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Alternating irradiation and chemotherapy in stage III A and B nonsmall cell lung cancer: Report of a cancer and leukemia group b phase II study 8636
Int. J. Radiation
Oncology
Pergamon
Biol. Phys., Vol. 29, No. 5, pp. 1085-1088, 1994 Copyright 0 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0360.3016/94 $6.00 + .OO
0360-3016(94)E0129-8
??Phase I/II Clinical Trials
ALTERNATING IRRADIATION AND CHEMOTHERAPY IN STAGE III A AND B NONSMALL CELL LUNG CANCER: REPORT OF A CANCER AND LEUKEMIA GROUP B PHASE II STUDY 8636 STEPHEN L. SEAGREN, MURRAY
M.D.,*
BOLES, M.D.,*
JAMES E. HERNDON, CHUNG
CHUNG,
PH.D.,’ JAMES R. BAEKER,
M.D.§ AND MARK R. GREEN,
M.D.,*
M.D.*
*Division of Radiation Oncology, Division of Hematology-Oncology, University of California Medical Center at San Diego, CA; +Cancer Center Biostatistics, Duke University School of Medicine, Durham, NC; *Ellis Fischel Cancer Center, University of Missouri, Columbia, MO; and “State University of New York, Syracuse, NY
Purpose: A pilot trial testing the feasibility of chemotherapy and radiotherapy was done in Stage III A and B nonsmall cell lung cancer. The schedule was designed to be consistent with the laboratory model of Looney and Hopkins. Methods and Materials: Treatment began with thrice-per-day radiotherapy for 3 days (16.2 Gy/nine fractions), followed by chemotherapy (cis-platinum 100 mg/m’ day 10, and vinblastine 4 mg/m’ days 10 and 12). A second cycle started on day 22, a third on day 43, and a fourth on day 64. We treated three cohorts. The first cohort received three cycles of radiotherapy alone, (48.6 Gy). The second cohort received three completed cycles, and the third received three completed cycles and a fourth radiotherapy course (64.8 Gy). Patients were evaluated for toxicity, protocol compliance, response, and survival. Results: The patients in the first cohort experienced no toxicity. Fifty-six percent (56%) of the patients treated in
cohort 2 experienced severe or life-threatening myelosuppression as did 82% of those in cohort 3. Nonhematologic toxicity was not severe; one case of Grade 3 esophagitis, one of reversible adult respiratory distress syndrome, and one radiation pneunomitis. We closed the trial after accrual to the third cohort because of significant myelosuppression. Conclusion: This schedule is too myelosuppressive to be used without modification.
Alternating chemo-radiotherapy,
Lung cancer. METHODS
INTRODUCTION
AND MATERIALS
Purpose
Cancer treatment clinical trials involving combined radiotherapy and chemotherapy began shortly after trials in chemotherapy alone. Based on empiricism, most used simultaneous or sequential schedules. Many Phase II trials of combined chemoradiotherapy have been judged promising or encouraging, but until recently most Phase III trials have been negative (20). In the past few years, however, several large credible trials have shown survival benefit for combined therapy (6, 11, 12, 19). Therefore, it may be important to optimize the schedule of chemotherapy and radiotherapy. Looney and Hopkins (14) have published a long series of radiobiology experiments using a transplanted rodent hepatoma model suggesting that a schedule alternating radio- and chemotherapy is superior to either sequential or simultaneous therapy. This Phase I-II trial was designed to simulate this laboratory experience in the clinic.
The explicit purpose was to and toxicity of sequenced thrice chemotherapy to establish the (MTD). The MTD was defined ule producing predictable and would not be incapacitating nor being and general activity.
determine the feasability per day radiotherapy and maximum tolerated dose as the highest dose schedreversible toxicity which interfere with patient well-
Eligibility Patients with histologically proven Stage III A or B, non-small cell lung cancer who were not eligible for competing Cancer and Leukemia Group B studies, due to a 5% weight loss in the 3 months preceeding entry and/or a performance status level 2 were entered in this study. Staging procedures included a history and physical examination, blood counts and blood chemistries, and a
Reprint requests to: Stephen L. Seagren, M.D., UCSD Medical Center, Radiation Oncology Department-8757,200 West Arbor Dr., San Diego, CA 92 103-8757.
Accepted
1085
for publication
28 January
1994.
1086
1. J. Radiation
Oncology
0 Biology 0 Physics
Volume
chest computerized axial tomography scan extending into the upper abdomen through the liver and adrenals. Bone scan and brain tomography were not mandatory.
The protocol was designed to treat four cohorts of six to twelve patients each in a Phase I/II dose escalating trial. If toxicity was judged tolerable. then the next level of therapy was activated. The first cohort received radiotherapy alone, three times a day for 3 consecutive days every 3 weeks for three cycles, a total of 48.6 Gy in 27 fractions given in 9 treatment days over 45 days. At least 3 h elapsed between fractions. Treatment volume included the radiographically computed tomography evident tumor mass, ipsilateral hilum. mediastinum and ipsilateral supraclavicular fossa. The middle daily fraction used cord sparing oblique portals. Subsequent cohorts received interdigitated radiotherapy and chemotherapy. The second cohort received the same radiotherapy as cohort 1. and chemotherapy on days IO12. 31-33, and 52-54. Chemotherapy was cisplatinum. 100 mg/m2 on day 10 and vinblastine 4 mg/m’ on days 10 and I2 with the same drugs and doses repeated every 3 weeks for two additional cycles. The third cohort received an additional cycle of thrice-per-day radiotherapy on days 64-66 (64.8 Gy). The fourth cohort was to receive a fourth cycle of chemotherapy (Fig. I). Blood counts were performed on days 22, 43, and 64. The vinblastine dose was to be reduced 50% for a granulocyte count between 1200/~1 and I800/~1 and/or platelet count between 75,000/~1 and lOO,OOO/yl on the day of chemotherapy. Both drugs were to be held for granulocytes < 1200/~1 and/or platelets < 7.5,000/~1 and reinstituted when counts permitted. Vinblastine dose was to be reduced 1 mg/m’ for day 14 nadir counts < 500 granulocytes/pl or 30,000 platelets. Irradiation was to be delayed for granulocyte counts < 500 and/or platelets < 75,000. The trial was to close after accrual to the fourth cohort or until the maximum tolerated dose (MTD) was discovered. The MTD was defined as the highest dose schedule producing predictable and reversible toxicity which was neither incapacitating nor interfering with patient well-being and general activity.
RESULTS
Paricnrs Thirty-three patients were registered onto this study between October 1986 and January 1989; two were removed before therapy because of development of metastatic disease and two were judged ineligible, leaving 29 for analysis. Twenty-five were male, 25 Caucasian. Histologic subdivisions were roughly equally divided among squamous (12), adeno (9) and undifferentiated large cell (8). Twenty-seven had performance status 0- 1. The mean age was 64 with a range of 49-78. Cohort I included six patients, all of whom completed therapy without evidence of significant toxicity. Cohort 2 included I I patients. Two developed distant metastases before receiving any protocol chemotherapy, and were removed from study, making them unevaluable for added toxicity. A third patient was withdrawn after a single course of chemotherapy because of the development of metastatic disease. Eight patients completed all three cycles. Cohort 3 consisted of 12 patients. Five were removed before completion of therapy, four because of development of metastases, and 1 who refused to continue after three cycles. Thus, among the 23 patients in cohorts 2 and 3 scheduled to receive alternating combined therapy, 15 completed the scheduled treatment. The trial was closed before accrual to the fourth cohort was initiated because of myelosuppression.
A total of 25 cycles of radiochemotherapy were given to the 9 patients in cohort 2 evaluable for toxicity. Thirteen cycles had a neutrophil nadir < 1000, one had a platelet count < 100,000. Six of these neutropenic episodes occurred after the first cycle. Thirty-two cycles of combined therapy were given in cohort 3 to I2 patients. Eighteen produced granulocytopenia cc 1000. Seven cycles were associated with Grade 1-2 (50-99 X 103), and one with grade 3 (20-50 X 103) thrombocytopenia. Overall 5/9
Patients were evaluated for toxicity, response, protocol compliance, and survival. Radiotherapy was evaluated by the Quality Assurance Review Center in Providence, Island,
and reviewed
separately
&
YKI
w
1-3
by the study chair.
CT
XRT
111.12
22.24
5. 1994
A complete response was defined as disappearance of all measurable or evaluable disease, and a partial response as a reduction of more than 50% of the sum of the products of its perpendicular diameter. Stable disease meant less than a 50% decrease to no clear cut increase, and progression, increase by at least 25%. Response was judged by serial chest radiographs. Patients developing distant metastases outside the irradiation field during treatment were dropped from the study.
Trrutmrnt method
Rhode
29. Number
cr
3133
XRT
43-45
CT
XRT
52.54
64-66
Fig. 1. Treatment schema. XRT = 1.X Gy thrice daily for three days: cohorts 1 and 2 received 3 cycles or 4X.6 Gy. Cohort 4 received 4 cycles or 64.4 Gy. CT = Vinblastine. 4 m&m’ on days IO and 12 and cis-platinum, 100 mg/m’ on day IO, etc. Cohort 2 and 3 received 3 cycles.
Alternating
irradiation
and chemotherapy
in stage III A & B nonsmall
(56%) in cohort 2 and 9/l 1 patients (82%) in cohort 3 experienced severe or life-threatening leukopenia. Cytopenias were seen about equally in each of the three cycles in both cohorts. Fifteen combined modality patients (eight cohort 2, seven cohort 3) who completed the protocol were evaluable for additional nonhematologic toxicity. Five of 15 had esophagitis (4 grade 1 and one Grade 3); no patient was hospitalized because of esophagitis. The risk of esophagitis was neither predictable nor cumulative. Two patients had it with cycle 1 and never again; two had it in the second and third cycle. Five patients developed infection during neutropenic nadirs. One patient developed adult respiratory distress syndrome, probably due to therapy, and one patient developed clinical and radiologic evidence of radiation pneumonitis. No patient died of toxicity while under therapy.
Response and survival In cohort 1, three of six had an objective response, one had a complete response. In cohort 2 there were two partial responders among nine patients who received at least the first 3 days (nine fractions) of radiation and one dose of chemotherapy. In cohort 3, two achieved complete and three achieved partial responses among seven patients who completed all therapy. Nine (56%) among the 16 fully evaluable patients showed local progression in the chest before death. Median survival for all 32 patients was 9 months (range l-35). All but two patients are now dead.
Compliance In cohorts 2 and 3, dose adjustment decisions for nadir granulocyte counts were necessary for 36 cycles. Thirteen times (33%) the dose was not properly adjusted. Radiotherapy dose and schedule were accurate in all but two patients. Review of port films for treatment volume showed the entire CT determined tumor volume was irradiated in all but two cases.
DISCUSSION Simultaneous radio-chemotherapy generally results in enhanced toxicity in the radiation field (4, 10). It is not clear if simultaneous schedules enhance therapeutic ratio or simply enhance cell killing in general (8, 16). The recent European Organization for Research in Treatment of Cancer (EORTC) trial in patients with nonsmall cell lung cancer demonstrated that concurrent radiation and daily cisplatin improved local control and overall survival (19). Similar randomized trials using more intermittent schedules of chemotherapy have not demonstrated comparable benefits (1). Sequential schedules of radiation and chemotherapy result in less acute local toxicity than concurrent strategies. Many sequential multi-modality Phase III trials, in a variety of disease settings, have been disappointing (18) although several recent trials in lung cancer
cell lung cancer 0 S. L. SEAGREN et ul.
IO87
show a positive impact on metastasis formation and survival (6, 12, 19). In 1976, Looney and Hopkins began a long series of laboratory experiments using a transplantable rat hepatoma model. They reached several conclusions from their work: (a) Both chemotherapy and radiotherapy were necessary for cure (b) Dose and schedule were both important variables(c) An alternating schedule rather than sequential or simultaneous therapy was optimal (d) The best results were achieved when treatment course began with irradiation (e) Hyperfractionated radiotherapy, administering a higher dose in a shorter time, was optimal (f) The best treatment results were found with a dose-intensive schedule (1 1, 12, 18). Our trial was designed to simulate Looney’s optimal schedule and drugs known to be “active” in non-small cell lung cancer were used. Since the primary endpoint of this trial was toxicity and feasibility, and the clinical efficacy of this approach was unknown, we chose patients with clinical Stage III+ or IIIB disease. We excluded patients with blood borne metastases since significant toxicity was anticipated, and only those who might benefit from enhanced local control were judged suitable. The radiotherapy schedule was chosen for two reasons. Looney’s model used thrice daily treatment, and we wished to simulate the animal experience as closely as possible. Also an accelerated schedule (16.2 Gy, nine fractions, 3 days) allowed a 3 week cycle for chemotherapy, simulation other CALGB trials (6). At least 3 h were required between fractions since most repair of sublethal injury is completed within 3 h (7). To minimize risk of spinal cord injury, even more, we required the middle fraction each day to be given by beams angled to avoid the spinal cord thus allowing at least 6 h. Our patients developed significant myelosuppression, especially neutropenia, by the third and often the second chemotherapy cycle. Similar chemotherapy had been quite tolerable when given for two cycles before radiotherapy in generally similar patients in a previous CALGB study (6). While myelosuppression appeared to be enhanced by the schedule tested, esophagitis was not significant. We acknowledge that response rates to combined modality therapy in lung cancer are inaccurate when compared to the pathologic specimens (2 1). Accepting these inherent limitations, 13 of 16 fully treated patients had measurable disease regression including three complete responses. Nine of sixteen (56%) progressed in the chest before death. There is substantial published clinical experience with alternating schedules of chemotherapy and radiation. In small cell lung cancer, the largest is that at Villejuif (3) where three radiotherapy courses are alternated with four of chemotherapy. Radiation toxicity was similar to that expected from radiation alone, but mean drug doses were attenuated 20% because of myelosuppression and toxic death rate was 8%. Local control was 68%, survivorship
IO88
1. J. Radiation
Oncology
0 Biology 0 Physics
was 25% at 2 years and 15% at 5 years. Other, smaller, promising trials in lung cancer and solid tumors have also been published (2,5, 17, 18) and review articles have been done (I 3, 22). The laboratory studies of Looney and Hopkins suggest not only an alternating schedule, but also initiation of treatment with radiotherapy, since this could possibly abrogate the eventual treatment failure caused by intrinsic chemotherapy resistance (9). By hyperfractionating radiotherapy into a three-times-per-day schedule, we not only simulated Looney’s schedule, but also demonstrated the feasibility of this rather cumbersome schedule in a cooperative group setting. Most other schedules of alter-
Volume
29, Number
5, 1994
nating modalities have not translated these principles as rigorously to patient care. The main endpoints for this Phase I/II trial were toxicity and feasibility. The protocol schedule proved feasible, although chemotherapy does was not properly modified for cytopenia in 33% of patients. This may have enhanced toxicity in the second and third chemotherapy courses. We found a significant degree of myelosuppression in this alternating schedule, but other toxicities were acceptable. Further efforts to test alternating radiation and chemotherapy will require either different schedules, different chemotherapy, or hematopoietic growth factors to minimize myelosuppression.
REFERENCES I. Ansari, R.; Tokars, R.; Fisher, W.; Pennington,
2.
3.
4.
5.
6.
7.
8.
9.
10.
R.; Mantravadi, R.; O’Connor, T.; Ryard, S.; Miller, M.; Einhorn, L. A Phase III study of thoracic irradiation with or without concomitant cisplatin in locoregional unresectable nonsmall cell lung cancer (NSCLC): A Hoosier Oncology Group Protocol (Abst. 823). Proc. Am. Sot. Clin. Oncol. lo:24 I; 199 1. Arriagada, R.; Mouriesse, H.; Spielmann, M.; Mezlini, A.; Oudinot, P.; LeChevalier, T.; Cuvier, C.; Fontaine, F.; Travagli, J.; May-Levin, F.; Sarrazin, D. Alternating radiotherapy in nonmetastatic inflammatory breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 19: 1207- 12 10; 1990. Arriagada. R.: LeChevalier, T.; Ruffie. P.; Baldeyrou, P.; De Cremoux, H.; Martin, M.; Chomy, P.; Cerrina, M. L.; Pellae-Cosset, B.; Tarayare, M.; Sancho-Garnier, H. Alternating radiotherapy and chemotherapy in I73 consecutive patients with limited small cell lung carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 19: 1 135-I 138; 1990. Brooks, B. J., Jr.; Seifter, E. J.; Walsh, T. E.; Lichter, A. S.: Bunn, P. A.; Zabell, A.; Johnston-Early, A.; Edison, M.; Makuch, R. W.; Cohen, M. H. Pulmonary toxicity with combined modality therapy for limited stage small cell lung cancer. J. Clin. Oncol. 7:47-68; 1986. Corvo, R.; Merlano, M.; Looney, W. B.; Benasso, M.; Bacigalupo, A.; Margarino, G. Integration of chemotherapy in an MFD-radiotherapy plan for advanced inoperable squamous cell carcinoma of the head and neck. Head Neck 12( 1):60-65; 1990. Dillman, R. 0.; Seagren, S. L.; Propert, K. J.: Guerra. J.; Eaton, W. L.; Perry. M. C.; Carey, R. W.; Frei, E. F.; Green, M. R. A randomized trial of induction chemotherapy plus high dose radiation versus radiation alone in Stage III nonsmall cell lung cancer. N. Eng. J. Med. 323:945; 1990. Elkind, M. M.; Sutton, H. Radiation response of mammalian cells grown in culture. 1. Repair of x-ray damage in surviving Chinese hamster cells. Radiat. Res. 13:556-593; 1960. Fu, K. K. Biological basis for the interaction of chemotherapeutic agents and radiation therapy. Cancer 55:2 1232 130; 1985. Goldie, J. H.; Coldman, A. J.; Ng, V.; Hopkins, H. A.; Looney, W. B. A mathematical and computer-based model of alternating chemotherapy and radiation therapy in experimental neoplasms. Antibiot. Chemother. 4 I : 1 l-20; 1988. Gore, S. M.; Come, S. M.; Greim, K.; Rose, M. A.; Recht, A.; Botnick, L. E.; Rose, C.; Beadle, G.; Henderson, I. C.; Silver, B. Influence of the sequencing of chemotherapy and radiation therapy in node-negative breast cancer patients treated by conservative surgery and radiation therapy. In: Salmon, S. E., ed. Adjuvant therapy of cancer. V. Orlando: Grune & Stratton: 1989:365-373.
L. L.; Wieand, I I. Krook, J. E.; Moertel, C. G.; Gunderson, H. S.; Collins, R. T.; Beart, R. W.: Kubista, T. P.; Poon, M. A.; Meyers, W. C.; Mailliard, J. A. Effective surgical adjuvant therapy for high risk rectal cancer. N. Eng. J. Med. 324:709-715; 1991. 12. LeChevalier, T.; Arriagada, R.; Quoix, E.; Tarayre, M.; Ruffie, P.; Martin, M.; Lacombe-Ferrier, M.; Douillard, J.; LaPlanche, A. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable nonsmall cell lung cancer: First analysis of a randomized trial in 353 patients. JNCI 83:4 17-423; I99 1. 13. Looney, W. B.; Hopkins, H. A. Rationale for different chemotherapeutic and radiation therapy strategies in cancer management. Cancer 67: 147 I- 1483; 199 I. 14. Looney, W. B. Alternating chemotherapy and radiotherapy. NC1 Monog. 6:85-94; 1988. 15. Looney, W. B.; Hopkins, H. A. The integration of multifractionated radiotherapy into combined chemotherapeuticradiotherapeutic approaches to lung cancer treatment. Antibiot. Chemother. 41: 176-183; 1988. 16. Maase, H., von der. Experimental studies on interactions of radiation and cancer chemotherapeutic drugs in normal tissues and a solid tumor. Radiother. Oncol. 7:47-68; 1986. 17. Mandell, L. R.; Fereshteh, G.; Exelby, P.; Fuks, Z. Preliminary results of alternating combination chemotherapy (CT) and hyperfractionated radiotherapy (HART) in advanced rhabdomyosarcoma (RMS). Int. J. Radiat. Oncol. Biol. Phys. 15: 197-203; 1988. 18. Mornex, F.; Trillet, V.: Chauvin, F.; Ardiet, J. M.; Schmitt, T.; Mornex, J. F.; Romestaing, F.; Carrie, C.: Mahe, M.: Fournee, P.; Sougret, P. J.; Boniface, E.; Vincent, M.: Piperno, D.; Regattu, P.; Gerard, J. P. Hyperfractionated radiotherapy alternating with multidrug chemotherapy in the treatment of limited small cell lung cancer (SCLC). Int. J. Radiat. Oncol. Biol. Phys. 19:23-30; 1990. 19. Schaake-Koning, C.; van der Bogaert, W.: Dalesio, 0.; Festen, J.; Hoogenhout. J.; Van Houtte, P.; Kirkpatrick, A.; Koolen, M.; Maat, B.; Nijs, A. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall cell lung cancer. N. Eng. J. Med. 326:524-530; 1992. 20. Tannock. I. F. Combined modality treatment with radiotherapy and chemotherapy. Radiother. Oncol. 16:83-101; 1989. 21. Taylor, IV, S. G.; Trybula, M.; Bonomi, P. D.; Faber, L. P.; Lee, M. D.; Reddy, S.; Maffey, S. C.; Mathisen, D. J.; Jensik, R. J.; Kittle, C. F. Simultaneous cisplatin fluorouracil and radiation. 22. Tubiana, M. The combination of radiotherapy and chemotherapy. In: Arrigada, R., ed. Treatment modalities in lung cancer. Antibiot. Chemotherapy. 4 1:I- IO: 1988.
Oncology
Pergamon
Biol. Phys., Vol. 29, No. 5, pp. 1085-1088, 1994 Copyright 0 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0360.3016/94 $6.00 + .OO
0360-3016(94)E0129-8
??Phase I/II Clinical Trials
ALTERNATING IRRADIATION AND CHEMOTHERAPY IN STAGE III A AND B NONSMALL CELL LUNG CANCER: REPORT OF A CANCER AND LEUKEMIA GROUP B PHASE II STUDY 8636 STEPHEN L. SEAGREN, MURRAY
M.D.,*
BOLES, M.D.,*
JAMES E. HERNDON, CHUNG
CHUNG,
PH.D.,’ JAMES R. BAEKER,
M.D.§ AND MARK R. GREEN,
M.D.,*
M.D.*
*Division of Radiation Oncology, Division of Hematology-Oncology, University of California Medical Center at San Diego, CA; +Cancer Center Biostatistics, Duke University School of Medicine, Durham, NC; *Ellis Fischel Cancer Center, University of Missouri, Columbia, MO; and “State University of New York, Syracuse, NY
Purpose: A pilot trial testing the feasibility of chemotherapy and radiotherapy was done in Stage III A and B nonsmall cell lung cancer. The schedule was designed to be consistent with the laboratory model of Looney and Hopkins. Methods and Materials: Treatment began with thrice-per-day radiotherapy for 3 days (16.2 Gy/nine fractions), followed by chemotherapy (cis-platinum 100 mg/m’ day 10, and vinblastine 4 mg/m’ days 10 and 12). A second cycle started on day 22, a third on day 43, and a fourth on day 64. We treated three cohorts. The first cohort received three cycles of radiotherapy alone, (48.6 Gy). The second cohort received three completed cycles, and the third received three completed cycles and a fourth radiotherapy course (64.8 Gy). Patients were evaluated for toxicity, protocol compliance, response, and survival. Results: The patients in the first cohort experienced no toxicity. Fifty-six percent (56%) of the patients treated in
cohort 2 experienced severe or life-threatening myelosuppression as did 82% of those in cohort 3. Nonhematologic toxicity was not severe; one case of Grade 3 esophagitis, one of reversible adult respiratory distress syndrome, and one radiation pneunomitis. We closed the trial after accrual to the third cohort because of significant myelosuppression. Conclusion: This schedule is too myelosuppressive to be used without modification.
Alternating chemo-radiotherapy,
Lung cancer. METHODS
INTRODUCTION
AND MATERIALS
Purpose
Cancer treatment clinical trials involving combined radiotherapy and chemotherapy began shortly after trials in chemotherapy alone. Based on empiricism, most used simultaneous or sequential schedules. Many Phase II trials of combined chemoradiotherapy have been judged promising or encouraging, but until recently most Phase III trials have been negative (20). In the past few years, however, several large credible trials have shown survival benefit for combined therapy (6, 11, 12, 19). Therefore, it may be important to optimize the schedule of chemotherapy and radiotherapy. Looney and Hopkins (14) have published a long series of radiobiology experiments using a transplanted rodent hepatoma model suggesting that a schedule alternating radio- and chemotherapy is superior to either sequential or simultaneous therapy. This Phase I-II trial was designed to simulate this laboratory experience in the clinic.
The explicit purpose was to and toxicity of sequenced thrice chemotherapy to establish the (MTD). The MTD was defined ule producing predictable and would not be incapacitating nor being and general activity.
determine the feasability per day radiotherapy and maximum tolerated dose as the highest dose schedreversible toxicity which interfere with patient well-
Eligibility Patients with histologically proven Stage III A or B, non-small cell lung cancer who were not eligible for competing Cancer and Leukemia Group B studies, due to a 5% weight loss in the 3 months preceeding entry and/or a performance status level 2 were entered in this study. Staging procedures included a history and physical examination, blood counts and blood chemistries, and a
Reprint requests to: Stephen L. Seagren, M.D., UCSD Medical Center, Radiation Oncology Department-8757,200 West Arbor Dr., San Diego, CA 92 103-8757.
Accepted
1085
for publication
28 January
1994.
1086
1. J. Radiation
Oncology
0 Biology 0 Physics
Volume
chest computerized axial tomography scan extending into the upper abdomen through the liver and adrenals. Bone scan and brain tomography were not mandatory.
The protocol was designed to treat four cohorts of six to twelve patients each in a Phase I/II dose escalating trial. If toxicity was judged tolerable. then the next level of therapy was activated. The first cohort received radiotherapy alone, three times a day for 3 consecutive days every 3 weeks for three cycles, a total of 48.6 Gy in 27 fractions given in 9 treatment days over 45 days. At least 3 h elapsed between fractions. Treatment volume included the radiographically computed tomography evident tumor mass, ipsilateral hilum. mediastinum and ipsilateral supraclavicular fossa. The middle daily fraction used cord sparing oblique portals. Subsequent cohorts received interdigitated radiotherapy and chemotherapy. The second cohort received the same radiotherapy as cohort 1. and chemotherapy on days IO12. 31-33, and 52-54. Chemotherapy was cisplatinum. 100 mg/m2 on day 10 and vinblastine 4 mg/m’ on days 10 and I2 with the same drugs and doses repeated every 3 weeks for two additional cycles. The third cohort received an additional cycle of thrice-per-day radiotherapy on days 64-66 (64.8 Gy). The fourth cohort was to receive a fourth cycle of chemotherapy (Fig. I). Blood counts were performed on days 22, 43, and 64. The vinblastine dose was to be reduced 50% for a granulocyte count between 1200/~1 and I800/~1 and/or platelet count between 75,000/~1 and lOO,OOO/yl on the day of chemotherapy. Both drugs were to be held for granulocytes < 1200/~1 and/or platelets < 7.5,000/~1 and reinstituted when counts permitted. Vinblastine dose was to be reduced 1 mg/m’ for day 14 nadir counts < 500 granulocytes/pl or 30,000 platelets. Irradiation was to be delayed for granulocyte counts < 500 and/or platelets < 75,000. The trial was to close after accrual to the fourth cohort or until the maximum tolerated dose (MTD) was discovered. The MTD was defined as the highest dose schedule producing predictable and reversible toxicity which was neither incapacitating nor interfering with patient well-being and general activity.
RESULTS
Paricnrs Thirty-three patients were registered onto this study between October 1986 and January 1989; two were removed before therapy because of development of metastatic disease and two were judged ineligible, leaving 29 for analysis. Twenty-five were male, 25 Caucasian. Histologic subdivisions were roughly equally divided among squamous (12), adeno (9) and undifferentiated large cell (8). Twenty-seven had performance status 0- 1. The mean age was 64 with a range of 49-78. Cohort I included six patients, all of whom completed therapy without evidence of significant toxicity. Cohort 2 included I I patients. Two developed distant metastases before receiving any protocol chemotherapy, and were removed from study, making them unevaluable for added toxicity. A third patient was withdrawn after a single course of chemotherapy because of the development of metastatic disease. Eight patients completed all three cycles. Cohort 3 consisted of 12 patients. Five were removed before completion of therapy, four because of development of metastases, and 1 who refused to continue after three cycles. Thus, among the 23 patients in cohorts 2 and 3 scheduled to receive alternating combined therapy, 15 completed the scheduled treatment. The trial was closed before accrual to the fourth cohort was initiated because of myelosuppression.
A total of 25 cycles of radiochemotherapy were given to the 9 patients in cohort 2 evaluable for toxicity. Thirteen cycles had a neutrophil nadir < 1000, one had a platelet count < 100,000. Six of these neutropenic episodes occurred after the first cycle. Thirty-two cycles of combined therapy were given in cohort 3 to I2 patients. Eighteen produced granulocytopenia cc 1000. Seven cycles were associated with Grade 1-2 (50-99 X 103), and one with grade 3 (20-50 X 103) thrombocytopenia. Overall 5/9
Patients were evaluated for toxicity, response, protocol compliance, and survival. Radiotherapy was evaluated by the Quality Assurance Review Center in Providence, Island,
and reviewed
separately
&
YKI
w
1-3
by the study chair.
CT
XRT
111.12
22.24
5. 1994
A complete response was defined as disappearance of all measurable or evaluable disease, and a partial response as a reduction of more than 50% of the sum of the products of its perpendicular diameter. Stable disease meant less than a 50% decrease to no clear cut increase, and progression, increase by at least 25%. Response was judged by serial chest radiographs. Patients developing distant metastases outside the irradiation field during treatment were dropped from the study.
Trrutmrnt method
Rhode
29. Number
cr
3133
XRT
43-45
CT
XRT
52.54
64-66
Fig. 1. Treatment schema. XRT = 1.X Gy thrice daily for three days: cohorts 1 and 2 received 3 cycles or 4X.6 Gy. Cohort 4 received 4 cycles or 64.4 Gy. CT = Vinblastine. 4 m&m’ on days IO and 12 and cis-platinum, 100 mg/m’ on day IO, etc. Cohort 2 and 3 received 3 cycles.
Alternating
irradiation
and chemotherapy
in stage III A & B nonsmall
(56%) in cohort 2 and 9/l 1 patients (82%) in cohort 3 experienced severe or life-threatening leukopenia. Cytopenias were seen about equally in each of the three cycles in both cohorts. Fifteen combined modality patients (eight cohort 2, seven cohort 3) who completed the protocol were evaluable for additional nonhematologic toxicity. Five of 15 had esophagitis (4 grade 1 and one Grade 3); no patient was hospitalized because of esophagitis. The risk of esophagitis was neither predictable nor cumulative. Two patients had it with cycle 1 and never again; two had it in the second and third cycle. Five patients developed infection during neutropenic nadirs. One patient developed adult respiratory distress syndrome, probably due to therapy, and one patient developed clinical and radiologic evidence of radiation pneumonitis. No patient died of toxicity while under therapy.
Response and survival In cohort 1, three of six had an objective response, one had a complete response. In cohort 2 there were two partial responders among nine patients who received at least the first 3 days (nine fractions) of radiation and one dose of chemotherapy. In cohort 3, two achieved complete and three achieved partial responses among seven patients who completed all therapy. Nine (56%) among the 16 fully evaluable patients showed local progression in the chest before death. Median survival for all 32 patients was 9 months (range l-35). All but two patients are now dead.
Compliance In cohorts 2 and 3, dose adjustment decisions for nadir granulocyte counts were necessary for 36 cycles. Thirteen times (33%) the dose was not properly adjusted. Radiotherapy dose and schedule were accurate in all but two patients. Review of port films for treatment volume showed the entire CT determined tumor volume was irradiated in all but two cases.
DISCUSSION Simultaneous radio-chemotherapy generally results in enhanced toxicity in the radiation field (4, 10). It is not clear if simultaneous schedules enhance therapeutic ratio or simply enhance cell killing in general (8, 16). The recent European Organization for Research in Treatment of Cancer (EORTC) trial in patients with nonsmall cell lung cancer demonstrated that concurrent radiation and daily cisplatin improved local control and overall survival (19). Similar randomized trials using more intermittent schedules of chemotherapy have not demonstrated comparable benefits (1). Sequential schedules of radiation and chemotherapy result in less acute local toxicity than concurrent strategies. Many sequential multi-modality Phase III trials, in a variety of disease settings, have been disappointing (18) although several recent trials in lung cancer
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show a positive impact on metastasis formation and survival (6, 12, 19). In 1976, Looney and Hopkins began a long series of laboratory experiments using a transplantable rat hepatoma model. They reached several conclusions from their work: (a) Both chemotherapy and radiotherapy were necessary for cure (b) Dose and schedule were both important variables(c) An alternating schedule rather than sequential or simultaneous therapy was optimal (d) The best results were achieved when treatment course began with irradiation (e) Hyperfractionated radiotherapy, administering a higher dose in a shorter time, was optimal (f) The best treatment results were found with a dose-intensive schedule (1 1, 12, 18). Our trial was designed to simulate Looney’s optimal schedule and drugs known to be “active” in non-small cell lung cancer were used. Since the primary endpoint of this trial was toxicity and feasibility, and the clinical efficacy of this approach was unknown, we chose patients with clinical Stage III+ or IIIB disease. We excluded patients with blood borne metastases since significant toxicity was anticipated, and only those who might benefit from enhanced local control were judged suitable. The radiotherapy schedule was chosen for two reasons. Looney’s model used thrice daily treatment, and we wished to simulate the animal experience as closely as possible. Also an accelerated schedule (16.2 Gy, nine fractions, 3 days) allowed a 3 week cycle for chemotherapy, simulation other CALGB trials (6). At least 3 h were required between fractions since most repair of sublethal injury is completed within 3 h (7). To minimize risk of spinal cord injury, even more, we required the middle fraction each day to be given by beams angled to avoid the spinal cord thus allowing at least 6 h. Our patients developed significant myelosuppression, especially neutropenia, by the third and often the second chemotherapy cycle. Similar chemotherapy had been quite tolerable when given for two cycles before radiotherapy in generally similar patients in a previous CALGB study (6). While myelosuppression appeared to be enhanced by the schedule tested, esophagitis was not significant. We acknowledge that response rates to combined modality therapy in lung cancer are inaccurate when compared to the pathologic specimens (2 1). Accepting these inherent limitations, 13 of 16 fully treated patients had measurable disease regression including three complete responses. Nine of sixteen (56%) progressed in the chest before death. There is substantial published clinical experience with alternating schedules of chemotherapy and radiation. In small cell lung cancer, the largest is that at Villejuif (3) where three radiotherapy courses are alternated with four of chemotherapy. Radiation toxicity was similar to that expected from radiation alone, but mean drug doses were attenuated 20% because of myelosuppression and toxic death rate was 8%. Local control was 68%, survivorship
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was 25% at 2 years and 15% at 5 years. Other, smaller, promising trials in lung cancer and solid tumors have also been published (2,5, 17, 18) and review articles have been done (I 3, 22). The laboratory studies of Looney and Hopkins suggest not only an alternating schedule, but also initiation of treatment with radiotherapy, since this could possibly abrogate the eventual treatment failure caused by intrinsic chemotherapy resistance (9). By hyperfractionating radiotherapy into a three-times-per-day schedule, we not only simulated Looney’s schedule, but also demonstrated the feasibility of this rather cumbersome schedule in a cooperative group setting. Most other schedules of alter-
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nating modalities have not translated these principles as rigorously to patient care. The main endpoints for this Phase I/II trial were toxicity and feasibility. The protocol schedule proved feasible, although chemotherapy does was not properly modified for cytopenia in 33% of patients. This may have enhanced toxicity in the second and third chemotherapy courses. We found a significant degree of myelosuppression in this alternating schedule, but other toxicities were acceptable. Further efforts to test alternating radiation and chemotherapy will require either different schedules, different chemotherapy, or hematopoietic growth factors to minimize myelosuppression.
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