??Editorial

ACCELERATED RADIATION THERAPY IN SMALL CELL LUNG CANCER: RATIONALE AND LIMITATION IN ITS UTILITY

NOAH C. CHOI, M.D.

Department of Radiation Medicine. Massachusetts General Hospital Cancer Center. Department of Radiation Therapy, Harvard Medical School, Boston, MA 02 I 14

Ever since the advent in the late 1970’s of more effective chemotherapy (CT), we have witnessed a significant im- provement in the median survival time (MST) of patients with limited stage small cell lung cancer (SCLC), from 5- 6 months with radiation therapy (RT) alone to lo- 14 months with CT + RT or CT alone (3). However, this dramatic effect of the induction CT on SCLC has been a short-term response, and tumor progression at the initial sites of the disease, after a 6-10 month duration of re- sponse, has been observed in 60% to 80% of patients ( 14, 17). A recent report of a randomized study by Cancer and Leukemia Group B (CALGB), in which CT + thoracic RT were compared with CT alone for limited stage SCLC, showed that control rates of loco-regional tumor and 2- year failure-free survival rates were 54% and 20% versus 13% and 8% by CT + thoracic RT versus CT alone ( 17). Results showing improved long-term survival by CT + RT over CT alone were also reported by others (4, 7). An emergence of tumor cell clones resistant to drugs has been attributed to the recent slow down in advancing the sur- vival beyond the current plateau by multiagent CT ( 10. 1 1). Attempts made to overcome this problem by alter- nating non-cross resistant CT regimens have been unsuc- cessful ( 1, 15).

Radiation is a powerful agent against cancer cells and non-cross resistant to chemotherapeutic drugs. The report by Turrisi and Glover in the current issue of Int J Radiat Oncol Biol Phys is a timely one in exploring an altered RT schedule tailored to tumor cell kinetics (21). Their combined program consisted of concurrent CT and ac- celerated thoracic RT, which delivered a total dose of 4500 cGy in 3 weeks by using 150 cGy dose fractions, twice daily with an intertreatment interval of a minimum of 4 hr and 5 days per week. The overall duration of this treat- ment was 2 weeks shorter than that of a conventional fractionation schedule delivering the same total dose of 4500 cGy in 180 cGy of daily fractions, 5 days a week.

Accepted for publication 2 1 June 1990.

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The induction CT regimen consisted of 2 cycles of plat- inum-etoposide and this was followed by 6 more cycles of platinum-etoposide alternating with cyclophospham- ide, doxorubicin, and vincristine.

The accelerated fractionation strategy is based on the following radiobiological rationale: a) Repair of the sub- lethal radiation damage in aerobic mammalian cells is essentially complete within 2 to 4 hr (9). If the interval between treatments is greater than 4 hr, rapidly prolifer- ating tumor cells, that is, SCLC. can have an advantage over non-proliferating or slowly proliferating normal tis- sue. In such a situation, greater therapeutic efficacy may be expected by using 2 treatment sessions per day with a fraction size smaller than that of conventional schedule ( 180-200 cGy), normal total dose (5000 cGy). and an intertreatment interval of 5 to 7 hours (8. 19); b) radio- biological data suggest that the shape of the dose-response relationship differs for early and late responding tissues (18, 22). A decrease in the size of dose per fraction is expected to increase the total dose tolerated for a given level of late normal tissue injury more than for acutely reacting normal tissue, and presumably for most tumors. The LU/@ ratio, the dose at which the linear ((u) and qua- dratic (0) components of cell inactivation are equal, is of the order of 1000 cGy for early reacting tissues [skin (acute), jejunum] and 200-400 cGy for late reacting tissue [lung, kidney, skin (late)] (22). Thus, the therapeutic ratio for late reacting normal tissue (except for spinal cord) over the acutely reacting tissues is expected to be improved with RT using fraction sizes smaller than conventional ones ( 180-200 cGy); c) the third radiobiological rationale deals with radiosensitization of cells through redistribution within the cell cycle (22). Tumor ceils and stem cells of acutely reacting normal tissue have shorter cell cycle time than that of late reacting normal tissue. Therefore, accel- erated RT is expected to increase inactivation of tumor cells or stem cells of acutely reacting normal tissue more

1624 I. J. Radiation Oncology 0 Biology 0 Physics December 1990, Volume 19. Number 6

than that of late reacting normal tissue; d) the fourth ra- tionale deals with oxygen enhancement ratio (OER) in cell inactivation by radiation. As the size of dose per frac- tion decreases, cell inactivation by single-hit lethal events, which is less oxygen dependent. becomes a predominant phenomenon. Thus, accelerated RT might be more ef- fective than conventional one in sterilizing macroscopic tumors ( 18).

and MST of over 2 years, 74% of patients relapsed and the long-term results remain to be evaluated.

Although this accelerated strategy spares late reacting tissue by using dose fractions smaller than the conven- tional ones (180 to 200 cGy) and the overall duration of RT is also shortened to overcome the rapid proliferation rate of SCLC, the early reacting normal tissue, that is, esophageal mucosa becomes a limiting factor. The ma- jority of patients with limited stage SCLC have extensive involvement of the mediastinal lymph nodes for which a significant length of the esophagus needs to be in the me- diastinal target volume. A phase II study of CALGB in which an accelerated RT (167 cGy dose fractions, twice daily, 5 days per week for a total dose of 5010 cGy) fol- lowed by CT was tested for locally recurrent SCLC after induction CT (6). The result was impressive, with a com- plete response rate in 8 of 11 patients and a partial re- sponse in the remaining 3 patients. However, marked dysphagia secondary to acute esophagitis was a common early side effect. Two of I 1 patients required hospitaliza- tion for intravenous hydration, and one patient with a history of hiatus hernia required a gastrostomy feeding tube. A similar study using concurrent CT (etoposide and cisplatin) and upfront accelerated RT ( 150 cGy dose frac- tions, twice daily, 5 days a week, for a total dose of 4500 cGy) by Ihde d al. showed enhanced esophagitis requiring hospitalization in 3 1% and esophageal stricture in 15% of patients ( 13). This study was associated with marked bone marrow suppression, and the symptoms of esophagitis might have been enhanced by the bone marrow toxicity. Although the initial result of this study was remarkable. with complete and partial response rates of 73% and 23%

There is a pilot study in CALGB in which the maximal tolerable dose of accelerated RT to the esophageal mucosa is being tested in the context of concurrent CT and ac- celerated RT by a gradual escalation of radiation dose fractions from 125 cGy to 135 cGy and then to 150 cGy and the total dose from 4500 cGy to 5000 cGy. This is an interesting study, since the response of early reacting normal tissue to accelerated RT is determined by both the fraction size and overall treatment time. Another on- going Phase III study of Eastern Cooperative Oncology Group (ECOG) and Radiation Therapy Oncology Group (RTOG) is based on the pilot data of Turrisi and Glover (21). This study compares the same total dose of 4500 cGy by either conventional RT ( 180 cGy dose fractions. one treatment per day, 5 days a week over a period of 5 weeks) or accelerated RT ( 150 cGy dose fractions, twice daily, 5 days a week over a period of 3 weeks) for limited stage SCLC.

Important questions to be asked in future studies in- clude the following: a) whether or not the potential gain in loco-regional tumor control and survival by accelerated RT can be met by a conventional once a day schedule using the maximal tolerable total dose (? 6000 cGy) with less toxicity to esophageal mucosa (5); and b) an integra- tion of CT and split course RT might be another approach in an attempt to improve results in SCLC by allowing the esophageal mucosa to recover between the courses of RT (2, 20). Doxorubicin should be avoided during, imme- diately before, and after RT for its known enhancement of radiation induced esophageal reaction ( 12, 16). The data of the pilot study by Turrisi and Glover with 96% (26/27) rate of loco-regional tumor control and nearly 50% actuarial disease-free survival rate at 2 years are very encouraging. However, further studies are needed because more often than not, many pilot data have not been re- produced in a large scale study.

REFERENCES

I. Aisner, J.; Whitacre, M.: Van Echo, D. A.; Wiernik. P. H. Combination chemotherapy for small-cell carcinoma ofthe lung: continuous versus alternating non-cross-resistant combination. Cancer Treat. Rep. 66:221-230: 1982.

2. Arriagada, R.; Le Chevalier, T.: Baldeyrou, P.; Pica, J. L.: Ruffie, P.; Martin, M.; ElBakry, H. M.; Duroux, P.; Bignon. J.; Lenfant, B.; Hayat, M.; Rouesse, J. G.: Sancho-Garnier, H.; Tubiana, M. Alternating radiotherapy and chemother- apy schedules in small-cell lung cancer, limited disease. Int. J. Radiat. Oncol. Biol. Phys. 11:1461-1467; 1985.

3. Bleehen, N. M.; Bunn, P. A.: Cox, J. D.; Dombernowsky, P.; Fox, R. M.; Host, H.; Joss, R.; White, J. E.; Wittes, R. E. Role of radiation therapy in small cell anaplastic car- cinoma of the lung. Cancer Treat. Rep. 67: 1 l-19: 1983.

4. Bunn, P. A., Jr.: Lichter, A. S.; Makuch, R. W.; Cohen. M. H.; Veach, S. R.; Matthews, M. J.; Anderson, A. J.: Edison, M.: Glatstein, E.; Minna. J. D.: Ihde, D. C. Che-

motherapy alone or chemotherapy with chest radiation therapy in limited stage small-cell lung cancer. Ann. Intern. Med. 106:655-662; 1987.

5. Choi, N. C.; Carey, R. W. Importance of radiation dose in achieving improved loco-regional tumor control in limited stage small-cell lung carcinoma: an update. Int. J. Radiat. Oncol. Biol. Phys. 17:307-310: 1989.

6. Choi. N. C.; Propert, K.: Carey, R.: Eaton, W.; Leone, L. A.; Silberfarb P.; Green, M. Accelerated radiotherapy followed by chemotherapy for locally recurrent small-cell carcinoma of the lung. A phase II study of Cancer and Leu- kemia Group B. Int. J. Radiat. Oncol. Biol. Phys. 13:263- 266; 1987.

7. Choi, N. C.; Carey, R. W.; Kaufman, S. D.: Grille, H. C.: Younger, J.: Wilkins, E. W.; Jr. Small cell carcinoma of the lung: a progress report of 15 years’ experience. Cancer 59: 6-14: 1987.

Accelerated RT in small cell lung cancer 0 N. C. CHOI 1625

8.

9.

IO.

I I.

12.

13.

14.

Choi, N. C.; Suit, H. D. Evaluation of rapid radiation treat- ment schedules utilizing two treatment sessions per day. Radiology I 16:703-707; 1975. Elkind, M. M.; Sutton. H. Radiation response of mam- malian cells grown in culture. 1. Repair of x-ray damage in surviving Chinese hamster cells. Radiat. Res. 35:556-593: 1960. Goldie, J. H.; Coldman. A. J. A mathematic model for re- lating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat. Rep. 63:1727-1733: 1979. Goldie, J. H.: Coldman, A. J.; Gudauskas, G. A. Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat. Rep. 66:439-449; 1982. Greco, F. A.: Brereton. H. D.: Kent, H.: Zimbler, H.; Merrill. J.: Johnson, R. E. Adriamycin and enhanced radiation re- action in normal esophagus and skin. Ann. Intern. Med. 85:294-298: 1976. Ihde, D. C.; Grayson, J.; Woods, E.; Gazdar. A. F.: Ander- son, M.; Lesar. M.; Linnoila, 1.: Minna, J. D.: Glatstein. E.; Johnson, B. E. Limited stage small-cell lung cancer treated with concurrent etoposide/cisplatin and twice daily chest irradiation. Proceedings of 6th International Conference on the Adjuvant Therapy of Cancer, Tucson. Arizona: 1990: 37. Kies, M. S.; Mira, J. G.; Crowley. J. J.: Chen, T.: Pazdur. R.: Grozea. P. N.: Rivkin. S. E.: Coltman, C. A., Jr.; Ward J. H.; Livingston. R. B. Multimodal therapy for limited small-cell lung cancer: A randomized study of induction combination chemotherapy with or without thoracic radia- tion in complete responders: and with wide-field versus re-

15.

16.

17.

18.

19.

20.

21.

22.

duced-field radiation in partial responders: A Southwest Oncology Group study. J. Clin. Oncol. 5:592-600; 1987. Natale, R. B.; Wittes, R. E. Alternating combination che- motherapy regimens in small-cell lung cancer. Sem. Oncol. 12:7-13: 1985. Newburger, P. E.: Cassady, J. R.: Jaffe. N. Esophagitis due to Adriamycin and radiation therapy for childhood malig- nancy. Cancer 42:4 17-423; 1978. Perry, M. C.: Eaton. W. L.; Proper-t, K. J.; Ware, J. H.: Zimmer, B.; Chahinian, P.; Skarin, A.; Carey, R. W.; Kreis- man, H.; Faulkner, C.: Comis, R.: Green, M. R. Chemo- therapy with or without radiation therapy in limited small- cell carcinoma of the lung. N. Engl. J. Med. 3 I6:9 12-9 18: 1987. Peters, L. J.: Ang, K. K. Unconventional fractionation schemes in radiotherapy. In: DeVita. V. T.. Jr., Hellman, S., Rosenberg, S. A. eds. Important advances in oncology. Philadelphia: Lippincott: 1986:269-286. Suit, H. D. Supcrfractionation. Int. J. Radiat. Oncol. Biol. Phys. 2:591-592; 1977. Tubiana. M.: Arriagada. R.: Cosset. J. M. Sequencing of drugs and radiation: The integrated alternating regimen. Cancer 55:2131-2139; 1985.

Turrisi, A. T., III; Glover, D. J. Thoracic radiotherapy vari- ables: influence on local control in small cell lung cancer limited disease. Int. J. Radiat. Oncol. Biol. Phys. 19: 1471- 1477; 1990. Withers, H. R. Biologic basis for altered fractionation schemes. Cancer 55:2086-2095: 1985.