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Weekly Irinotecan and Concurrent Radiation Therapy for Stage III Unresectable NSCLC

Weekly Irinotecan and Concurrent Radiation Therapy for Stage III Unresectable NSCLC

ABSTRACT: In preclinical studies, the topoisomerase I inhibitor irinotecan (Camptosar, CPT-11) has demonstrated activity as a radiosensitizer, probably due to its ability to inhibit potentially lethal radiation damage repair. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly irinotecan with concurrent thoracic radiation therapy for patients with unresectable stage III non–small-cell lung cancer. For this study, 13 patients received three dose escalations (from 30 to 40 to 50 mg/m²/wk). At the first dose level, one patient developed grade 5 esophagitis. Accrual was expanded to seven patients. None of the remaining six patients developed esophagitis. At the second dose level (40 mg/m²/wk), the worst toxicity, which developed in one patient, was grade 2 esophagitis. At the third dose level (50 mg/m²/wk), two of three patients developed grade 4 nausea and vomiting; grade 3 or 4 esophagitis also occurred in two patients. Of the 12 evaluable patients, seven achieved a partial response, for an overall response rate of 58%. In conclusion, nausea, vomiting, and esophagitis appear to be the principal DLTs of concurrent weekly irinotecan and thoracic radiation in the outpatient setting. The MTD of concurrent weekly irinotecan with thoracic radiation therapy appears to be 40 mg/m² weekly for 6 weeks. To confirm the MTD of this combination, this study is still open to accrual at the second dose level (40 mg/m²) in combination with carboplatin. [ONCOLOGY 14(Suppl 5):43-46, 2000]

Introduction

Lung cancer is the leading cause of cancer death in the United States. Current projections indicate that 164,100 new cases will be diagnosed in the year 2000 while 156,900 deaths will occur.[1] Remarkably, although the incidence of lung cancer between 1999 and 2000 may decrease by approximately 10,000 cases, the mortality rate will decrease by less than 1% over the same time period. Because of the low cure rate, lung cancer kills more individuals than cancers of the breast, ovary, and colon combined and is, therefore, one of the major public health challenges for the next decade and beyond.

Previously, radiation alone was considered the standard of care for patients with unresectable non–small-cell lung cancer (NSCLC). Unfortunately, older series examining the role of radiation have not always demonstrated a survival advantage.[2,3] Instead, these poor results have led to the recent development of combined modality treatments, using more effective systemic therapy incorporating agents that have the potential for radiosensitization.

Large randomized studies have shown that concurrent chemotherapy and radiation is advantageous over induction chemotherapy prior to radiation.[4,5] There was also a significant effect on the rate of distant metastases in the patients receiving concurrent chemotherapy.[6,7] These studies have prompted both the American Society of Clinical Oncology[8] and the Ontario Lung Cancer Disease Site Group[9] to recommend combined modality therapy as the standard of care for good performance patients with locally advanced NSCLC.

A meta-analysis using data from 14 randomized trials and 2,589 patients found that the addition of chemotherapy to radiation reduced the risk of death at 2 years (relative risk 0.87; CI, 0.81 to 0.94).[10] This corresponded to a mean increase in life expectancy of 2 months. And, although there is a small benefit to the addition of chemotherapy to radiation, this must be balanced against the increased toxicity of combined modality treatment. Therefore, the investigation into combined modality therapy continues. However, the overall survival of patients with lung cancer remains unacceptably low. Clearly, new treatment strategies are needed.

Several newer chemotherapeutic agents are currently being combined with radiation in an attempt to improve both systemic and local control. These include vinorelbine (Navelbine), paclitaxel (Taxol), docetaxel (Taxotere), irinotecan (Camptosar, CPT-11), and gemcitabine (Gemzar). Each of these drugs produce single-agent response rates in the range of 15% to 25%, median survivals of 30 to 40 weeks, and 1-year survivals of 25% to 45%.[11] Phase II trials combining these agents with cisplatin (Platinol) or carboplatin (Paraplatin) yield outcomes superior to those of single-agent trials. Response rates are as high as 63%, median survival rates approach 1 year, and 1-year survival rates come close to 50% in the more promising studies.[12]

The identification of active new regimens in NSCLC is important for patients with advanced disease, but even more importantly, promising regimens with tolerable toxicity profiles may improve the cure rates in patients with early stage disease.

Preclinical Studies of Concurrent Irinotecan and Radiation

Irinotecan is a novel antineoplastic compound targeting DNA topoisomerase.[13-16] Its mechanism of action appears to be in its interference with the topoisomerase I-mediated breakage-rejoining of DNA strands.[13-18] In addition, irinotecan has demonstrated activity as a radiosensitizer in numerous preclinical studies, probably due to its ability to inhibit potentially lethal DNA damage repair.[19-26]

The precise molecular mechanism of radiosensitization of drugs that target DNA topoisomerase I still remains to be defined. It is possible that stabilization of cleavable complexes by topoisomerase I inhibitors initiates radiosensitization. This drug-stabilized cleavable complex, with a conceded single-strand DNA break, may possibly be the cause of “potentially lethal” DNA damage. Interaction with undefined cellular processes such as DNA replication, RNA transcription, and DNA repair may transform such “potentially sublethal” DNA damage into “sublethal” DNA damage. It is plausible that such “sublethal” DNA damage could then be converted into “lethal” DNA damage with the addition of radiation-induced DNA damage.[17,18]

Radiation sensitization with irinotecan has been reported in two human lung cancer xenografts.[27] In these experiments, irinotecan was administered in nontoxic doses 1 hour prior to a single dose of irradiation. In other reports, radiation sensitization with a camptothecin derivative occurred when the drug was given either during or after irradiation.[28]

All of the topoisomerase I targeting drugs currently in clinical development are camptothecin derivatives. Among them, irinotecan, topotecan (Hycamtin), and 9-aminocamptothecin have undergone the most extensive clinical evaluation.[29,30] A wide spectrum of clinical antitumor activity—including activity against colorectal, ovarian, small-cell and non–small-cell lung cancers, and malignant lymphomas—have been observed for these agents.[29,30] Based on the single modality clinical activity observed for these agents, systemic chemotherapy for patients with metastatic cancers, and the preclinical activity demonstrated for these agents when combined with radiation, a number of clinical trials utilizing irinotecan with ionizing radiation have now been performed, primarily in patients with locally advanced NSCLC.

Clinical Studies of Concurrent Irinotecan and Radiation

In a clinical phase I/II trial conducted by Kudoh and colleagues that used escalating doses of weekly irinotecan with concurrent irradiation (60 Gy in 30 fractions over 6 weeks), the maximum-tolerated dose (MTD) of irinotecan was 60 mg/m² (administered by 90-minute intravenous infusion) when given weekly for 6 weeks. Dose-limiting toxicities (DLT) were observed at the 60-mg/m²/week dose level in the form of esophagitis, pneumonitis, and diarrhea. The recommended Phase II dose was 45 mg/m². Out of 24 evaluable patients, two achieved complete responses (CR); 16 achieved partial responses, for an overall response rate of 76%.[31]

A follow-up phase II trial was conducted in 24 previously untreated patients with unresectable stage IIIA/IIIB disease and good performance status. Their median age was 60 years (range, 44–72 years). In this study, Saka and colleagues evaluated irinotecan at 60 mg/m²/week with concurrent thoracic radiation (60 Gy in 30 fractions over 6 weeks). All six doses were delivered in 71% of patients; 21% were able to receive five of the six planned doses and 88% completed the course as planned. Partial responses were observed in 19 of 24 evaluable patients (79%). No patient experienced grade 4 toxicity. Grade 3 toxicities were observed in eight patients, including neutropenia (2), hypoxemia (3), esophagitis (2), and fever (1); no one experienced grade 3 or 4 diarrhea.[32]

Due to the intrinsic activity of the platinums against NSCLC, the radiation-sensitizing effect of platinum against a variety of solid tumors (including lung cancer), and the preclinical synergy demonstrated for platinum and irinotecan combinations in vitro, irinotecan with radiation is now being evaluated with regimens that integrate carboplatin. Nakagawa and colleagues treated 23 stage IIIA or IIIB patients with escalating doses of irinotecan plus a fixed dose of carboplatin (20 mg/m²) on a weekly basis for the first 4 weeks of radiation (60 Gy in 30 fractions over 6 weeks). At the time of the report, the irinotecan had been escalated from 30 to 50 mg/m²/week without the appearance of dose-limiting toxicity. Grade 3/4 diarrhea had been observed in only 2 of 23 patients (8.7%) and grade 3/4 pulmonary toxicity in 1 patient (4.3%). Objective responses were seen in 14 of the first 23 evaluable patients (60.9%).[33]

Recently, other Japanese investigators reported their experiences in a phase I study of irinotecan and carboplatin with concurrent thoracic radiotherapy for unresectable stage III disease. In their study, patients with stage IIIA or IIIB disease received weekly carboplatin at a dose of 20 mg/m² daily for 5 days per week with irinotecan from 30 mg/m² in increments of 10 mg/m². Radiation was administered at 60 Gy, in 2 Gy fractions, for 6 weeks. The MTD was 60 mg/m²; the dose-limiting toxicities (DLT) included pneumonitis, esophagitis, neutropenia, and thrombocytopenia. Of 30 patients, 3 achieved a complete response and 15 a partial response, resulting in an overall response rate of 60%. The median survival has not yet been reached. At 55.5% and 51.3%, respectively, the 1- and 2-year survivals are impressive.[34]

In general, objective response rates were also impressive, with a range of 60% to 80% achieved in patients treated with various chemoradiation combinations with irinotecan and carboplatin. Severe treatment-related toxicities (grade 3 and higher) including fever, neutropenia, thrombocytopenia, pneumonitis, and esophagitis were rarely observed.

Phase I Pilot Study

A phase I pilot study of irinotecan, carboplatin, and thoracic radiation therapy for medically and/or surgically inoperable NSCLC is being conducted at the Vanderbilt-Ingram Cancer Center Affiliate Network (VICCAN). The primary objectives of this study are twofold: (1) to determine the MTD of irinotecan when administered with carboplatin and radiation therapy in patients with unresectable stage IIIA/IIIB NSCLC and (2) to evaluate the toxicities of the combinations of irinotecan and radiation therapy as well as those associated with the combination of irinotecan/carboplatin and radiotherapy. The secondary objectives are to evaluate the response rate and response duration of advanced medically inoperable and/or surgically inoperable NSCLC treated with the combination of irinotecan (± carboplatin) and local irradiation.

To be eligible for this study, patients are required to have histologically- or cytologically-documented unresectable stage IIIA or IIIB, an ECOG performance of 0 to 2, weight loss < 15% in the 3 months prior to diagnosis, and no prior chemotherapy or radiation therapy. Successive groups of three to six patients will receive progressively higher doses of irinotecan alone or with carboplatin in conjunction with fixed doses of radiotherapy. At least three patients in each group must be observed for DLT during the 6 weeks of therapy before subsequent patients can be enrolled at a higher dose level (Table 1).

Radiation therapy commenced on day 1 of the chemotherapy dose schedule. Chemotherapy was always given prior to radiation. The initial volume of the irradiated field, consisting of the tumor and mediastinum, received 40 Gy, at 2 Gy per fraction 5 days per week. This was followed by a boost to the primary and involved nodes of 20 Gy over 2 weeks, also administered in 2 Gy per fraction, 5 days per week. The initial treatment volume was treated with fields, which kept the maximum spinal cord dose at 45 Gy.

A total of 13 patients were entered into this study through three dose escalations (from 30 to 50 mg/m² weekly). At the first dose level, one patient developed grade 5 esophagitis, and accrual was expanded to seven patients. None of the six remaining patients at the first dose level experienced esophagitis. At the second dose level (40 mg/m²/week), the worst toxicity was grade 2 esophagitis in one patient. At the third dose level (50 mg/m²/week), two of three patients developed grade 4 nausea and vomiting. Additionally, grade 3 or 4 esophagitis occurred in two patients. Of the 12 evaluable patients, 7 achieved a partial response for an overall response rate of 58%.

In conclusion, nausea, vomiting, and esophagitis appear to be the principal DLTs of concurrent weekly irinotecan and thoracic radiation in the outpatient setting. The MTD of concurrent weekly irinotecan with thoracic radiation therapy appears to be 40 mg/m2 weekly for 6 weeks. This study is still open to accrual at the second dose level (40 mg/m2) with the addition of carboplatin and thoracic radiation.[35] Concurrent radiation with weekly carboplatin and irinotecan has been adopted as one of the treatment arms in the new Radiation Therapy Oncology Group randomized phase II trial for patients with locally advanced non–small-cell lung cancer.

References

1. American Cancer Society: Cancer Facts & Figures—2000. Atlanta, Ga: American Cancer Society, 2000.

2. Dosoretz DE, Katin MJ, Blitzer PH, et al: Radiation therapy in the management of medically inoperable carcinoma of the lung: Results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24:3-9, 1992.

3. Perez CA, Stanley K, Rubin P, et al: A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 45:2744-2753, 1980.

4. Dillman RO, Seagren SL, Propert KJ, et al: A randomized trial of induction chemotherapy plus high-dose radiation vs radiation alone in stage III non–small-cell lung cancer. N Engl J Med 323:940-945, 1990.

5. Sause WT, Scott C, Taylor S, et al: Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non–small-cell lung cancer. J Natl Cancer Inst 87:198-205, 1995.

6. Le Chevalier T, Arriagada R, Quoix E, et al: Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non–small-cell lung cancer: First analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83:417-423, 1991.

7. Jeremic B, Shibamoto Y, Acimovic L, et al: Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non–small-cell lung cancer: A randomized study. J Clin Oncol 14:1065-1070, 1996.

8. American Society of Clinical Oncology: Clinical practice guidelines for the treatment of unresectable non–small-cell lung cancer. J Clin Oncol 15:2996-3018, 1997.

9. Evans WK, Newman T, Graham I, et al: Lung cancer practice guidelines: Lessons learned and issues addressed by the Ontario Lung Cancer Disease Site Group. J Clin Oncol 15:3049-3059, 1997.

10. Pritchard RS, Anthony SP: Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small cell lung cancer. A meta-analysis. Ann Intern Med 125:723-729, 1996.

11. Rowinsky EK, Ettinger DS: Drug development and new drugs for lung cancer, in: Pass HI, Mitchell JB, Johnson DH, et al (eds): Lung Cancer, 793-810. Philadelphia, Pa, Lippincott-Raven Publishers, 1995.

12. Langer CJ, Leighton JC, Comis RL, et al: Paclitaxel and carboplatin in combination in the treatment of advanced non–small-cell lung cancer: A phase II toxicity, response, and survival analysis. J Clin Oncol 13:1860-1870, 1995.

13. Hsiang YH, Hertzberg R, Hecht S, et al: Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14873-14878, 1985.

14. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722-1726, 1988.

15. Andoh T, Ishii K, Suzuki Y, et al: Characterization of a mammalian mutant with a camptothecin-resistant DNA topoisomerase I. Proc Natl Acad Sci USA 84:5565-5569, 1987.

16. Nitiss J, Wang JC: DNA topoisomerase-targeting antitumor drugs can be studied in yeast. Proc Natl Acad Sci USA 85:7501-7505, 1988.

17. Chen AY, Yu C, Gatto B, et al: DNA minor groove-binding ligands: A different class of mammalian DNA topoisomerase I inhibitors. Proc Natl Acad Sci USA 90:8131-8135, 1993.

18. Chen AY, Yu C, Bodley A, et al: A new mammalian DNA topoisomerase I poison Hoechst 33342: Cytotoxicity and drug resistance in human cell cultures. Cancer Res 53:1332-1337, 1993.

19. Boothman DA, Trask DK, Pardee AB: Inhibition of potentially lethal DNA damage repair in human tumor cells by beta-lapachone, an activator of topoisomerase I. Cancer Res 49:605-612, 1989.

20. Mattern MR, Hofmann GA, McCabe FL, et al: Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864). Cancer Res 51:5813-5816, 1991.

21. Kim JH, Kim SH, Kolozsvary A, et al: Potentiation of radiation response in human carcinoma cells in vitro and murine fibrosarcoma in vivo by topotecan, an inhibitor of DNA topoisomerase I. Int J Radiat Oncol Biol Phys 22:515-518, 1992.

22. Boothman DA, Wang M, Schea RA, et al: Posttreatment exposure to camptothecin enhances the lethal effects of x-rays on radioresistant human malignant melanoma cells. Int J Radiat Oncol Biol Phys 24:939-948, 1992.

23. Roffler SR, Chan J, Yeh MY: Potentiation of radioimmunotherapy by inhibition of topoisomerase I. Cancer Res 54:1276-1285, 1994.

24. Boothman DA, Fukunaga N, Wang M: Down-regulation of topoisomerase I in mammalian cells following ionizing radiation. Cancer Res 54:4618-4626, 1994.

25. Falk SJ, Smith PJ: DNA damaging and cell cycle effects of the topoisomerase I poison camptothecin in irradiated human cells. Int J Radiat Biol 61:749-757, 1992.

26. Hennequin C, Giocanti N, Balosso J, et al: Interaction of ionizing radiation with the topoisomerase I poison camptothecin in growing V-79 and HeLa cells. Cancer Res 54:1720-1728, 1994.

27. Tamura K, Takada M, Kawase I, et al: Enhancement of tumor radio-response by irinotecan in human lung tumor xenografts. Jpn J Cancer Res 88:218-223, 1997.

28. Omura M, Torigoe S, Kubota N: SN-38, a metabolite of the camptothecin derivative CPT—11, potentiates the cytotoxic effect of radiation in human colon adenocarcinoma cells grown as spheroids. Radiother Oncol 43:197-201, 1997.

29. Clinical status and future directions of irinotecan: Proceedings of a symposium at The University of Texas M. D. Anderson Cancer Center. Oncology 12(suppl 6):11-128, 1998.

30. Pantazis P, Early J A, Kozielski AJ, et al: Regression of human breast carcinoma tumors in immunodeficient mice treated with 9-nitrocamptothecin: differential response of nontumorigenic and tumorigenic human breast cells in vitro. Cancer Res 53: 1577-1582, 1993.

31. Kudoh S, Kurihara N, Okishio K, et al: A phase I-II study of weekly irinotecan and simultaneous thoracic radiotherapy for unresectable locally advanced non-small cell lung cancer (abstract). Proc Am Soc Clin Oncol 15:372, 1996.

32. Saka H, Shimokata K, Yoshida S, et al: Irinotecan and concurrent radiotherapy in locally advanced non-small cell lung cancer: A phase II study of Japan Clinical Oncology Group (JCOG 9504) (abstract 1909). Proc Am Soc Clin Oncol 16:447a, 1997.

33. Nakagawa K, Yamamoto N, Kudoh S, et al: Irinotecan and carboplatin with concurrent thoracic radiotherapy for unresectable, stage III non-small cell lung cancer—preliminary results (abstract). Proc Am Soc Clin Oncol 17:496a, 1998.

34. Yamada M, Kudoh S, Negoro S, et al: A phase I study of irinotecan and carboplatin with concurrent thoracic radiotherapy for unresectable stage III non-small cell lung cancer (abstract 2035). Proc Am Soc Clin Oncol 18:528a, 1999.

35. Chakravarthy A, Choy H, Devore RF, et al: Phase I trial of outpatient weekly irinotecan and concurrent radiation therapy for stage III unresectable non-small-cell lung cancer: A Vanderbilt Cancer Center Affiliate Network trial (abstract 1924). Proc Am Soc Clin Oncol 18:498a, 1999.

 
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