Topics:

Treatment of Non-Small-Cell Lung Cancer in North America: The Emerging Role of Irinotecan

Treatment of Non-Small-Cell Lung Cancer in North America: The Emerging Role of Irinotecan

ABSTRACT: Topoisomerase I inhibitors have demonstrated significant activity in non-small-cell lung cancer. In phase II studies, particularly in Japan, single-agent irinotecan (Camptosar, CPT-11) has produced response rates as high as 35%. In combinations with cisplatin (Platinol), it has also resulted in overall response rates of 41% to 52%, with median survival of 10.2 to 13 months, and 1-year survival rates of 33% and 58%. A Japanese phase III randomized trial of irinotecan, either alone or in combination with cisplatin vs vindesine/cisplatin in previously untreated stage IIIB/IV non-small-cell lung cancer, demonstrated that survival among stage IV patients was significantly better in the irinotecan arms compared to the vindesine/cisplatin group. However, another Japanese phase III study comparing irinotecan/cisplatin to vindesine/cisplatin failed to show a survival difference. Initial North American efforts recapitulated this work, while a follow-up study incorporated weekly irinotecan with weekly cisplatin, yielding a response rate of 36%, median survival of 11.6 months, and a 1-year survival rate of 46%. Irinotecan/taxane combinations have also shown promise. Phase I/II studies in advanced non-small-cell lung cancer with paclitaxel (Taxol), irinotecan, and carboplatin (Paraplatin) produced a response rate of 38%, median survival of 11 months, and a 1-year survival rate of 47%; other trials with irinotecan and paclitaxel are ongoing. Phase I data for irinotecan/docetaxel (Taxotere) have indicated an overall response rate of 32%, median survival of 39 weeks, and a 1-year survival rate of 38%; subsequent phase II trials used either cisplatin or irinotecan in combination with docetaxel and yielded a promising median survival of 45.6 weeks, comparable to the standard cisplatin/docetaxel combination. Phase I trials with irinotecan and gemcitabine (Gemzar) have also yielded promising results. Follow-up efforts include phase II studies in both chemonaive advanced non-small-cell lung cancer and progressive small-cell lung cancer (salvage therapy). Clearly, clinical trial data have demonstrated the utility of irinotecan in the treatment of advanced non-small-cell lung cancer. Planned combinations with new chemotherapeutic agents and biological response modifiers may provide additional treatment options. [ONCOLOGY 15(Suppl 1):19-24, 2001]

Introduction

Even though its annual incidence is eclipsed by breast cancer and prostate cancer, lung cancer remains the leading cause of cancer death in North America. Although the incidence of lung cancer is starting to plateau in North American males, it continues to rise in American women and in both genders outside the United States, particularly in Europe and Asia. The 5-year survival rate in the United States is only 14% overall, and 50% more women die of lung cancer than breast cancer.[1] Generally, the disease is either systemic at diagnosis, or manifests distant spread after local regional therapy. Hence, new agents with improved systemic activity are desperately needed. This article will review the activity of irinotecan (Camptosar, CPT-11), both alone and in combination with cisplatin (Platinol) and other agents in advanced non-small-cell lung cancer. It will also touch on planned and ongoing phase III trials establishing its utility in non-small-cell lung cancer.

Single-Agent Therapy

Multiple phase II studies, particularly in Japan, have established the utility of irinotecan in the treatment of advanced non-small-cell lung cancer. Response rates have ranged as high as 30% to 35%, using conventional schedules of 100 to 125 mg/m2/wk ´ 4 weeksfollowed by a 2-week rest every 6 weeks,[2-4] or doses of 300 to 350 mg/m2 every 3 weeks with or without hematopoietic growth factor support.[5] In one US study evaluating single-agent irinotecan, the response rate was disappointing at only 15% using a conventional schedule of 100 mg/m2/wk ´ 4 every 6 weeks, and the median survival was only 6.2 months.[6] Toxicities have generally included myelosuppression and diarrhea. The results from these studies are summarized in Table 1.

Cisplatin/Irinotecan Combinations

Cisplatin remains the cornerstone of combination therapy in advanced non-small-cell lung cancer, and meta-analyses have demonstrated a statistically significant survival benefit for cisplatin-based regimens vs best supportive care.[7,8] Consequently, investigators have sought to assess the activity of irinotecan in combination with cisplatin, with the earliest efforts emanating from Japan. Masuda and colleagues evaluated cisplatin at 80 mg/m2 day 1 every 4 weeks in combination with irinotecan at 60 mg/m2 days 1, 8, and 15.[9] The overall response rate was 52%; time to progression was 4.4 months, median survival 10.2 months, and the 1-year survival rate was 33%. In an attempt to capitalize on their putative therapeutic synergy, Ueoka and collaborators assessed the irinotecan and cisplatin combination at doses of 50 and 60 mg/m2, respectively, days 1 and 8 every 4 weeks.[10] The overall response rate was slightly lower at 41%, but median survival was 13 months and the 1-year survival rate was 58%.

Phase III Randomized Trials

Masuda and colleagues conducted a phase III trial of irinotecan, either alone or in combination with cisplatin, vs vindesine/cisplatin, the reference arm.[11] Eligible patients were those with previously untreated stage IIIB or IV measurable non-small-cell lung cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and adequate marrow, hepatic, renal, and pulmonary function; patients older than 75 were excluded. A total of 385 evaluable patients were enrolled, 246 of whom had stage IV disease. Demographics with respect to age, performance status, prior weight loss, albumin, and lactate dehydrogenase were well matched for each arm. Patients were randomized to one of three arms: (A) irinotecan at 60 mg/m2 days 1, 8, and 15 and cisplatin at 80 mg/m2 day 1 every 4 weeks; (B) vindesine at 3 mg/m2 days 1, 8, and 15 and cisplatin at 80 mg/m2 day 1 every 4 weeks; or (C) irinotecan at 100 mg/m2 days 1, 8, and 15 every 4 weeks. The results are shown in Table 2.

Leukopenia was much more pronounced in the vindesine/cisplatin combination, while thrombocytopenia was more common in the irinotecan/cisplatin combination. Both irinotecan arms resulted in substantially more grade 3 and 4 diarrhea; the cisplatin arms yielded considerably more nausea and vomiting. The incidence of anemia was driven by cisplatin: 39% grade ³ 3 for irinotecan/cisplatin, compared to 23% for vindesine/cisplatin, vs 6% for irinotecan alone. Survival among stage IV patients was significantly better for those receiving irinotecan (arms A or C) compared to those receiving vindesine/cisplatin (Figure 1). This established irinotecan, along with vinorelbine (Navelbine) and paclitaxel (Taxol),[12,13] as one of three "new" agents which, in combination with cisplatin, has proven superior to "standard" older cisplatin combinations.

However, a separate phase III study comparing irinotecan/cisplatin to vindesine/cisplatin in 210 patients with advanced non-small-cell lung cancer failed to show a survival difference.[14] The median survival for irinotecan/cisplatin was 44.7 weeks, with respective 1- and 2-year survival rates of 36.4% and 8.7% in stage IV patients. The median survival in the vindesine/cisplatin arm was 45.3 weeks, with 1- and 2-year survival rates of 41.4% and 10.3%, respectively (P = .668).

North American Trials

The initial combination effort in North America reported by DeVore and colleagues recapitulated the Japanese study of Masuda and coworkers: cisplatin at 80 mg/m2 day 1 and irinotecan at 60 mg/m2 weekly × 3 every 4 weeks.[15] In the 52 patients enrolled, the overall response rate was 29%, with a median time to progression of 5.1 months, median survival of 9.9 months, and a 1-year survival rate of 37%. Grade ³ 3 neutropenia occurred in 46% of patients, with an overall 11.5% incidence of febrile neutropenia. Nausea/vomiting and asthenia were driven by cisplatin; grade ³ 3 incidences were 32.7%/5.8% and 23.1%, respectively, and grade 3 or 4 diarrhea occurred in 17.3% and 11.5% of patients, respectively. The relative dose intensity of irinotecan was 75.5%. Seventy-three percent of the patients required dose reductions of irinotecan; most patients ultimately had their irinotecan dose reduced to ≤ 40 mg/m2.

Consequently, a follow-up study, in which Vanderbilt Cancer Center, its affiliated network (VCCAN), and Fox Chase Cancer Center (FCCC) joined forces, combined weekly irinotecan with weekly cisplatin.[16] There were three rationales behind this move: (1) in vitro preclinical models had demonstrated the putative synergy of these two agents, which could be better exploited by same-day administration, (2) improved sequencing of irinotecan and cisplatin might potentially improve efficacy, and (3) attenuation of the cisplatin dose with each administration could reduce toxicity and preserve dose intensity. The regimen was modeled after the phase I data of Saltz and colleagues.[17]

Eligible patients received irinotecan at 65 mg/m2 and cisplatin at 30 mg/m2, each given weekly × 4 weeks followed by a 2-week rest, and treatment was repeated at 6-week intervals. Fifty patients were enrolled. The overall response rate was 36%, which was slightly higher than that observed in the previous North American study. Median time to progression was 6.9 months, median survival 11.6 months, and the 1-year survival rate 46%—the best results ever observed at the VCCAN in advanced non-small-cell lung cancer patients, and comparable to previous results observed at Fox Chase and in the FCCC network.[18-20]

The overall incidence of grade ³ 3 neutropenia was 25.5%, febrile neutropenia occurred in 6% of patients, grade ³ 3 thrombocytopenia occurred in 12%, and grade ³ 3 nausea/vomiting occurred in 26%. The relative dose intensity of irinotecan in this combination was 89%, and the dose intensity was fairly well maintained for both agents. A comparison of these two regimens is depicted in Table 3. Data to date would favor the approach employing weekly as opposed to monthly cisplatin.

Taxane/Irinotecan Combinations

Burtness and colleagues mounted an open phase I trial of irinotecan and paclitaxel, with both agents administered weekly × 4 weeks every 6 weeks.[21] Twenty-one patients were enrolled in this phase I study, and a total of 53 cycles were administered. The maximum tolerated dose in this schedule was irinotecan at 50 mg/m2 and paclitaxel at 75 mg/m2 weekly. Pharmacokinetics revealed no drug-drug interaction based on levels of irinotecan and its active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin).

The same investigators are conducting a formal phase II study of this combination in advanced non-small-cell lung cancer patients with an ECOG performance status of 0 to 2. It employs an abbreviated schedule: irinotecan at 50 mg/m2 in combination with paclitaxel at 75 mg/m2, both agents given weekly ´ 2 every 3 weeks. To date, seven patients have been accrued. No grade 4 neutropenia has been observed. Two of six evaluable patients have sustained partial response (18+ weeks), three have had stable disease, and only one has shown progressive disease (J. Murren, personal communication, July 2000).

Rosen and coworkers combined irinotecan with paclitaxel, with both agents given once every 3 weeks.[22] This open phase I study included a number of cancer diagnoses, including lung (n = 3), hepatobiliary (n = 4), pancreas (n = 2), gastric (n = 2), and other (n = 6). The maximum tolerated dose was 225 mg/m2 for irinotecan and 100 mg/m2 for paclitaxel. Grade ³ 3 diarrhea was observed in only one of nine treatment courses at the maximum tolerated dose, whereas at higher doses, grade ³ 3 diarrhea occurred in 5 of 17 patients. Objective responses were seen in non-small-cell lung cancer and occult primary squamous malignancy. Paclitaxel coadministration did not alter irinotecan pharmacokinetics, based on high-performance liquid chromatography quantification of plasma concentrations of irinotecan, its active metabolite SN-38, and glucuronide SN-38G in patients who were administered doses up to the maximum tolerated dose.

Socinski and colleagues have conducted phase I and II studies of paclitaxel, irinotecan, and carboplatin (Paraplatin) in patients with advanced non-small-cell lung cancer.[23] At the initial dose levels, irinotecan was administered on a day 1 and 8 schedule, and incorporated full-dose paclitaxel at 225 mg/m2 every 3 weeks and carboplatin at an area under the concentration-time curve (AUC) of 6 every 3 weeks. But dose-limiting toxicity in three of the first seven patients accrued led to dose reductions of paclitaxel and carboplatin and the elimination of day 8 irinotecan. The maximum tolerated doses for these three agents using an every-3-week schedule were paclitaxel at 175 mg/m2, irinotecan at 100 mg/m2, and carboplatin at an AUC of 5.

Thirty-three patients were enrolled in the phase I effort, and the overall response rate in 31 evaluable patients was 39% (10% complete response rate). The most common grade ³ 3 toxicity was neutropenia, which occurred in 50% of patients. Five (16%) developed neutropenic fever. Median time to progression was a promising 6.8 months, median survival 11 months, and the 1-year survival rate 47%.

To date, 40 patients have been enrolled in the phase II effort. The response rate of 38% is comparable to the phase I effort and time to progression at 6.2 months is similar, while median survival is somewhat lower at 8.8 months (the 1-year survival rate has not yet been reached). Disappointingly, the incidence of neutropenic fever is 30%, higher than that observed in the phase I study. Future studies will either lower the carboplatin dose to an AUC of 4 or add a hematopoietic growth factor in an effort to mitigate this toxicity.

Finally, a phase I effort assessed irinotecan in combination with docetaxel (Taxotere).[24] Twenty-six treatment-naive advanced non-small-cell lung cancer patients (22 stage IV) received docetaxel day 2 and irinotecan days 1, 8, and 15, with doses being escalated across sequential cohorts. The maximum tolerated dose was 50 mg/m2 for docetaxel and 60 mg/m2 for irinotecan. Higher doses led to dose-limiting toxicity, primarily neutropenia. The overall response rate was 32%, median survival 39 weeks, and the 1-year survival rate 38%.

In a subsequent randomized phase II effort that assessed either cisplatin or irinotecan in combination with docetaxel,[25] 57 advanced non-small-cell lung cancer patients received docetaxel at 60 mg/m2 day 8 and irinotecan at 60 mg/m2 days 1 and 8. Median time to progression was 18.1 weeks, and median survival was promising at 45.6 weeks. Grade ³ 3 neutropenia occurred in 82.5%, grade ³ 2 nausea/vomiting in 52.6%, and grade ³ 2 diarrhea in 43.9%. Results with this nonplatinum combination proved comparable to the standard cisplatin/docetaxel combination.

Irinotecan and Gemcitabine

Rocha-Lima and colleagues from the Medical University of South Carolina at Charleston have assessed irinotecan in combination with gemcitabine (Gemzar) (IrinoGem).[26] Preclinical data evaluating the combination of irinotecan and gemcitabine have demonstrated dose-dependent interactions between the two drugs. Combination index analyses have revealed antagonism at low concentrations, but synergism at concentrations of gemcitabine above 0.1 mM and irinotecan above 3.2 mM in the human SCOG small-cell lung cancer cell line.[27,28] Rocha-Lima and coworkers conducted a phase I trial using a days 1 and 8 every-3-week schedule to determine the maximum tolerated dose of irinotecan that could be administered as a 90-minute IV infusion immediately after gemcitabine at a dose of 1,000 mg/m2 by 30-minute IV infusion in patients with solid tumors.[27] Nineteen patients were enrolled at four irinotecan dose levels of 50, 75, 100, and 115 mg/m2.

Grade 4 diarrhea in two of seven patients constituted the dose-limiting toxicity at an irinotecan dose of 115 mg/m2; hematologic toxicity was not dose-limiting. Three patients required omission of day 8 cycle 1 chemotherapy due to grade 3 myelosuppression. Three out of four previously treated non-small-cell lung cancer patients who were treated with irinotecan doses of 50, 75, and 100 mg/m2 had stable disease for more than 4 cycles; no non-small-cell lung cancer patients were treated with irinotecan at 115 mg/m2.[26]

The maximum tolerated dose of irinotecan in this combination was 100 mg/m2—the recommended starting dose for phase II studies. Cancer and Leukemia Group B is spearheading a phase II trial of irinotecan and gemcitabine in advanced non-small-cell lung cancer and a similar trial as salvage therapy in progressive small-cell lung cancer (Figure 2). Results should be available in the next 12 to 18 months.

Future Efforts in Advanced Disease

A phase III trial comparing cisplatin/irinotecan and gemcitabine/cisplatin using a day 1 and 8 schedule every 3 weeks to the noncisplatin constituents—irinotecan and gemcitabine—is being contemplated (Figure 3), as is a phase III study comparing the weekly cisplatin/irinotecan × 4 every-6-week schedule to standard therapy. Proposed phase II studies will also assess the role of angiogenesis inhibitors and proapoptotic agents introduced into weekly schedules of cisplatin and irinotecan. Finally, the Japanese are spearheading a four-arm phase III trial comparing irinotecan/cisplatin, their new standard, to other state-of-the-art combinations, including vinorelbine/cisplatin, gemcitabine/cisplatin, and carboplatin/paclitaxel.

Conclusion

In summary, a survival advantage has been observed in stage IV non-small-cell lung cancer patients in at least one randomized prospective phase III trial using monthly cisplatin and weekly irinotecan compared to vindesine/cisplatin. On the other hand, weekly irinotecan and cisplatin appears to be more active and better tolerated. Future studies will elucidate the status of irinotecan combinations vis-à-vis other standard combinations. They will also assess the role of irinotecan, either alone or in combination with gemcitabine, as salvage therapy in chemotherapy-exposed patients.

Irinotecan and Gemcitabine

Rocha-Lima and colleagues from the Medical University of South Carolina at Charleston have assessed irinotecan in combination with gemcitabine (Gemzar) (IrinoGem).[26] Preclinical data evaluating the combination of irinotecan and gemcitabine have demonstrated dose-dependent interactions between the two drugs. Combination index analyses have revealed antagonism at low concentrations, but synergism at concentrations of gemcitabine above 0.1 mM and irinotecan above 3.2 mM in the human SCOG small-cell lung cancer cell line.[27,28] Rocha-Lima and coworkers conducted a phase I trial using a days 1 and 8 every-3-week schedule to determine the maximum tolerated dose of irinotecan that could be administered as a 90-minute IV infusion immediately after gemcitabine at a dose of 1,000 mg/m2 by 30-minute IV infusion in patients with solid tumors.[27] Nineteen patients were enrolled at four irinotecan dose levels of 50, 75, 100, and 115 mg/m2.

Grade 4 diarrhea in two of seven patients constituted the dose-limiting toxicity at an irinotecan dose of 115 mg/m2; hematologic toxicity was not dose-limiting. Three patients required omission of day 8 cycle 1 chemotherapy due to grade 3 myelosuppression. Three out of four previously treated non-small-cell lung cancer patients who were treated with irinotecan doses of 50, 75, and 100 mg/m2 had stable disease for more than 4 cycles; no non-small-cell lung cancer patients were treated with irinotecan at 115 mg/m2.[26]

The maximum tolerated dose of irinotecan in this combination was 100 mg/m2—the recommended starting dose for phase II studies. Cancer and Leukemia Group B is spearheading a phase II trial of irinotecan and gemcitabine in advanced non-small-cell lung cancer and a similar trial as salvage therapy in progressive small-cell lung cancer (Figure 2). Results should be available in the next 12 to 18 months.

Future Efforts in Advanced Disease

A phase III trial comparing cisplatin/irinotecan and gemcitabine/cisplatin using a day 1 and 8 schedule every 3 weeks to the noncisplatin constituents—irinotecan and gemcitabine—is being contemplated (Figure 3), as is a phase III study comparing the weekly cisplatin/irinotecan × 4 every-6-week schedule to standard therapy. Proposed phase II studies will also assess the role of angiogenesis inhibitors and proapoptotic agents introduced into weekly schedules of cisplatin and irinotecan. Finally, the Japanese are spearheading a four-arm phase III trial comparing irinotecan/cisplatin, their new standard, to other state-of-the-art combinations, including vinorelbine/cisplatin, gemcitabine/cisplatin, and carboplatin/paclitaxel.

Conclusion

In summary, a survival advantage has been observed in stage IV non-small-cell lung cancer patients in at least one randomized prospective phase III trial using monthly cisplatin and weekly irinotecan compared to vindesine/cisplatin. On the other hand, weekly irinotecan and cisplatin appears to be more active and better tolerated. Future studies will elucidate the status of irinotecan combinations vis-à-vis other standard combinations. They will also assess the role of irinotecan, either alone or in combination with gemcitabine, as salvage therapy in chemotherapy-exposed patients.

References

1. Parkin DM, Pisani P, Ferlay J: Global Cancer Statistics, CA Cancer J Clin 49:33-64, 1999.

2. Fukuoka M, Masuda N: Clinical studies of irinotecan alone and in combination with cisplatin. Cancer Chemother Pharmacol 34(suppl):S105-S111, 1994.

3. Fukuoka M, Niitani H, Suzuki A, et al: A phase II study of CPT-11, a new derivative of camptothecin for previously untreated non-small cell lung cancer. J Clin Oncol 10:16-20, 1992.

4. Negoro S, Fukuoka M, Masuda N, et al: A phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin in the treatment of non-small cell lung cancer. J Natl Cancer Inst 83:1164-1168, 1991.

5. Douillard JY, Ibrahim N, Riviere A, et al: A phase II study of CPT-11 in non-small cell lung cancer (abstract 1118). Proc Am Soc Clin Oncol 14:365a, 1995.

6. Baker L, Khan R, Lynch T, et al: Phase II study of irinotecan in advanced NSCLC (abstract 1650). Proc Am Soc Clin Oncol 16:461a, 1997.

7. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 311:899-909, 1995.

8. Albain KS, Crowley JJ, LeBlanc, et al: Survival determinants in extensive-stage non-small-cell lung cancer: The Southwest Oncology Group experience. J Clin Oncol 9:1618-1626, 1991.

9. Masuda N, Fukuoka M, Fujita A, et al: A phase II trial of combination of CPT-11 and cisplatin for advanced non-small cell lung cancer. Br J Cancer 78:251-256, 1998.

10. Ueoka H, Kiura K, Hireki S, et al: Fractionated administration of cisplatin and irinotecan in patients with stage IIIB and IV non-small cell lung cancer: A phase II study (abstract 2026). Proc Am Soc Clin Oncol 18:525a, 1999.

11. Masuda N, Fukuoka M, Nagoro S, et al: A randomized trial comparing cisplatin and irinotecan vs cisplatin and vindesine vs CPT-11 alone in advanced non-small cell lung cancer (NSCLC): A multicenter phase III study (abstract 1774). Proc Am Soc Clin Oncol 18:459a, 1999.

12. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer: A Southwest Oncology Group Study. J Clin Oncol 16:2459-2465, 1998.

13. Bonomi P, Kim K, Fairclough D, et al: Comparison of survival and quality of life in advanced non-small cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: Results of an Eastern Cooperative Oncology Group (ECOG) trial. J Clin Oncol 18:623-631, 2000.

14. Niho S, Nagao K, Nishiwaki Y, et al: A randomized multicenter phase III trial of irinotecan and cisplatin vs cisplatin and vindesine in patients with advanced non-small cell lung cancer (abstract 1897). Proc Am Soc Clin Oncol 18:429a, 1999.

15. DeVore RF, Johnson DH, Crawford J, et al: A phase II study of irinotecan plus cisplatin in patients with advanced non-small cell lung cancer. J Clin Oncol 17:2710-2720, 1999.

16. Jagasia M, Langer C, Yunis F, et al: Preliminary results of a multicenter phase II trial of weekly cisplatin and irinotecan in patients with advanced non-small cell lung cancer (NSCLC): A Vanderbilt Cancer Center affiliate network study (abstract 1967). Proc Am Soc Clin Oncol 18:510a, 1999.

17. Saltz LB, Spriggs D, Schaaf LJ, et al: A phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors. J Clin Oncol 16:3858-3865, 1998.

18. Johnson VK, Zaretsky S, Natale RB: Phase I/II trial of combination carboplatin and taxol in advanced non-small cell lung cancer. J Clin Oncol 14:2054-2060, 1996.

19. 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.

20. Langer CJ, McAleer CA, Bonjo CA, et al: Paclitaxel by one-hour infusion in combination with carboplatin in advanced non-small cell lung carcinoma (NSCLC). Eur J Cancer 36:183-193, 2000.

21. Burtness B, Argiris A, Rich RS, et al: Weekly chemotherapy with irinotecan plus taxane in advanced pancreatic carcinoma (abstract 1081). Proc Am Soc Clin Oncol 19:277a, 2000.

22. Rosen P, Schaaf LJ, Knuth DW, et al: Phase I pharmacokinetic trial of irinotecan and paclitaxel in patients with advanced cancers (abstract 679). Proc Am Soc Clin Oncol 18:177a, 1999.

23. Socinski M, Sandler A, Miller L, et al: Phase I/II trial of irinotecan, paclitaxel and carboplatin in advanced or metastatic non-small cell lung cancer (abstract 67). Cancer Invest 18(suppl 1):89, 1999.

24. Kudoh S, Negoro S, Masuda T, et al: Phase I/II study of docetaxel and irinotecan for previously untreated advanced NSCLC (abstract 1891). Proc Am Soc Clin Oncol 17:491a, 1998.

25. Takeda K, Yamamoto N, Negoro S, et al: Randomized phase II study of docetaxel plus cisplatin versus docetaxel plus irinotecan in advanced non-small cell lung cancer: A West Japan Thoracic Oncology Group (abstract 1944). Proc Am Soc Clin Oncol 19:497a, 2000.

26. Rocha-Lima C, Leong S, Sherman C, et al: Phase I study of irinotecan and gemcitabine in patients with solid tumors. Cancer Therapeut 2:56-66, 1999.

27. Kanzawa F, Saijo N: In vitro interaction between gemcitabine and other anticancer drugs using a novel three-dimensional model. Semin Oncol 24(suppl 7):7-16, 1997.

28. Bahadori HR, Ogretmen B, Rocha Lima CM, et al: Evaluation of irinotecan (CPT-11) and gemcitabine as single agents and in combination in small-cell lung cancer cells (abstract 1837). Proc Am Soc Clin Oncol 17:477a, 1998.

 
Loading comments...

By clicking Accept, you agree to become a member of the UBM Medica Community.