Department of Radiology and Radiation Oncology, Gunma University School of Medicine, Maebashi, Japan

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1 Original Article The Role of Radiation Therapy for Stage IIIB Non-Sall Cell Lung Cancer: Ipact of Clinical Nodal Stage on Survival Kazushige Hayakawa,* Norio Mitsuhashi, Masaya Furuta, Yoshihiro Saito, Yuko Nakayaa, Susuu Katano, Tatsuya Ohno, and Hideo Niibe Departent of Radiology and Radiation Oncology, Guna University School of Medicine, Maebashi, Japan Background: Fro 1976 through 1989, 46 patients with stage IIIB non-sall cell lung cancer (NSCLC) without alignant effusion were treated with definitive radiation therapy (RT) at Guna University Hospital. Melhods: All patients were treated with 10 MV x-rays using antero posterior parallel opposed fields. The total dose ranged fro 60 Gy to 70 Gy (ean dose; 66 Gy) with once daily standard fractionation. Results: The actuarial two and five-year survival rates of the entire group were 22% and 10% respectively with a edian survival tie (MST) of 10 onths. The survival of 18 patients with stage NO-2 disease was significantly better than the 28 patients with stage N3 disease (MST 21 versus 9 onths; P< 0.05). There were no significant differences in survival based on age and sex. However, there was a borderline difference in survival rates between patients with a perforance status of 0-1 and those with a status of 2-3 (P= 0.06). Three patients with squaous cell carcinoa were alive after 5 years and were without disease progression. No patients with non-squaous cell carcinoa were free of disease after 5 years. Conclusion: These results provide support for the use of definitive RT to anage those patients with liited stage IIIB squaous cell carcinoa not extending to N3 stage. Int J Clin Oncol 1996;1:13-17 Key words: non-sall cell lung cancer, radiation therapy, clinical nodal staging INTRODUCTION In the ajority of the patients with lung cancer, the tuor is unresectable at diagnosis due to locally advanced disease or distant etastases, and the overall survival rate is disal. 1-2 Although radiation therapy (RT) is generally reserved for unresectable non-sall cell lung cancer (NSCLC) without clinical distant etastasis, 3-9 the rote of RT in the treatent of advanced NS CLC is a subject of ongoing controversy and investigation. Reports describe RT as being useful for iproving the local control and survival in patients with nonetastatic unresectable carcinoas, and relief of syptos in the patients with ore advanced disease, s'l~ This report evaluates the role of RT in patients with stage IIIB NSCLC and discusses the influence of various prognostic factors on survival by uni- and ultivariate analyses. MATERIALS AND METHODS Fro 1976 through 1989, a total of 573 patients with NSCLC were referred to our departent at Guna Received Nov. 29, 1995; revised Jan. I, 1996; accepted for publication in revised for Jan. 24, *Correspondence and reprint requests to: Departent of Radiology and Radiation Oncology, Guna University School of Medicine, Showa-achi, Maebashi, Guna 371, Japan. University Hospital. Seventy five patients had Stage IIIB disease. Fifteen patients, who developed progressively alignant pleural effusions or extrathoracic spread during the course of irradiation, or who were in poor general condition (perforance status, 4), were excluded fro definitive RT delivering doses in excess of 60 Gy. However, fourteen patients with controllable or sall pleural effusions were not excluded. In our review of edical records, 60 patients with a TNM classification of clinical stage IIIB disease were identified. There was no evidence of distant etastases at the tie of diagnosis in the study group. Clinical staging procedures inially included a history and physical exaination, routine blood studies, ultrasonography of the upper abdoen, and bone and galliu-67 scintigraphy. Soe patients underwent CT scan of the brain and upper abdoen. Mediastinal spread was evaluated by radiographic studies such as plain chest radiographs and toographs. Since 1980, no patients had undergone ediastinoscopic evaluation of the ediastinal nodes, although ost patients had received a thoracic CT. All patients were categorized as surgically unresectable and referred to our progra because of the extensive spreading of disease to the adjacent structures or organs. The patient and tuor characteristics are shown in Table 1. All patients were treated with 10MV x-rays using the conventional fractionation of 2 Gy per day. The initial /96/ /US$ JSCO/CLJ

2 Radiation Therapy for Stage IIIB NSCLC treatent field utilized anteroposterior parallel opposed fields. All regional nodes were included in the initial treatent field and were irradiated up to 40 Gy for prophylaxis. Both the priary lesions and involved nodes were given doses greater than 60 Gy. A shrinkingfield technique was generally used after 40 Gy with the exact field deterined by the response of the tuor. The fields were changed to adequate oblique parallel opposed fields or decreased in size to exclude the spinal cord and reduce the possibility of late toxicity. The ajority of patients were given a total dose of Gy in 6-7 weeks. Only one patient with good tuor response to radiation after 70 Gy, was given a boost dose of 20 Gy with ore reduced-field to achieve reliable tuor control. Only four patients received systeic cheotherapy in the initial treatent course. All patients were followed until death or for at least 5 years at onthly intervals. Chest radiographs and blood studies were routinely carried out. Galliu-67 scintigraphy, bronchofiberscopic exaination and other studies were perfored as clinically indicated. No patient was lost to follow-up. Local failure was defined by the pathological deterination of recurrent carcinoa or progressive radiographic abnoralities thought to be consistent with tuor progression rather than radiation-related changes. Survival was calculated based on the first day of RT by the Kaplan-Meier ethod and the survival coparison was copleted by the logrank test for univariate analysis. Furtherore, ultivariate analysis was perfored using Cox's proportional hazard odel to assess the prognostic significance of factors associated with patient, tuor and treatent. The paraeters evaluated by univariate and ultivariate analyses were as follows: age at diagnosis, sex, perforance status, tuor spread pattern, N stage, tuor size, priary site, histologic type, total radiation dose, and radiation field size given over 40 Gy. RESULTS The actuarial two- and five-year survival rates for the 60 patients with stage IIIB disease were 18% and 8% respectively, with a edian survival tie (MST) of 9.5 onths. In contrast, 2 and 5 year survival rates for Stage IIIA patients were 27% and 12% with a edian surival tie (MST) of 14.5 onths (P = 0.05). However, the survival rates for 46 patients without pleural effusion were 22% at 2 years and 10% at 5 years with a survival curve siilar to that of the stage IIIA patients (Fig. 1). In these patients without effusion, the survival rate of 18 patients with stage N0-2 disease was significantly better than that of 28 patients with stage N3 disease (MST 21 versus 9 onths; P < 0.05, Fig. 2). There were no significant differences in survival based on age and sex. However, the patients with a perforance status of 0-1 had a greater probability of long-ter survival than those with a status of 2-3 (P= 0.06, Fig. 3). Three patients with 100, => 50-7 r. -I... O. i. ],. 1. z., Fig. 1. Survival Rates of Stage IIIB NSCLC Patients with or without Pleural Effusion. Survival curves without pleural effusion (O), and with cytology negative effusion (0), copared with survival curves of stage IliA NSCLC patients treated with RT during the sae tie period (--). oi 100 5O 0 z I z I 9 Fig. 2. Survival Rates of Patients with Stage Ill B NSCLC but without Pleural Effusion According to Clinical Nodal Stage. Survivals with N0-2 d isease (O), and with N3 disease (0). There was a significant difference in survival between the two groups (P < 0.05). A > "E -j O ~ Fig. 3. Survival Rates of the Patients with Stage lllb NSCLC but without Pleural Effusion According to Perforance Status (PS). Survivals of patients with PS 0-I (O), and with PS 2-3 (0). There was a borderline difference in survival between the two groups (P = 0.06). o 14

3 Hayakawa et al. Table 1. Stage IIIB Non-Sall Cell Lung Cancer Survivals According to Patient and Tuor Characteristics Treated with Definitive Radiation Therapy. Characteristics No. Survival rates (%) Median survival P value 1 y 3 y (o) Patient characteristics: Age < 70 y NS > 70 y Sex Feale NS Male PS NS Tuor characteristics: Tuor size < 5 c NS > 5 c T stage T NS T T N stage N < 0.05 N Histologic type Squaous NS Adeno-Large Priary sites Upper NS ~ Sup-seg* Lower* Main-int* Treatent factors: Total dose Field size" > 60 Gy NS > 70 Gy < 100 c NS > 100 c *Sup-seg, the superior segent 0fthe lower lobe; *lower, lower lobe except for the superior segent;*ain-int, ain or interediate bronchus. ~aong upper lobes, sup-seg vs. lower lobe vs. ain-int. "Field size, the size of the shrinking field after 40 Gy. squaous cell carcinoa were alive and well after 5 years without disease progression. No patients with non-squaous cell carcinoa were free of disease after 5 years. There were no other iportant factors that affected survival by univariate analysis (Table 1). Multivariate analysis indicated that age (P < 0.02) and N stage (P < 0.01) were the significant factors that affected survival (Table 2). In the patterns of failure, the ultiate local/regional control rate was only 33% until the last follow-up. Distant failures occurred in 6 (21%) out of 28 patients with squaous cell carcinoa, as copared to 11 (61%) out of 18 patients with non-squaous cell carcinoa. There were no patients who experienced treatent interruption due to acute toxicity. No patients suffered fro late coplications associated with RT. DISCUSSION Surgical resection is still considered the treatent of choice for early stage NSCLC. However, any patients have locally advanced disease or distant etastasis at the tie of diagnosis. Total surgical excision is possible on occasion in ost T3 tuors with inial N2 disease; but, it is rare in T4 or N3 disease. Although patients with locally advanced NSCLC have been treated with thoracic RT cobined with or without cheotherapeutic agents, therapeutic options for patients with stage IIIB disease and stage IIIA patients with huge T3 tuors or bulky N2 disease are ainly palliative. Thoracic RT yields a 5-year survival rate of 5% to 10%. 1 RT offers a great relief of syptos and a long-ter control of disease. For those factors affecting the prognosis of patients with unresectable NSCLC, it was reported that the correlation of prognostic paraeters, such as perforance status 4,11-13 and extent (size and stage) of the tuor, was very iportant. 4,12,13 The characteristics of a patient's age and sex were reported not to correlate with prognosis. 11,13,14 However, our result of RT use in only patients with stage IIIB indicated that age should have an unfavorable influence on the prognosis of lung cancer treated with RT. The Radiation Therapy Oncology Group reported that the tuor response after receiving Gy was highly correlated with tuor size. 12 However, it was also reported that there was no correlation between tuor size and ultiate survival. In our stage IIIB series there was no correlation of tuor size to local control and survival. In the analysis of treatent outcoes of those patients with ore 15

4 Radiation Therapy for Stage IIIB NSCLC Table 2. Multivariate Analyses of Prognostic Factors on Survival Using Cox's Proportional Hazard Model. Prognostic factors HR (95% C]) P value Age* 1.52 ( ) Sex Feale 1.00 (Referent) 0.81 Male 0.91 ( ) Peforance status (Referent) ( ) ( ) ( ) Histology Squaous 1.00 (Referent) 0.31 Non-squaous 1.40 ( ) Tuor size < 5 c 1.00 (Referent) 0.35 > 5 c 1.41 ( ) Tuor stage T (Referent) 0.19 T3-4 t 1.28 ( ) Thoracic bony wall 1.63 ( ) Pleura] effusion 2.09 ( ) N stage N (Referent) N ( ) N3 Supraclavicular 2.86 ( ) Contralateral 4.83 ( ) Priary site Upper lobes & sup-seg 1.00 (Referent) 0.39 Lower lobes 1.27 ( ) Main-int 1.60 ( ) Total dose > 60 Gy 1.00 (Referent) 0.99 >_ 70 Gy 0.99 ( ) Field size _< 100 c (Referent) 0.37 > 100 c ( ) HR, hazard ratio; CI, confidence interval. *For the 10-year interval. *Not including thoracic bony invasion and pleural effusion. advanced NSCLC, ost patients had distant failures. Therefore, the reason for the discrepancy in local control and survival rates ay result fro the deaths due to distant etastases that overshadowed the iproveents in the local control of saller tuors in stage IIIB patients. In this study the edian survival was significantly longer in the patients with stage N0-2 disease in coparison with stage N3 disease. The ultivariate analysis also deonstrated that clinical N stage was only one iportant factor affecting survival (P < 0.01) in the tuor characteristic variables. This phenoenon ay be due to at least two ajor factors that liited the curative potential of RT alone in stage IIIB NSCLC. The first is the presence of extra-thoracic icroetastatic spread at the tie of diagnosis in the ajority of patients. The second factor is the biological efficacy-toxic ratio of the RT itself. Many reports indicate that those patients who had received higher radiation doses had a better prognosis. Dosoretz et al. 15 presents additional interesting data that showed only those patients with tuors saller than 3 c deonstrated a doseresponse correlation with iproved local control after eploying doses in excess of 65 Gy. In those patients with larger tuors there is no significant additional advantage in local control by giving doses in excess of 65 Gy. Katz et al. 6 reviewed any reports of definitive RT for NSCLC and described no iproveent in survival with the higher doses (70 Gy or ore) because the dose over 70 Gy exceeded the acceptable tolerance levels critical for noral tissues in the sizes of fields coonly used in the definitive irradiation of lung cancer. Furtherore, the radiation portal size encopassing intrathoracic disease for stage N3 patients ay be larger than that for stage N0-2 patients. The irradiated volue is correlated with the tolerable dose for noral tissues. Therefore, at the tolerated total doses with standard RT, in-field sterilization only occurs in a saller percentage of treated N3 patients rather than in N0-2 patients. The addition of cheotherapy plus RT has been proposed and various treatent schedules have been used in randoized clinical trials to iprove the results of RT for patients with stage IIIB disease. Recent reports deonstrate a survival benefit for cobined cheoradiotherapy. However, the therapeutic gain was liited Furtherore, the elderly patients or poor perforance status patients can not always receive intensive cheotherapy due to the toxicity of the odality itself. Our results provide support for the use of definitive RT to anage the liited stage IIIB patients without N3 disease or alignant effusion. A new strategy to lower the risk-benefit ratio in using cobined cheoradiotherapy erits further investigation. This ay be accoplished by the use of a 3-diensional plan 2~ to reduce irradiated 16

5 Hayakawa et al. volue and increase radiatiotherapy doses to the tuor targets with or without biological reponse odifiers, including noral tissue protectors. ACKNOWLEDGMENTS We are grateful to Dr. Kiryu of the Departent of Public Health, Guna University School of Medicine for his statistical analyses of our data. This work was partially supported by a Grant-in-Aid for Cancer Research fro the Ministry of Education, Science and Culture ( , ), and the Ministry of Health and Welfare of Japan (6-13). REFERENCES 1. Dastrup L, Poulsen HS. Review of the curative role of radiotherapy in the treatent of non-sall cell lung cancer. Lung Cancer 1994; 11: Sandler AB, Buzaid AC. Lung cancer: a review of current therapeutic odalities. Lung 1992; 170: Gordon,W. The anageent of lung cancer with radiation therapy: where we are now and where we are going. J Thorac Iaging 1991 ;7: Hayakawa K, Mitsuhashi N, Nakajia T, SaitoY, Mitoo O, Nakayaa Y, Katano S, Niibe H. Radiation therapy for stage I-III epideroid carcinoa of the lung. Lung Cancer 1992;8: Hazuka MB, Bunn PA. Controversies in the nonsurgical treatent of stage III non-sall cell lung cancer. A Rev Respir Dis 1992;145: Katz HR, Alberts RW A coparison of high-dose continuous and split-course irradiation in non-oat cell carcinoa of the lung. A J Clin Oncol 1983;6: Koaki R, Cox JD, Hartz AJ, Byhardt RW, Perez-Taayo C, Clowry L, Choi H, Wilson F, Da Conceicao AL, Rangala N. Characteristics of long ter survivors after treatent for inoperable carcinoa of the lung. A J Clin Oncol 1985;8: Mantravadi RVP, Gates JO, Crawford JN, Bajpai D, Trenkner JD, Jordan LN. Unresectable non-oat cell carcinoa of the lung: definitive radiation therapy. Radiology 1989;172: Talton BM, Constable WC, Kersh CR. Curative radiotherapy in non-sall cell carcinoa of the lung. Int J Radiat Oncol Biol Phys 1990;19: Choi NCH, Doucette JA. Iproved survival of patients with unresectable non-sall-cell bronchogenic carcinoa by an innovated high-dose en-bloc radiotherapeutic approach. Cancer 1981;48: Feld R, Borges M, Giner V, Ginsberg R, Harper P, Klastersky J, Lacquet L, Paesans M, Payne D, Rosell R, Sause W, Sculier JP, Shaw W, Sorensen JB, Splinter T, Stahel R, Bunn P. Prognostic factors in non-sall cell lung cancer. Lung Cancer 1994; 11 (suppl 3) :S 19-$ Perez CA, Stanley K, Grundy G, Hanson W, Rubin 17, Kraer S, Brady LW, Marks JE, Perez-Taayo R, Brown GS, Concannon JP, Rotan M. Ipact of irradiation technique and tuor extent in tuor control and survival of patients with unresectable non-oat cell carcinoa of the lung. Cancer 1982; 50: Sorensen JB. Ipact of prognostic factors on endpoints for clinical studies. Lung Cancer 1994; 11 (suppl 3):$45-$ Aristizabal SA, Meyerson M, Caldwell WL, Mayer EG. Age as a prognostic indicator in carcinoa of the lung. Radiology 1976;121: Dosoretz DE, Katin MJ, Blitzer PH, Rubenstein JH, Salenius S, Rashid M, Dosani RA, Mestas (3, Siegel AD, ChadhaTT, ChandrahasaT, Hannah SE, Bhat SB, Metke MP. Radiation therapy in the anageent of edically inoperable carcinoa of the lung: results and iplications for future treatent strategies. Int J Radiat Oncol Biol Phys 1992;24: Dillan RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, Carey RW, Frei EF III, Green MR. A randoized trial of induction cheotherapy plus highdose radiation versus radiation alone in stage III non-sall cell lung cancer. N Engl J Med 1990;323: Arriagada R, LeChevalier T, Quoix E, Ruffie P, De Creoux H, Dorlillard JY, Tarayre M, Pignon JP, Laplanche A, the GETCB, the FNCLCC, the CEBI trialists. ASTRO plenary: effect of cheotherapy on locally advanced non-sall cell lung carcinoa: a randoized study of 353 patients. Int J Radiat Oncol Biol Plays 1991;20: Mattson K, Holsti LR. Inoperable non-sall cell lung cancer: radiation with or without cheotherapy. Eur J Cancer Clin Oncol 1988;24: Marino P, Preatoni A, Cantoni A. Randoized trials of radiotherapy alone versus cobined cheotherapy and radiotherapy in stages IIIa and IIIb non-sall cell lung cancer: a eta-analysis. Cancer 1995;76: Eai B, Graha MV, Purdy JA. Three-diensional conforal radiotherapy in bronchogenic carcinoa: considerations for ipleentation. Lung Cancer 1994; 11 (suppl 3):S117-S