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Hyperfractionated radiotherapy alternating with multidrug chemotherapy in the treatment of limited small cell lung cancer (SCLC)
IN. J. Rndrnkm Oncology Bio/ Printed in the U.S.A. All nghts
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??Original Contribution
HYPERFRACTIONATED RADIOTHERAPY ALTERNATING WITH MULTIDRUG CHEMOTHERAPY IN THE TREATMENT OF LIMITED SMALL CELL LUNG CANCER (SCLC) FRANCOISE MORNEX, M.D., VERONIQUE TRILLET, M.D., FRANCK CHAUVIN, M.D., JEAN-MICHEL ARDIET, M.D., THIERRY SCHMITT, M.D., PASCALE ROMESTAING, M.D., CHRISTIAN CARRIE, M.D., MARC MAHE, M.D., JEAN-FRANCOIS MORNEX, M.D., PIERRE FOURNEL, M.D., PIERRE-JEAN SOUQUET, M.D., ELISABETH BONIFACE, M.D., MICHEL VINCENT, M.D., DANIEL PIPERNO, M.D., PAUL REBATTU, M.D., JEAN-PIERRE GERARD, M.D. AND the Groupe Lyonnais d’oncologie Thoracique Groupe Lyonnais d’oncologie Thoracique (G.L.O.T.) Lyon, France From January 1986 through December 1988, 227 patients were included in a multi-institutional pilot study for small cell lung cancer (SCLC). Out of the 211 patients who fully completed the staging procedures, 77 (35%) appeared to have SCLC limited to the thorax. All patients received combination therapy consisting of AVI (Adriamycin, VP-16 and Ifosfamide), except during radiotherapy when the Adriamycin was omitted, plus twice daily fractionated 18 MV radiotherapy. Treatment protocol consisted of 4 initial courses of AVI, followed by 3 courses of radiotherapy alternating with modified chemotherapy (VP-16 and Ifosfamide), completed by 2 courses of initial chemotherapy (AVI). Radiotherapy consisted of 1.5 Gy/fraction, 2 fractions/day, 5 days/week in the first course, and 1.8 Gy/fraction, 2 fractions/day, 5 days/week, in the second and third courses, for a total tumor dose of 51 Gy, felt to be equivalent to 60 Gy at normal fractionation. CT treatment planning was employed to design a treatment consisting of multiport radiotherapy, using AP-PA and laterals or obliques beams. During the first course, the homolateral hemithorax received 9 Gy total dose on days 1,3, 5. During the third course, 360” arctherapy was generally used to boost the reduced tumor volume to a 51 Gy. Besides chest X ray and CT scan, staging and restaging procedures included fiberoptic bronchoscopy. Response rate after irradiation is 61%, with 46% complete responders and 51% local control. The median survival is 14 months, and disease-free survival 42% at 1 year. Complications consisted of cardiac toxicity in 2 patients, 1 death of acute pulmonary toxicity, and 4 instances of moderate chronic radiation pneumonitis. Thus, high doses of radiation can be delivered combined with chemotherapy using this protocol, with an acceptable toxicity and encouraging results in response rate and local control. A longer follow-up is needed to evaluate the impact of these results on survival. Hyperfractionated
radiotherapy, Limited small cell lung cancer, Combination radiotherapy and chemotherapy.
INTRODUCTION
viva1 (greater than 2 years) among patients with extensive stage disease is very rare. Radiation therapy has long played a major role in the treatment of limited-stage SCLC. In one of the earliest prospective randomized trials performed for this disease, radiotherapy proved superior to surgery therapy in terms of both median and long-term survival duration in operable patients of limited stage (11). Progresses in the treatment of SCLC have included single-agent chemotherapy ( 14), combination chemotherapy (2), and irradiation initially restricted to loco-regional
Despite its high initial chemosensitivity and radiosensitivity, (1, 31) small cell lung cancer (SCLC) continues to demonstrate a poor prognosis, with a median survival of 2-3 months without treatment. Complete remission, when obtained, is usually macroscopic, since local and systemic recurrences are highly probable, with a very low percentage (8-20%) of long-term survivors among patients with limited stage disease ( 13, 15, 22, 23, 28). Long-term sur_
Presented at the 3 1st Annual Meeting of the American Society of Therapeutic Radiology and Oncology, San Francisco, CA l6 October 1989. Reprint requests to: F. Momex, Department Therapy, Centre Leon Berard, 28 rue Laennec, Cedex, France.
Acknowledgements-We
wish to thank J. R. Castro and E. Glatstein for helpful suggestions. This work was supported by la Ligue Nationale de Lutte contre le Cancer. ComitC Dtpartemental du RhBne. Accepted for publication 9 February 1990.
of Radiation 69373 Lyon
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1. J. Radiation Oncology 0 Biology 0 Physics
failures (7, 8). More recently, radiation administered in combination with chemotherapy reduces the incidence of chest recurrence in several studies (3, 12, 18, 20, 25, 26, 27) but not in all (30). A survival advantage has been reported in some (3, 26, 27) but not in all studies after combined modality therapy (20, 25). The sequencing of modalities depends on many considerations and optimal sequences are not known: sequential, concurrent or alternating. Alternating protocols, defined as “a combined modality therapy in which radiotherapy is given on days of the chemotherapy cycle in which no chemotherapy is administered”, offers a major theoretical advantage: avoidance of the toxic effects resulting from the concurrent administration of drugs and radiation. Alternating two different treatment modalities with minimal cross-toxicity gives more time for recovery of critical normal tissue after each modality. Full doses of radiotherapy and chemotherapy may then be delivered. In addition alternating protocols may avoid a long gap in the chemotherapy delivery and may shorten the time interval between the various agents. Furthermore, the high growth fraction, short cell cycle time and absence of shoulder (24) of SCLC cell lines make this tumor a ideal candidate for hyperfractionation, which allows the delivery of high radiation doses in an overall short time period. However, high doses of radiation must be balanced against the additional toxicity that results from such treatment. Hyperfractionation can help to minimize toxicity, by sparing the normal tissues, since the rationale for multiple fractions per day radiation is that late-responding normal tissues recover more rapidly than the tumor, and the size of each individual exposure is modest. Biologically, in vitro data show lack of a “shoulder” for SCLC cell lines (24). Small fractions cause less damage to most normal tissues, but cells without a shoulder (like SCLC) are killed exponentially. The interval between doses enables repair by “shouldered” cells (like normal tissues), but allows further kill of surviving “shoulderless” small cells. Preliminary results suggest recommendation of this treatment modality (21, 29, 3 1, 36). In this context, we designed a pilot study to evaluate the advantages of combining hyperfractionated radiotherapy, including hemithoracic irradiation, alternating with a new multidrug chemotherapy protocol in patients presenting with limited-stage SCLC. The objectives of our protocol were as follows: (a) to determine the overall and complete response rate, as well as local control, in patients with limited-stage SCLC treated with chemotherapy alternating with radiotherapy administered in a twice-daily regimen; (b) to determine the acute and late adverse effects of this combined modality regimen; (c) to evaluate patterns of failure after treatment with this regimen with particular emphasis on local intrathoracic control of tumor; (d) to evaluate the feasibility and the potential benefit of hyperfmctionation and lowdose homolateral hemithorax irradiation.
July 1990. Volume 19. Number I
METHODS
AND MATERIALS
Patients Between January 1986 and December 1988, 227 patients were included in a multiinstitutional pilot study for SCLC. Patients entered in this study were previously untreated and had histologically proven SCLC. Staging included chest X ray, blood counts, blood chemistries including liver and renal function tests, calcemia, CEA, bombesin, fiberoptic bronchoscopy, abdominal ultrasonography in every case and CT scan in some patients, thorax and brain CT, radionuclide bone scan, and bone marrow aspiration and biopsy. Seventy-seven patients were staged as having a limited disease. Patients with contralateral mediastinal, hilar involvement, as well as 11 patients with positive (4) or negative (7) cytological pleural effusion were included. Limited disease was defined as disease encompassable within a single radiation field. Patients with initial supraclavicular involvement were not considered as having a limited disease. No patient was excluded because of the presence of a very large initial tumor mass. Patients aged >70 years or with Karnofsky performance status < 50% were excluded. Patient characteristics are shown in Table 1. Treatment protocol An alternating treatment protocol was used. Four courses of chemotherapy preceded 3 courses of alternating twice daily radiotherapy to the primary tumor and modified chemotherapy. Two cycles of chemotherapy completed the treatment protocol. Total treatment duration is of 29 weeks (200 days). Chemotherapy (CT) consisted of AVI (Adriamycin 50 mg/m2 day 1, VP-16 150 mg/ m2 day 1 and 2, Ifosfamide 2g/m2 day 1 and 2), except during radiotherapy when the Adriamycin was omitted (CT’), plus twice daily fractionated 18 MV radiotherapy. Treatment protocol consisted of 4 initial courses of AVI, followed by 3 courses of radiotherapy alternating with modified chemotherapy (VP- 16, Ifosfamide), completed by 2 courses of AVI. Radiotherapy consisted of 1.5 Gy/ fraction, 2 fractions/day, 5 days/week, in the first course, and 1.8 Gylfraction, 2 fractions/day, 5 days/week, in the second and third courses, for a total tumor dose of 5 1 Gy; this was felt to be equivalent to 60 Gy at normal fractionation. An interval of 6 hr or more was required each day between the 2 radiation fractions. CT treatment planning was used to design a treatment consisting of multiport Table 1. Patient characteristics Number entered Male:female Age, years Karnofsky
(W)
Prior therapy
Mean Range SO-70 80-100
71 73:4 54.7 38-70 9 68 None
Hyperhactionated
radiotherapy alternating with chemotherapy in limited SCLC 0 F. MORNEXef al.
radiotherapy, using AP-PA and laterals or obliques, avoiding the spinal cord. Pulmonary density was taken into account for the calculation of parenchymal doses delivered. During the first course of radiotherapy, the homolateral hemithorax received 9 Gy total dose on days 1,3,5. During the third course, 360” arctherapy was generally used to boost a reduced tumor volume to the final total dose of 5 1 Gy. Both supraclavicular fossae were irradiated during RT2 and RT3, using Cobalt 60 or electrons (20 Gy in 5 fractions each radiation course). Details of protocol are described in Table 2. The target volume used for first and second courses of radiotherapy included all post-chemotherapy tumor volume, with a 2 cm margin of normal lung tissue, as well as mediastinum, both hilar and bilateral supraclavicular regions. During the third course of radiotherapy, the target volume was restricted to the tumor mass. None of these patients received a prophylactic cranial irradiation. Staging of patients was performed during the first course of AVI (evaluation 1); evaluation of patient response and toxicity was performed after 3 courses of AVI, prior to radiotherapy (evaluation 2) with restaging consisting of chest X ray, routine blood tests and fiberoptic bronchoscopy; after completion of radiotherapy (evaluation 3), with restaging consisting of chest X ray, blood tests (fiberoptic bronchoscopy was repeated only if abnormal at evaluation
2); and at the end of treatment protocol (evaluation 4), with restaging consisting of chest X ray, routine blood tests, fiberoptic bronchoscopy, abdominal ultrasonography or CT scan, thorax and brain CT, radionuclide bone scan, and bone marrow aspiration and biopsy. Each of the staging procedures included fiberoptic bronchoscopy with cytological and histological analysis of abnormal findings. Response evaluation and follow-up Responders were patients with complete or partial response: Complete response (CR) was defined as a complete disappearance of all objective tumor on the chest X ray, optically and histologically at the time of fiberoptic bronchoscopy, without evidence of new disease elsewhere. Partial response (PR) was defined as a decrease of 50% or more of the product of the two largest perpendicular diameters of measurable disease radiologically with concurrent endoscopic verification, without evidence of new disease elsewhere, or if cytologies or biopsies remained positive with disappearance of radiological abnormalities. Non-responding patients included minor response, stable disease, and/or progression: Minor response meant a decrease of 25 to 50% of the product of the two largest perpendicular diameters of measurable disease radiologically with concurrent endoscopic verification, without evidence
Table 2. Treatment Week 0 or 1
Stage (evaluation
Week l-4-7-10
Adriamycin VP-16 Ifosfamide
Week 12
Re-stage (evaluation
Week 13 RTl
25
protocol
1) 50 mg/m2 150 mg/m2 2 g/m2
d.l d.1 +2 d.1 +2
Radiotherapy
1.5 Gy b.i.d. Sd./wk; Mon.-Fri. total dose 15 Gy
d. 1 2fx./d.;
Week 16
VP-16 Ifosfamide
150 mg/m2 2 g/m2
d.l + 2 d.l + 2
Week 18 RT2
Radiotherapy
1.8 Gy b.i.d. 5d.wk; Mon.-Fri. total dose 18 Gy Supraclav. 20 Gy
d. 1 2fx./d.;
Week 2 1
VP-16 Ifosfamide
150 mg/m2 2 g/m2
d.1 + 2 d.l + 2
Week 23 RT3
Radiotherapy
1.8 Gy b.i.d. 5d. Jwk; Mon.-Fri. total dose 18 Gy Supraclav. 20 Gy
d. 1 Zfx./d.;
Week 25
Re-stage (evaluation
Week 26-29
Adriamycin VP-16 Ifosfamide
50 mg/m2 150 mg/ms2 2 g/m2
d.l d.l + 2 d.1 +2
Week 3 1
Re-stage (evaluation
2)
3)
4)
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of new disease elsewhere. Stable disease was defined as a decrease of less than 25% or progression of less than 25% of the product of the two largest perpendicular diameters of measurable disease radiologically with concurrent endoscopic verification, without evidence of new disease elsewhere. Progression was defined as an increase of more than 25% of the product of the two largest perpendicular diameters of measurable disease radiologically with concurrent endoscopic verification, or appearance of distant disease. Patients with normal chest X ray, normal CT scan and normal fiberoptic endoscopy, but with positive cytologies or biopsies were always staged as partial responders. Patients with normal chest X ray, negative cytologies but abnormal CT scan were staged as partial responders. Local control of chest disease was defined as the complete disappearance of SCLC in the chest. Thus. by definition, no partial responders achieved local control. These patients were not cured because of the inability to control local disease. Among the 77 patients presenting with limited disease, only patients demonstrating partial or complete response (PR or CR) at the time of evaluation 2 were included in the radiotherapeutic protocol. Patients presenting with minor response, stable disease or progression were evaluated, then included in a second-line protocol. The same criteria were used for evaluation 3. Follow-up was performed as a regular schedule. After completion of treatment, patients were assessed radiologically every 2 months or whenever a new event appeared.
Statistical analysis All patients were considered for statistical analysis. The results were analyzed for tumor response, local control, treatment toxicity (according to the WHO scale grading) (35). Overall survival and relapse-free survival were calculated according to the Kaplan Meier method (17). Local control time was measured from the date of first treatment to the date on which local recurrence was detected or to the date of last follow-up without local recurrence.
RESULTS Altogether, 77 patients were included in the protocol described above. After 3 courses of chemotherapy, at the time of evaluation 2, 58 patients were included in the radiotherapy protocol. Among the 19 patients who were excluded, 6 had a minor response, 6 had a stable disease, and 6 had progression. In addition, one patient died suddenly of unknown cause. Seventy-six patients were thus evaluable for response. Fifty-eight patients were irradiated and evaluable for toxicity, but only 53 were evaluable at the time of this study, for response. The median followup was 18 months (7 months-40 months). The response rate (CR + PR) after 3 courses of chemotherapy (evaluation 2) was 58/76 (76%) with 42% showing complete response. After completion of radiotherapy alternating
July 1990. Volume 19, Number 1 Table 3. Effect of radiotherapy on tumor response and survival Before XRT Evaluable for response Responders Complete responders
76* 58 (76%) 32
Partial responders
26
Response rate Local control rate Partial responders converted into complete responders Overall median survival Disease-free survival
76%
After XRT 53+ 46 (61%) 4 unevaluable 4 progressions 24 complete responders 1 unevaluable 3 progressions 1I complete responders 11 partial responders 61% 51% 1 l/26 (42%)
14 months 42% at 1 year
* Among the 77 limited patients, one died during induction chemotherapy. + Fifty-three of 58 patients were evaluable after radiotherapy.
with modified chemotherapy (evaluation 3), the response rate was 46/76 (61%) with 35/76 (46%) complete response. Radiation therapy converted 11 partial responders into complete responders (42%). Two patients had only a positive biopsy before irradiation, 8 had a remaining tumor mass, 1 had a positive biopsy and a remaining tumor mass. Several of these patients had a complete radiological and endoscopic regression, but positive biopsies before radiotherapy, which were negative after irradiation. The local control rate, obtained by this chemotherapyradiotherapy combination, was 39/76 (5 1%): thirty-five patients demonstrated a complete response; among the patients who progressed, four had no local relapse; they were therefore included as locally controlled. The percentage of complete responders having a disease-free survival of 12 months was 42%. The actuarial overall median survival was 14 months. The median response duration was 14 months for responders. The results are summarized in Table 3.
Patterns 0fJizilure Local: Among the 35 patients in complete response after radiotherapy, 11 (3 1%) ultimately manifested a local recurrence: 8 patients had local recurrence only, 3 had both local and distant recurrence. The relapse-free survival at 12 months was 68% for complete responders. The median time for recurrence to appear was 10 months after initiation of treatment protocol. Distant: Among the 35 patients in complete response
Hyperfiactionated radiotherapy alternating with chemotherapy in limited SCLC 0 F. MORNEXet a/.
after radiotherapy, 11 patients (3 1%) had metastases only (10 brain metastases and 1 skin metastases). Three patients demonstrated both local recurrence and distant metastases (2 liver metastases, 1 osseous metastases). The results are summarized in Table 4.
Table 5. Toxicity of chemo-radiotherapy (number of patients). Among the 77 limited-stage patients, 58 were irradiated and 53 were evaluable after radiotherapy, for response and toxicity
Toxicity
Pulmonary: Fourteen patients showed radiologic changes of pulmonary toxicity. Eleven of these patients had clinical evidence of radiation acute pneumonitis; six patients were hospitalized (9 to 30 days). Four patients developed fibrosis, with moderate dyspnea on exertion, which was nonetheless compatible with a normal daily life. One patient died with acute pulmonary toxicity after radiotherapy. In total, five patients showed a critical pulmonary event due to irradiation or combined therapy. Clinical or radiological signs appeared between 1 and 169 days after the beginning of radiotherapy. Cardiac: Eight patients had clinical evidence of cardiac toxicity: 4 patients had a myocardiopathy, 3 patients had a pericarditis, and 1 patient had a pericarditis and myocardiopathy. EKG or radiologic changes were inconstant. Four patients were hospitalized ( 10 to 60 days). Two patients had a chronic cardiac complication, requiring permanent care: In 1 patient the tumor was located in the right lung (lower lobe), in the other patient, there was a large left upper lobe tumor. Esophageal: During radiotherapy patients experienced mild dysphagia or nausea, grade 1 or 2 in general (according to the WHO classification). For example, the third course of radiotherapy induced 9 grade 1,6 grade 2, and 1 grade 3 dysphagia. Hematologic: Ten patients manifested febrile aplasia, requiring hospitalization in 9, for 2 to 30 days. Seven of them required antibiotics. No cutaneous toxicity was observed. No patient received a reduced radiation dose because of toxicity. However, the second radiotherapy cycle was delayed in 6 patients from 1 to 3 weeks, and the third cycle was delayed from 1 to 2 weeks in 7 patients, due to toxicity. The toxicities are listed in Table 5. DISCUSSION The overall response rate was 6 1% after irradiation. The role of radiotherapy to achieve complete response Table 4. Patterns of failure in complete response patients (35 patients)
Local recurrence only Local and distant recurrence Total of local recurrences 11 (3 1%) Metastases only: Brain Skin Total of local and distant relapses Relapse-free survival at 12 months
08 03 10 01 22135 (63%) 68%
27
Lung Symptoms Deaths Heart Symptoms Hematopoietic system Febrile aplasia Esophagus Dysphagia Grade 1 Grade 2 Grade 3
Acute toxicity
Chronic clinical toxicity
11 1
4 (7.5%) 0
8
2 (3.8%)
10
0
19* 08 02
0 0 0
* Cumulation of digestive toxicities observed at each of 3 times of radiotherapy.
must be emphasized, since among 26 partial responders before irradiation, 11 (42%) were converted into complete responders after irradiation. This fact is important, because other groups (20, 34) have already shown the possibility of converting a chemotherapy partial responder into a complete responder with the use of thoracic irradiation: White et al. (34) described 38% of PR converted into CR. Furthermore, conversion may lead to prolonged survival. In this context, it is critical to have extensive and precise staging and restaging procedures. We therefore included a systematic evaluation of the endobronchial response using fiberoptic bronchoscopy. The local control rate was 5 1%. The follow-up is not yet long enough for meaningful analysis of median and disease-free survival. These promising results must be interpreted in the context of recent studies using combined modalities, which show lower or comparable results, especially when considering the sizeable number of patients in our study, and the inclusion of patients presenting with a very large initial mass, reaching the chest wall in many patients. In addition, we included 11 patients presenting with pleural effusion (four with proven malignant cells) as limited. These two types of patients are often excluded in other series. This high local control rate is probably related to the high radiation dose, as shown in different studies attempting to correlate radiation dose and locoregional tumor control in limited stage SCLC (5, 9, 10, 19, 20, 34). However, the value of higher doses must be balanced against the additional toxicity that results from such treatment. The NC1 experience for example showed that a modest increase in the dose (30 to 45 Gy) markedly increased the complications of therapy (4). The overall results obtained by the present protocol are
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inkeeping with previous reports by Bunn et al. and Turrisi et al. (3, 32). In both reports, high complete response rate were obtained by using combined therapy. Furthermore, Bunn et al. (3) have demonstrated a higher response rate in combined therapy when compared to chemotherapy a high response alone. Turrisi et al. (32) demonstrated rate when using a twice daily fractionation as we did. The high radiation dose delivered has been well-tolerated. Significant complications include pulmonary and cardiac events. Among 58 evaluable patients, one died of acute radiation pneumonitis. Four patients (7.5%) suffered chronic radiation pneumonitis, which was responsible for moderate dyspnea on exertion. Cardiac events are attributed to the combination of anthracyclines and radiotherapy. Two patients (3.8%) developed a chronic myocardiopathy, requiring treatment with diuretics and digitalis. In both patients the tumor location can be incriminated (1 lower right lobe, 1 left lobe including a large part of the cardiac area). These cardiac complications indicate a need for greater attention to dosimetric detail in the future, and also a need to measure cardiac ejection fraction isotopically in patients who present with critical tumor location. Less cardiotoxic chemotherapy might also be considered. Despite the use of high doses of radiation, patients otherwise tolerated treatment well. This can be explained by the use of twice-daily fractionation, which allows repair of normal tissues, even when high doses are delivered daily to the tumor (2 1,29,3 1,36). The interval of 6 hr between the 2 daily fractions seems to be important (36). In our protocol, the hyperfractionation employed high daily doses (3 to 3.6 Gy), which represents accelerated hyperfractionation (36). In addition, this protocol addressed the question of the treatment volume: should one irradiate the initial tumor volume, or a reduced volume? Complete response to chemotherapy is unfortunately microscopic only, since the probability of local recurrence is very high (20). Radiation delivered only to reduced volumes appears to be inadequate, and current recommendations are to deliver at least one-third to one-half of the radiation dose to the original prechemotherapy tumor volume (20). When faced with a large initial mass, can low-dose irradiation of an initial
July 1990, Volume 19, Number 1
large tumor volume help to decrease the relapse rate, by treating microscopic residual disease? SCLC is a radioresponsive tumor and the analogy of successful large field irradiation in lymphoma led to our interest in trying this therapy in patients with SCLC. Urtasun et al. (33) obtained a 87% response rate with a 47% CR rate in SCLC patients treated by hemibody irradiation. Hurman et al. ( 16) treated limited stage patients with 6 cycles of chemotherapy, and the upper hemibody irradiation being delivered during the second chemotherapy cycle. CR rate was 83%, but a high rate of pneumonitis (5/21 patients) was observed, probably due to interactions between drugs and radiation. The authors suggest shielding the controlateral lung to decrease the pulmonary toxicity. Our results are preliminary, and not conclusive, but suggest that irradiating such a large volume can be performed without toxicity. Local intrathoracic failure rate was 3 1% ( 11 patients). This result is encouraging since 11 patients included in our study presented initially with pleural effusion, which is considered systemic dissemination by most investigators. Thoracic failure often occurred within the treated volume, suggesting insufficient dose rather than insufficient tumor coverage. Because the radiation dose has been well tolerated, we think an increased dose can be proposed, as recommended by Choi et al. (6) in their last study. Brain metastasis, commonly the first site of relapse in our study, again raises the question of the value of prophylactic cranial irradiation, alone or in combination with appropriate chemotherapy, to eradicate micrometastases. In conclusion, alternating different modality protocols have the advantage of permitting a continuous chemotherapy schedule. Accelerated hyperfractionation allows delivery of a high dose of radiation with an acceptable toxicity. We have shown that radiotherapy is capable of increasing the response rate markedly, especially the complete response rate in patients. This is important since complete responders seem to represent a potential population of long-term survivors. Optimal protocols have not yet been designed, but quality of life must be taken into account, in a disease where “quantity of life” is often the major aim.
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34.
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fractionated radiotherapy into combined chemotherapeuticradiotherapeutic approaches to lung cancer treatment. In: Aniagada, R., ed. Treatment modalities in lung cancer. Basel: Karger; 1988:176-183. Matthews, M. J.; Rosencweig, M.; Staquet, M. J.; Minna, J. D.; Muggia, F. M. Long term survivors with small cell carcinoma of the lung. Eur. J. Cancer 16:527-531; 1979. Minna, J. D.; Lichter, A.; Brereton, H.; Bunn, P.; Cohen, N.; Fossieck, B.; Ihde, D.; Johnson, R.; Matthews, M.; Glatstein, E. Small cell lung cancer: long-term potentially cured survivors in National Cancer Institute Trials. Clin. Res. 28: 419; 1980. Mitchell, J. B.; Morstyn, G.; Russo, A.; Camey, D. N. In vitro radiobiology of human lung cancer. Cancer Treat. Symp. 2:3-10; 1985. Osterlind, K.; Hansen, H. H.; Hansen, H. S.; Dombernowsky, P.; Hansen, M.; Rorth, M. Chemotherapy versus chemotherapy plus irradiation in limited small cell lung cancer: results of a controlled trial with 5 years’ follow-up. Br. J. Cancer 54:7-l 7; 1986. Perez, C. A.: Einhorn, L.; Oldham, R. K.; Greco, F. A.; Cohen, H. J.; Silberman, H.; Krauss, S.; Homback, N.; Comas, F.; Omura, G.; Salter, M.: Keller, J. W.; McLaren, J.; Kellermeyer, R.; Storaasli. J.; Birch, R.; Dandy, M. Randomized trial of radiotherapy to the thorax in limited small cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: A preliminary report. J. Clin. Oncol. 2: 1200- 1208; 1984. Perry, M. C.; Eaton, W. L.; Propet-t, K. J.; Ware, J. H.; Zimmer, B.; Chahinian, P.; Skarin, A.; Carey, R. W.; Kreisman, H.; Faulkner, C.; Comis, R.; Green, M. R. Chemotherapy with or without radiation therapy in limited smallcell carcinoma of the lung. N. Engl. J. Med. 3 16:9 12-9 18; 1987. Peschel, R. E.; Kapp, D. S.; Carter, D.; Knowlton, A. Long term survivors with small cell carcinoma of the lung. Int. J. Radiat. Oncol. Biol. Phys. 7: 1545- 1548; 198 1. Scher, H.; Gralla, R.; Linares, L.; Kris, M.; Heelan, R.; Shank, B. Preliminary results of combination chemotherapy and sequential accelerated fractionation radiation therapy in limited-stage small cell carcinoma of the lung. In: Arriagada, R., ed. Treatment modalities in lung cancer. Basel: Karger; 1988: 184- 189. Souhami, R. L.; Geddes, D. M.; Spiro, S. G.; Harper, P. G.; Tobias, J. S.; Mantell, B. S.; Fearon, F.; Bradbury, I. Radiotherapy in small cell cancer of the lung treated with combination chemotherapy: a controlled trial. Br. Med. J. 288: 1643-1646: 1984. Thames, H. D.; Peters, L. S.; Withers, H. R.; Fletcher, G. H. Accelerated fractionation vs. hyperfractionation: rationales for several treatments per day. Int. J. Radiat. Oncol. Biol. Phys. 9:127-138; 1983. Turrisi, A. T.; Glover, D. J.; Mason, B. A. A preliminary report: concurrent twice-daily radiotherapy plus platinumetoposide chemotherapy for limited small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 15:183-187; 1988. Urtasun. R. C.; Belch, A.; Bodnar, R. N. Hemibody radiation on active therapeutic modality for the management of patients with small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 9:1575-1578; 1983. White, J. E.; Chen, T.; McCracken, J.; Kennedy, P.; Seydel, H. G.; Hartman, G.; Mira, J.; Khan, M.; Durrance, F. Y.; Skinner, 0. The influence of radiation therapy quality control on survival, response and sites of relapse in oat cell carcinoma of the lung. Cancer 50: 1084- 1090; 1982.
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35. WHO Handbook for reporting the results of cancer treatment. World Health Organization, Geneva, 1979. 36. Withers, H. R. Biological basis for altered fractionation
schemes. Cancer 55:2086-2095; 1985.
APPENDIX
1
This investigation was carried out by the following member institutions of the Groupe Lyonnais d’Oncologie Thoracique (G.L.O.T.): Service de Pneumologie Pr Brune, Pr Cordier, Hopital Louis Pradel, Lyon; Service de Pneumologie Pr Emonot, Hopital Nord, Saint-Etienne; Service de Pneumologie Pr Bernard, Hopital Jules Courmont, Lyon; Service de Pneumologie Pr Kalb, Pr G&tin, Ho-
July 1990, Volume 19, Number 1
pita1 Croix Rousse, Lyon; Service de MMecine Dr. Clavel, Centre Leon Btrard, Lyon; Service de Pneumologie Pr Perrin Fayolle, Pr Pacheco, Hopital Sainte EugCnie, Lyon; Service de Pneumologie Dr. Van Straaten, Dr. Vincent, Hopital Saint Joseph, Lyon; Service de Radiotherapie Pr Chassard, Dr. Lacroze, Dr. Ardiet, Centre Leon Btrard, Lyon; Service de Radiotherapie, Pr Gerard, Dr. Romestaing, Hopital Jules Courmont, Lyon; Service de Radiotherapie Dr. Schmitt, Hopital Bellevue, Saint-Etienne; Unite de Biostastistiques Dr. Chauvin, Centre Leon BCrard, Lyon. Evaluation Group: Drs. E. Boniface, C. Carrie, P. Fournel, F. Gormand, C. Lasset, E. Laennec, G. Letanche, G. Mazoyer, F. Mornex, J. F. Mornex, M. Perol, D. Pipemo, P. Rebattu, P. J. Souquet, V. T&let, B. Velay, J. M. Vergnon, A. Voloch.
Phy.. Vol. reserved.
19, pp.
23-30
0360-3016/90
Copyrigtlt 0 1990
$3.00 + .oO Pergamon Press plc
??Original Contribution
HYPERFRACTIONATED RADIOTHERAPY ALTERNATING WITH MULTIDRUG CHEMOTHERAPY IN THE TREATMENT OF LIMITED SMALL CELL LUNG CANCER (SCLC) FRANCOISE MORNEX, M.D., VERONIQUE TRILLET, M.D., FRANCK CHAUVIN, M.D., JEAN-MICHEL ARDIET, M.D., THIERRY SCHMITT, M.D., PASCALE ROMESTAING, M.D., CHRISTIAN CARRIE, M.D., MARC MAHE, M.D., JEAN-FRANCOIS MORNEX, M.D., PIERRE FOURNEL, M.D., PIERRE-JEAN SOUQUET, M.D., ELISABETH BONIFACE, M.D., MICHEL VINCENT, M.D., DANIEL PIPERNO, M.D., PAUL REBATTU, M.D., JEAN-PIERRE GERARD, M.D. AND the Groupe Lyonnais d’oncologie Thoracique Groupe Lyonnais d’oncologie Thoracique (G.L.O.T.) Lyon, France From January 1986 through December 1988, 227 patients were included in a multi-institutional pilot study for small cell lung cancer (SCLC). Out of the 211 patients who fully completed the staging procedures, 77 (35%) appeared to have SCLC limited to the thorax. All patients received combination therapy consisting of AVI (Adriamycin, VP-16 and Ifosfamide), except during radiotherapy when the Adriamycin was omitted, plus twice daily fractionated 18 MV radiotherapy. Treatment protocol consisted of 4 initial courses of AVI, followed by 3 courses of radiotherapy alternating with modified chemotherapy (VP-16 and Ifosfamide), completed by 2 courses of initial chemotherapy (AVI). Radiotherapy consisted of 1.5 Gy/fraction, 2 fractions/day, 5 days/week in the first course, and 1.8 Gy/fraction, 2 fractions/day, 5 days/week, in the second and third courses, for a total tumor dose of 51 Gy, felt to be equivalent to 60 Gy at normal fractionation. CT treatment planning was employed to design a treatment consisting of multiport radiotherapy, using AP-PA and laterals or obliques beams. During the first course, the homolateral hemithorax received 9 Gy total dose on days 1,3, 5. During the third course, 360” arctherapy was generally used to boost the reduced tumor volume to a 51 Gy. Besides chest X ray and CT scan, staging and restaging procedures included fiberoptic bronchoscopy. Response rate after irradiation is 61%, with 46% complete responders and 51% local control. The median survival is 14 months, and disease-free survival 42% at 1 year. Complications consisted of cardiac toxicity in 2 patients, 1 death of acute pulmonary toxicity, and 4 instances of moderate chronic radiation pneumonitis. Thus, high doses of radiation can be delivered combined with chemotherapy using this protocol, with an acceptable toxicity and encouraging results in response rate and local control. A longer follow-up is needed to evaluate the impact of these results on survival. Hyperfractionated
radiotherapy, Limited small cell lung cancer, Combination radiotherapy and chemotherapy.
INTRODUCTION
viva1 (greater than 2 years) among patients with extensive stage disease is very rare. Radiation therapy has long played a major role in the treatment of limited-stage SCLC. In one of the earliest prospective randomized trials performed for this disease, radiotherapy proved superior to surgery therapy in terms of both median and long-term survival duration in operable patients of limited stage (11). Progresses in the treatment of SCLC have included single-agent chemotherapy ( 14), combination chemotherapy (2), and irradiation initially restricted to loco-regional
Despite its high initial chemosensitivity and radiosensitivity, (1, 31) small cell lung cancer (SCLC) continues to demonstrate a poor prognosis, with a median survival of 2-3 months without treatment. Complete remission, when obtained, is usually macroscopic, since local and systemic recurrences are highly probable, with a very low percentage (8-20%) of long-term survivors among patients with limited stage disease ( 13, 15, 22, 23, 28). Long-term sur_
Presented at the 3 1st Annual Meeting of the American Society of Therapeutic Radiology and Oncology, San Francisco, CA l6 October 1989. Reprint requests to: F. Momex, Department Therapy, Centre Leon Berard, 28 rue Laennec, Cedex, France.
Acknowledgements-We
wish to thank J. R. Castro and E. Glatstein for helpful suggestions. This work was supported by la Ligue Nationale de Lutte contre le Cancer. ComitC Dtpartemental du RhBne. Accepted for publication 9 February 1990.
of Radiation 69373 Lyon
23
24
1. J. Radiation Oncology 0 Biology 0 Physics
failures (7, 8). More recently, radiation administered in combination with chemotherapy reduces the incidence of chest recurrence in several studies (3, 12, 18, 20, 25, 26, 27) but not in all (30). A survival advantage has been reported in some (3, 26, 27) but not in all studies after combined modality therapy (20, 25). The sequencing of modalities depends on many considerations and optimal sequences are not known: sequential, concurrent or alternating. Alternating protocols, defined as “a combined modality therapy in which radiotherapy is given on days of the chemotherapy cycle in which no chemotherapy is administered”, offers a major theoretical advantage: avoidance of the toxic effects resulting from the concurrent administration of drugs and radiation. Alternating two different treatment modalities with minimal cross-toxicity gives more time for recovery of critical normal tissue after each modality. Full doses of radiotherapy and chemotherapy may then be delivered. In addition alternating protocols may avoid a long gap in the chemotherapy delivery and may shorten the time interval between the various agents. Furthermore, the high growth fraction, short cell cycle time and absence of shoulder (24) of SCLC cell lines make this tumor a ideal candidate for hyperfractionation, which allows the delivery of high radiation doses in an overall short time period. However, high doses of radiation must be balanced against the additional toxicity that results from such treatment. Hyperfractionation can help to minimize toxicity, by sparing the normal tissues, since the rationale for multiple fractions per day radiation is that late-responding normal tissues recover more rapidly than the tumor, and the size of each individual exposure is modest. Biologically, in vitro data show lack of a “shoulder” for SCLC cell lines (24). Small fractions cause less damage to most normal tissues, but cells without a shoulder (like SCLC) are killed exponentially. The interval between doses enables repair by “shouldered” cells (like normal tissues), but allows further kill of surviving “shoulderless” small cells. Preliminary results suggest recommendation of this treatment modality (21, 29, 3 1, 36). In this context, we designed a pilot study to evaluate the advantages of combining hyperfractionated radiotherapy, including hemithoracic irradiation, alternating with a new multidrug chemotherapy protocol in patients presenting with limited-stage SCLC. The objectives of our protocol were as follows: (a) to determine the overall and complete response rate, as well as local control, in patients with limited-stage SCLC treated with chemotherapy alternating with radiotherapy administered in a twice-daily regimen; (b) to determine the acute and late adverse effects of this combined modality regimen; (c) to evaluate patterns of failure after treatment with this regimen with particular emphasis on local intrathoracic control of tumor; (d) to evaluate the feasibility and the potential benefit of hyperfmctionation and lowdose homolateral hemithorax irradiation.
July 1990. Volume 19. Number I
METHODS
AND MATERIALS
Patients Between January 1986 and December 1988, 227 patients were included in a multiinstitutional pilot study for SCLC. Patients entered in this study were previously untreated and had histologically proven SCLC. Staging included chest X ray, blood counts, blood chemistries including liver and renal function tests, calcemia, CEA, bombesin, fiberoptic bronchoscopy, abdominal ultrasonography in every case and CT scan in some patients, thorax and brain CT, radionuclide bone scan, and bone marrow aspiration and biopsy. Seventy-seven patients were staged as having a limited disease. Patients with contralateral mediastinal, hilar involvement, as well as 11 patients with positive (4) or negative (7) cytological pleural effusion were included. Limited disease was defined as disease encompassable within a single radiation field. Patients with initial supraclavicular involvement were not considered as having a limited disease. No patient was excluded because of the presence of a very large initial tumor mass. Patients aged >70 years or with Karnofsky performance status < 50% were excluded. Patient characteristics are shown in Table 1. Treatment protocol An alternating treatment protocol was used. Four courses of chemotherapy preceded 3 courses of alternating twice daily radiotherapy to the primary tumor and modified chemotherapy. Two cycles of chemotherapy completed the treatment protocol. Total treatment duration is of 29 weeks (200 days). Chemotherapy (CT) consisted of AVI (Adriamycin 50 mg/m2 day 1, VP-16 150 mg/ m2 day 1 and 2, Ifosfamide 2g/m2 day 1 and 2), except during radiotherapy when the Adriamycin was omitted (CT’), plus twice daily fractionated 18 MV radiotherapy. Treatment protocol consisted of 4 initial courses of AVI, followed by 3 courses of radiotherapy alternating with modified chemotherapy (VP- 16, Ifosfamide), completed by 2 courses of AVI. Radiotherapy consisted of 1.5 Gy/ fraction, 2 fractions/day, 5 days/week, in the first course, and 1.8 Gylfraction, 2 fractions/day, 5 days/week, in the second and third courses, for a total tumor dose of 5 1 Gy; this was felt to be equivalent to 60 Gy at normal fractionation. An interval of 6 hr or more was required each day between the 2 radiation fractions. CT treatment planning was used to design a treatment consisting of multiport Table 1. Patient characteristics Number entered Male:female Age, years Karnofsky
(W)
Prior therapy
Mean Range SO-70 80-100
71 73:4 54.7 38-70 9 68 None
Hyperhactionated
radiotherapy alternating with chemotherapy in limited SCLC 0 F. MORNEXef al.
radiotherapy, using AP-PA and laterals or obliques, avoiding the spinal cord. Pulmonary density was taken into account for the calculation of parenchymal doses delivered. During the first course of radiotherapy, the homolateral hemithorax received 9 Gy total dose on days 1,3,5. During the third course, 360” arctherapy was generally used to boost a reduced tumor volume to the final total dose of 5 1 Gy. Both supraclavicular fossae were irradiated during RT2 and RT3, using Cobalt 60 or electrons (20 Gy in 5 fractions each radiation course). Details of protocol are described in Table 2. The target volume used for first and second courses of radiotherapy included all post-chemotherapy tumor volume, with a 2 cm margin of normal lung tissue, as well as mediastinum, both hilar and bilateral supraclavicular regions. During the third course of radiotherapy, the target volume was restricted to the tumor mass. None of these patients received a prophylactic cranial irradiation. Staging of patients was performed during the first course of AVI (evaluation 1); evaluation of patient response and toxicity was performed after 3 courses of AVI, prior to radiotherapy (evaluation 2) with restaging consisting of chest X ray, routine blood tests and fiberoptic bronchoscopy; after completion of radiotherapy (evaluation 3), with restaging consisting of chest X ray, blood tests (fiberoptic bronchoscopy was repeated only if abnormal at evaluation
2); and at the end of treatment protocol (evaluation 4), with restaging consisting of chest X ray, routine blood tests, fiberoptic bronchoscopy, abdominal ultrasonography or CT scan, thorax and brain CT, radionuclide bone scan, and bone marrow aspiration and biopsy. Each of the staging procedures included fiberoptic bronchoscopy with cytological and histological analysis of abnormal findings. Response evaluation and follow-up Responders were patients with complete or partial response: Complete response (CR) was defined as a complete disappearance of all objective tumor on the chest X ray, optically and histologically at the time of fiberoptic bronchoscopy, without evidence of new disease elsewhere. Partial response (PR) was defined as a decrease of 50% or more of the product of the two largest perpendicular diameters of measurable disease radiologically with concurrent endoscopic verification, without evidence of new disease elsewhere, or if cytologies or biopsies remained positive with disappearance of radiological abnormalities. Non-responding patients included minor response, stable disease, and/or progression: Minor response meant a decrease of 25 to 50% of the product of the two largest perpendicular diameters of measurable disease radiologically with concurrent endoscopic verification, without evidence
Table 2. Treatment Week 0 or 1
Stage (evaluation
Week l-4-7-10
Adriamycin VP-16 Ifosfamide
Week 12
Re-stage (evaluation
Week 13 RTl
25
protocol
1) 50 mg/m2 150 mg/m2 2 g/m2
d.l d.1 +2 d.1 +2
Radiotherapy
1.5 Gy b.i.d. Sd./wk; Mon.-Fri. total dose 15 Gy
d. 1 2fx./d.;
Week 16
VP-16 Ifosfamide
150 mg/m2 2 g/m2
d.l + 2 d.l + 2
Week 18 RT2
Radiotherapy
1.8 Gy b.i.d. 5d.wk; Mon.-Fri. total dose 18 Gy Supraclav. 20 Gy
d. 1 2fx./d.;
Week 2 1
VP-16 Ifosfamide
150 mg/m2 2 g/m2
d.1 + 2 d.l + 2
Week 23 RT3
Radiotherapy
1.8 Gy b.i.d. 5d. Jwk; Mon.-Fri. total dose 18 Gy Supraclav. 20 Gy
d. 1 Zfx./d.;
Week 25
Re-stage (evaluation
Week 26-29
Adriamycin VP-16 Ifosfamide
50 mg/m2 150 mg/ms2 2 g/m2
d.l d.l + 2 d.1 +2
Week 3 1
Re-stage (evaluation
2)
3)
4)
26
1. J. Radiation Oncology 0 Biology 0 Physics
of new disease elsewhere. Stable disease was defined as a decrease of less than 25% or progression of less than 25% of the product of the two largest perpendicular diameters of measurable disease radiologically with concurrent endoscopic verification, without evidence of new disease elsewhere. Progression was defined as an increase of more than 25% of the product of the two largest perpendicular diameters of measurable disease radiologically with concurrent endoscopic verification, or appearance of distant disease. Patients with normal chest X ray, normal CT scan and normal fiberoptic endoscopy, but with positive cytologies or biopsies were always staged as partial responders. Patients with normal chest X ray, negative cytologies but abnormal CT scan were staged as partial responders. Local control of chest disease was defined as the complete disappearance of SCLC in the chest. Thus. by definition, no partial responders achieved local control. These patients were not cured because of the inability to control local disease. Among the 77 patients presenting with limited disease, only patients demonstrating partial or complete response (PR or CR) at the time of evaluation 2 were included in the radiotherapeutic protocol. Patients presenting with minor response, stable disease or progression were evaluated, then included in a second-line protocol. The same criteria were used for evaluation 3. Follow-up was performed as a regular schedule. After completion of treatment, patients were assessed radiologically every 2 months or whenever a new event appeared.
Statistical analysis All patients were considered for statistical analysis. The results were analyzed for tumor response, local control, treatment toxicity (according to the WHO scale grading) (35). Overall survival and relapse-free survival were calculated according to the Kaplan Meier method (17). Local control time was measured from the date of first treatment to the date on which local recurrence was detected or to the date of last follow-up without local recurrence.
RESULTS Altogether, 77 patients were included in the protocol described above. After 3 courses of chemotherapy, at the time of evaluation 2, 58 patients were included in the radiotherapy protocol. Among the 19 patients who were excluded, 6 had a minor response, 6 had a stable disease, and 6 had progression. In addition, one patient died suddenly of unknown cause. Seventy-six patients were thus evaluable for response. Fifty-eight patients were irradiated and evaluable for toxicity, but only 53 were evaluable at the time of this study, for response. The median followup was 18 months (7 months-40 months). The response rate (CR + PR) after 3 courses of chemotherapy (evaluation 2) was 58/76 (76%) with 42% showing complete response. After completion of radiotherapy alternating
July 1990. Volume 19, Number 1 Table 3. Effect of radiotherapy on tumor response and survival Before XRT Evaluable for response Responders Complete responders
76* 58 (76%) 32
Partial responders
26
Response rate Local control rate Partial responders converted into complete responders Overall median survival Disease-free survival
76%
After XRT 53+ 46 (61%) 4 unevaluable 4 progressions 24 complete responders 1 unevaluable 3 progressions 1I complete responders 11 partial responders 61% 51% 1 l/26 (42%)
14 months 42% at 1 year
* Among the 77 limited patients, one died during induction chemotherapy. + Fifty-three of 58 patients were evaluable after radiotherapy.
with modified chemotherapy (evaluation 3), the response rate was 46/76 (61%) with 35/76 (46%) complete response. Radiation therapy converted 11 partial responders into complete responders (42%). Two patients had only a positive biopsy before irradiation, 8 had a remaining tumor mass, 1 had a positive biopsy and a remaining tumor mass. Several of these patients had a complete radiological and endoscopic regression, but positive biopsies before radiotherapy, which were negative after irradiation. The local control rate, obtained by this chemotherapyradiotherapy combination, was 39/76 (5 1%): thirty-five patients demonstrated a complete response; among the patients who progressed, four had no local relapse; they were therefore included as locally controlled. The percentage of complete responders having a disease-free survival of 12 months was 42%. The actuarial overall median survival was 14 months. The median response duration was 14 months for responders. The results are summarized in Table 3.
Patterns 0fJizilure Local: Among the 35 patients in complete response after radiotherapy, 11 (3 1%) ultimately manifested a local recurrence: 8 patients had local recurrence only, 3 had both local and distant recurrence. The relapse-free survival at 12 months was 68% for complete responders. The median time for recurrence to appear was 10 months after initiation of treatment protocol. Distant: Among the 35 patients in complete response
Hyperfiactionated radiotherapy alternating with chemotherapy in limited SCLC 0 F. MORNEXet a/.
after radiotherapy, 11 patients (3 1%) had metastases only (10 brain metastases and 1 skin metastases). Three patients demonstrated both local recurrence and distant metastases (2 liver metastases, 1 osseous metastases). The results are summarized in Table 4.
Table 5. Toxicity of chemo-radiotherapy (number of patients). Among the 77 limited-stage patients, 58 were irradiated and 53 were evaluable after radiotherapy, for response and toxicity
Toxicity
Pulmonary: Fourteen patients showed radiologic changes of pulmonary toxicity. Eleven of these patients had clinical evidence of radiation acute pneumonitis; six patients were hospitalized (9 to 30 days). Four patients developed fibrosis, with moderate dyspnea on exertion, which was nonetheless compatible with a normal daily life. One patient died with acute pulmonary toxicity after radiotherapy. In total, five patients showed a critical pulmonary event due to irradiation or combined therapy. Clinical or radiological signs appeared between 1 and 169 days after the beginning of radiotherapy. Cardiac: Eight patients had clinical evidence of cardiac toxicity: 4 patients had a myocardiopathy, 3 patients had a pericarditis, and 1 patient had a pericarditis and myocardiopathy. EKG or radiologic changes were inconstant. Four patients were hospitalized ( 10 to 60 days). Two patients had a chronic cardiac complication, requiring permanent care: In 1 patient the tumor was located in the right lung (lower lobe), in the other patient, there was a large left upper lobe tumor. Esophageal: During radiotherapy patients experienced mild dysphagia or nausea, grade 1 or 2 in general (according to the WHO classification). For example, the third course of radiotherapy induced 9 grade 1,6 grade 2, and 1 grade 3 dysphagia. Hematologic: Ten patients manifested febrile aplasia, requiring hospitalization in 9, for 2 to 30 days. Seven of them required antibiotics. No cutaneous toxicity was observed. No patient received a reduced radiation dose because of toxicity. However, the second radiotherapy cycle was delayed in 6 patients from 1 to 3 weeks, and the third cycle was delayed from 1 to 2 weeks in 7 patients, due to toxicity. The toxicities are listed in Table 5. DISCUSSION The overall response rate was 6 1% after irradiation. The role of radiotherapy to achieve complete response Table 4. Patterns of failure in complete response patients (35 patients)
Local recurrence only Local and distant recurrence Total of local recurrences 11 (3 1%) Metastases only: Brain Skin Total of local and distant relapses Relapse-free survival at 12 months
08 03 10 01 22135 (63%) 68%
27
Lung Symptoms Deaths Heart Symptoms Hematopoietic system Febrile aplasia Esophagus Dysphagia Grade 1 Grade 2 Grade 3
Acute toxicity
Chronic clinical toxicity
11 1
4 (7.5%) 0
8
2 (3.8%)
10
0
19* 08 02
0 0 0
* Cumulation of digestive toxicities observed at each of 3 times of radiotherapy.
must be emphasized, since among 26 partial responders before irradiation, 11 (42%) were converted into complete responders after irradiation. This fact is important, because other groups (20, 34) have already shown the possibility of converting a chemotherapy partial responder into a complete responder with the use of thoracic irradiation: White et al. (34) described 38% of PR converted into CR. Furthermore, conversion may lead to prolonged survival. In this context, it is critical to have extensive and precise staging and restaging procedures. We therefore included a systematic evaluation of the endobronchial response using fiberoptic bronchoscopy. The local control rate was 5 1%. The follow-up is not yet long enough for meaningful analysis of median and disease-free survival. These promising results must be interpreted in the context of recent studies using combined modalities, which show lower or comparable results, especially when considering the sizeable number of patients in our study, and the inclusion of patients presenting with a very large initial mass, reaching the chest wall in many patients. In addition, we included 11 patients presenting with pleural effusion (four with proven malignant cells) as limited. These two types of patients are often excluded in other series. This high local control rate is probably related to the high radiation dose, as shown in different studies attempting to correlate radiation dose and locoregional tumor control in limited stage SCLC (5, 9, 10, 19, 20, 34). However, the value of higher doses must be balanced against the additional toxicity that results from such treatment. The NC1 experience for example showed that a modest increase in the dose (30 to 45 Gy) markedly increased the complications of therapy (4). The overall results obtained by the present protocol are
28
1. J. Radiation Oncology 0 Biology 0 Physics
inkeeping with previous reports by Bunn et al. and Turrisi et al. (3, 32). In both reports, high complete response rate were obtained by using combined therapy. Furthermore, Bunn et al. (3) have demonstrated a higher response rate in combined therapy when compared to chemotherapy a high response alone. Turrisi et al. (32) demonstrated rate when using a twice daily fractionation as we did. The high radiation dose delivered has been well-tolerated. Significant complications include pulmonary and cardiac events. Among 58 evaluable patients, one died of acute radiation pneumonitis. Four patients (7.5%) suffered chronic radiation pneumonitis, which was responsible for moderate dyspnea on exertion. Cardiac events are attributed to the combination of anthracyclines and radiotherapy. Two patients (3.8%) developed a chronic myocardiopathy, requiring treatment with diuretics and digitalis. In both patients the tumor location can be incriminated (1 lower right lobe, 1 left lobe including a large part of the cardiac area). These cardiac complications indicate a need for greater attention to dosimetric detail in the future, and also a need to measure cardiac ejection fraction isotopically in patients who present with critical tumor location. Less cardiotoxic chemotherapy might also be considered. Despite the use of high doses of radiation, patients otherwise tolerated treatment well. This can be explained by the use of twice-daily fractionation, which allows repair of normal tissues, even when high doses are delivered daily to the tumor (2 1,29,3 1,36). The interval of 6 hr between the 2 daily fractions seems to be important (36). In our protocol, the hyperfractionation employed high daily doses (3 to 3.6 Gy), which represents accelerated hyperfractionation (36). In addition, this protocol addressed the question of the treatment volume: should one irradiate the initial tumor volume, or a reduced volume? Complete response to chemotherapy is unfortunately microscopic only, since the probability of local recurrence is very high (20). Radiation delivered only to reduced volumes appears to be inadequate, and current recommendations are to deliver at least one-third to one-half of the radiation dose to the original prechemotherapy tumor volume (20). When faced with a large initial mass, can low-dose irradiation of an initial
July 1990, Volume 19, Number 1
large tumor volume help to decrease the relapse rate, by treating microscopic residual disease? SCLC is a radioresponsive tumor and the analogy of successful large field irradiation in lymphoma led to our interest in trying this therapy in patients with SCLC. Urtasun et al. (33) obtained a 87% response rate with a 47% CR rate in SCLC patients treated by hemibody irradiation. Hurman et al. ( 16) treated limited stage patients with 6 cycles of chemotherapy, and the upper hemibody irradiation being delivered during the second chemotherapy cycle. CR rate was 83%, but a high rate of pneumonitis (5/21 patients) was observed, probably due to interactions between drugs and radiation. The authors suggest shielding the controlateral lung to decrease the pulmonary toxicity. Our results are preliminary, and not conclusive, but suggest that irradiating such a large volume can be performed without toxicity. Local intrathoracic failure rate was 3 1% ( 11 patients). This result is encouraging since 11 patients included in our study presented initially with pleural effusion, which is considered systemic dissemination by most investigators. Thoracic failure often occurred within the treated volume, suggesting insufficient dose rather than insufficient tumor coverage. Because the radiation dose has been well tolerated, we think an increased dose can be proposed, as recommended by Choi et al. (6) in their last study. Brain metastasis, commonly the first site of relapse in our study, again raises the question of the value of prophylactic cranial irradiation, alone or in combination with appropriate chemotherapy, to eradicate micrometastases. In conclusion, alternating different modality protocols have the advantage of permitting a continuous chemotherapy schedule. Accelerated hyperfractionation allows delivery of a high dose of radiation with an acceptable toxicity. We have shown that radiotherapy is capable of increasing the response rate markedly, especially the complete response rate in patients. This is important since complete responders seem to represent a potential population of long-term survivors. Optimal protocols have not yet been designed, but quality of life must be taken into account, in a disease where “quantity of life” is often the major aim.
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APPENDIX
1
This investigation was carried out by the following member institutions of the Groupe Lyonnais d’Oncologie Thoracique (G.L.O.T.): Service de Pneumologie Pr Brune, Pr Cordier, Hopital Louis Pradel, Lyon; Service de Pneumologie Pr Emonot, Hopital Nord, Saint-Etienne; Service de Pneumologie Pr Bernard, Hopital Jules Courmont, Lyon; Service de Pneumologie Pr Kalb, Pr G&tin, Ho-
July 1990, Volume 19, Number 1
pita1 Croix Rousse, Lyon; Service de MMecine Dr. Clavel, Centre Leon Btrard, Lyon; Service de Pneumologie Pr Perrin Fayolle, Pr Pacheco, Hopital Sainte EugCnie, Lyon; Service de Pneumologie Dr. Van Straaten, Dr. Vincent, Hopital Saint Joseph, Lyon; Service de Radiotherapie Pr Chassard, Dr. Lacroze, Dr. Ardiet, Centre Leon Btrard, Lyon; Service de Radiotherapie, Pr Gerard, Dr. Romestaing, Hopital Jules Courmont, Lyon; Service de Radiotherapie Dr. Schmitt, Hopital Bellevue, Saint-Etienne; Unite de Biostastistiques Dr. Chauvin, Centre Leon BCrard, Lyon. Evaluation Group: Drs. E. Boniface, C. Carrie, P. Fournel, F. Gormand, C. Lasset, E. Laennec, G. Letanche, G. Mazoyer, F. Mornex, J. F. Mornex, M. Perol, D. Pipemo, P. Rebattu, P. J. Souquet, V. T&let, B. Velay, J. M. Vergnon, A. Voloch.