagakos S, Barkley T. Radiotherapy of regional epidermoid carcinoma of the lung: a study in fractionation. Cancer 1982; 49~ Carr DT, Childs DS Jr., Lee RE. Radiotherapy plus 5-FU compared to radiotherapy alone for inoperable and unresectable bronchogenic carcinoma. Cancer 1972; 29: Cox JD, Yesner R, Mietlowski W, Petrowich Z. Influence of cell type on failure pattern after irradiation for locally advanced carcinoma of the lung. Cancer 1979; 44: Eagan RT, Lee RE, Frytak S, Creagan ET, Richardson RL. Current results of combined therapy for unresectable lung cancer. In: Mountain CF, Carr DT, editors. Lung cancer: current status and prospects for the future. Austin: University of Texas Press, 1986: Eagan RT, Lee RE, Frytak S. Thoracic radiation therapy and Adriamycin/cisplatin containing chemotherapy for locally advanced non-small lung cancer. Cancer Cliri Trials 1981; 4: Mattson K, Holsti LR, Holsti P, Jakobsson M, Kajanti M, Lippo K, et al. Inoperable non-small cell lung cancer: radiation with or without chemotherapy. Eur ] Cancer Clin Oiicol 1988; 24: Morton RF, Jett JR, Maher L, Therneau T. Randomized trial of thoracic radiation therapy (TRT) with or without chemotherapy for treatment of locally unresectable non-small cell lung cancer (NSCLC) [abstract]. Proc AJTI Soc Cliii Oiicol 1988; 7: Petrowich Z, Mietlowski W, Ohanian M, Cox JD. Clinical report

5 3736 CANCER June 1, 2993, Volume 71, No. 13 on the treatment of locally advanced lung cancer. Cancer 1977; 40: Privitera G, Giottoli GB, Patane C, Palmucci T, Tafuri G, Marletta F, et al. Phase I1 double-blind randomized study of lonidamine and radiotherapy in epidermoid carcinoma of the lung. Radiofher Oncol 1987; 10: White JE, Chen T, Reed R, Mira J, Stuckey WJ, Weatherall T, et al. Limited squamous cell carcinoma of the lung: a Southwest Oncology Group randomized study of radiation with or without doxorubicin chemotherapy and with or without levamisole immunotherapy. Cancer Treat Rep 1982; 66: Cox ID, Azarnia N, Byhardt RW, Shin KH, Emami B, Pajak TA. A randomized phase l/ii trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible benefit with 69.6 Gy in favourable patients with Radiation Therapy Oncology Group stage 111 non-small cell lung carcinoma: report of Radiation Therapy Oncology Group ICliri Oncol 1990; 8: Dillman RO, Seagren SL, Propert K, Eaton WL, Frei EF, Green MR. Protochemotherapy improves survival in regional nonsmall cell lung cancer (NSCLC) [abstract]. Proc Am Soc Clin Oncol 1988; 7: Al-Sarraf M, Pajak T, Marcia1 V. Concurrent radiotherapy and chemotherapy with cisplatinum in inoperable squamous cell carcinoma of the head and neck: an RTOG study. Cancer 1987; 59: Jacobs MC, Eisenberger M, Oh MC, Sinibaldi V, Gray W, Elias G, et al. Carboplatin (CBDCA) and radiotherapy for stage IV carcinoma of the head and neck: a phase 1-11 study. lnt Radiaf Oncol Biol Phys 1989; 17: Tobias JS, Smith BJ, Blackman G, Finn G. Concurrent daily cisplatin and radiotherapy in locally advanced squamous carci- noma of the head and neck and bronchus. Radiother Oncol 1987; 9: von Hoff DD, Elson D. Clinical results with cisplatin in lung cancer. In: Prestayko AW, Crooke S, Carter SK, editors. Cisplatin: current status and new developments. vol 1. Orlando (FL): Academic Press, 1980: Schabel FM, Trader MW, Laster WK. Cjs-dichlorodiammine platinum (11) combination chemotherapy and cross resistance studies with tumors of mice. Cancer Treat Rep 1979; 63: Mabel JA, Little AD. Therapeutic synergism in murine tumors for combination diamminedichloroplatinum with VP or BCNU [abstract]. Proc Am Assoc Cancer Res 1979; Drewinko B, Green C, Loo TL. Combination chemotherapy in vitro with cis-dichlorodiammineplatinum (11). Cancer Treat Rep 1976; 60: Robinow JS, Shaw EG, Eagan RT, Lee RE, Creagan ET, Frytak S, et al. Results of combination chemotherapy and thoracic radiation therapy for unresectable non-small cell carcinoma of the lung. Int ] Radiat Oncol Biol Phys 1989; 17: Begg AC. Cisplatin and radiation: interaction probabilities and therapeutic possibilities. lnf ] Radiat Onrol Bid Phys 1990; 19: Begg AC, van der Kolk PJ, Emondt J, Bartelink H. Radiosensitization in vitro by cis-diammine(1,l -cyclobutanedicarboxylato) platinum (11) (carboplatin, JM 8) and ethylenediamine-malonatoplatinum (11) (JM 40). Radioflier Oncol 1987; 9: Schwachofer JHM, Croojimans RPMA, Hoogenhout J, Kal HB, Theeuwes AGM. Effectiveness in inhibition of recovery of cell survival by cisplatin and carboplatin: influence of treatment sequence. lnt I Radiat Oncol Biol Phys 1991; 20: Keizer HJ, Karim ABMF, Njo KH. Feasibility study on daily administration of cis-dichlorodiammineplatinum (11) in combination with radiotherapy. Radiother Oncol 1984; 1: