Paclitaxel/Carboplatin in the Treatment of Non-Small-Cell Lung Cancer

ABSTRACT: Chemotherapeutic intervention in advanced and metastatic non-small-cell lung cancer (NSCLC) has changed over the past 2 decades. The improvements offered by cisplatin (Platinol)-based regimens, though significant in terms of survival and quality of life, were modest at best. Carboplatin (Paraplatin), which possesses a toxicity profile favorable to that of its parent analogue cisplatin, yielded survival rates superior to that of the cisplatin-combination chemotherapy arms in a large randomized study of patients with metastatic non-small-cell lung cancer. With the introduction of taxanes in the early 1990s, paclitaxel (Taxol) demonstrated single-agent activity of 21% to 24%, with a 40% 1-year survival rate in metastatic disease. The next generation of phase I/II studies evaluated the efficacy of paclitaxel in combination with carboplatin. Results with this regimen have shown substantial promise, and 1-year survival rates as high as 54% have been reported. Full doses of both agents have been combined without any additional toxicity, and there appears to be a dose-response effect with paclitaxel. The combination of paclitaxel and carboplatin has been incorporated as the investigational arm of all the ongoing multicenter and cooperative group studies. While the results from these randomized studies are awaited, this combination has become the most widely used regimen in community practice for patients with non-small-cell lung cancer. It is also being evaluated for treatment at earlier disease stages, in the setting of minimal tumor burden, and in combined-modality regimens.[ONCOLOGY 12(Suppl 2):74-79, 1998]

While it has long been accepted that chemotherapeutic intervention provided some benefit for patients with non-small-cell lung cancer (NSCLC) in terms of quality of life and symptomatology as well as modest improvements in survival,[1-3] the overall outlook for patients with this disease remained bleak. Despite development and evaluation of a number of agents found to produce at least a 15% response among patients with non-small-cell lung cancer (Table 1[4-13]), in the 1970s and 1980s the 1-year survival rate did not exceed 10% to 12%. Subsequently, cisplatin (Platinol)-containing combination regimens, such as Platinol/etoposide (VePesid) (PE), Platinol/vinblastine (Velban) (PV), or mitomycin-C (Mutamycin)/vinblastine/Platinol (MVP) resulted in increased activity in some phase II studies, but 1-year survival increased to only 15%.[14-20] Although development of new agents remained a primary goal of research, cisplatin-based regimens were considered standard for over 2 decades.

Carboplatin (Paraplatin), the less-toxic analogue of cisplatin, had previously shown marginal activity in non-small-cell lung cancer,[21,22] but gave a surprisingly strong single-agent showing when compared with three cisplatin-based combination regimens, producing a superior 1-year survival rate of 28% with considerably less toxicity than was seen with the cisplatin-based combination regimens.[21]

It has been shown[23] that conventional dosing of carboplatin according to body surface area leads to unpredictable myelosuppression. When carboplatin dose is determined by Calvert’s formula[24] using a targeted area under the concentration-time curve (AUC) and calculated glomerular filtration rate, myelosuppression is manageable and the therapeutic index appears to be improved.

Still greater improvements in survival rates were seen with the introduction of the taxanes in the 1990s. Although paclitaxel (Taxol), the first prototype of the taxanes, was found to be active in non-small-cell lung cancer, with response rates of 21% to 24%, the most significant result of paclitaxel therapy was the markedly increased 1-year survival rates, which reached 40%[25-29] (Table 2). Thus, in the early 1990s, paclitaxel became the most active agent evaluated by the Eastern Cooperative Oncology Group (ECOG).[26]

Initial Trials of Paclitaxel Plus Platinum for NSCLC

Encouraging data from early studies of paclitaxel prompted the initiation of a variety of studies designed to evaluate the agent in combination with other drugs active against non-small-cell lung cancer. Of all studies conducted, those incorporating one of the platinum agents—cisplatin or carboplatin—elicited the greatest interest.

Cisplatin/Paclitaxel

Cisplatin-based trials revealed a sequence-dependent drug interaction, with an increase in myelotoxicity seen when paclitaxel was given after cis-platin.[30,31] Putting aside the toxicity profile, which includes cumulative, dose-limiting peripheral neuropathy, three phase II studies showed response rates ranging between 35% and 47% with this combination.[32-34]

This impressive response inspired a three-arm comparative trial to evaluate the dose-response effect of either low- or high-dose paclitaxel plus cisplatin vs a standard combination of etoposide (VePesid) plus cisplatin.[35] As shown in Table 3, the response rates seen with both low- and high-dose paclitaxel-based combinations (26.5% and 32.1%, respectively) were significantly better than those seen with the standard treatment (12.0%), as were 1-year survival rates (36.9%, 39.1%, and 31.6% for the three groups, respectively). These results led to the replacement of paclitaxel/cisplatin for etoposide/cisplatin as the new reference therapy for future ECOG studies involving patients with non-small-cell lung cancer.

Carboplatin/Paclitaxel

Given the activity seen with carboplatin and paclitaxel as single agents, and encouraging data from studies of cisplatin in combination with paclitaxel, combining paclitaxel with carboplatin was a logical next step. The carboplatin/paclitaxel combination proved to be exceptionally active in non-small-cell lung cancer and generated a great deal of interest. Initial studies of the combination used 24-hour infusions of paclitaxel and established that myelosuppression was the dose-limiting toxic reaction.[23,36,37] Other studies used a shorter infusion schedule of 1 or 3 hours and reported a significant decrease in myelosuppression, with neuropathy being dose-limiting.[38-42,45] The various infusion schedules, however, did not appear to have any important influence on the level of activity of paclitaxel/carboplatin in patients with non-small-cell lung cancer (Table 4).

The studies of paclitaxel/carboplatin yielded two important observations. First, the combination was not associated with platelet toxicity, suggesting that paclitaxel may exert a myeloprotective effect that counters the thrombocytopenia generally associated with carboplatin.[46] Although the precise mechanism involved in this platelet-protective effect is not yet clear, there may be some alteration of megakaryocytopoiesis or thrombocytopoiesis, resulting in increased levels of endogenous thrombopoietin or other cytokines. Ongoing studies are measuring the effect on thrombopoietin with this combination. It is possible that the inhibition of proplatelet formation associated with carboplatin may be suppressed with prior exposure to paclitaxel when measured in terms of pharmacodynamic effect on platelets, and a greater exposure to carboplatin can be achieved when it is given in combination with paclitaxel than when it is given as a single agent.[46]

The second noteworthy outcome from the paclitaxel/carboplatin studies was that most responses occurred in patients treated at paclitaxel doses greater than 175 mg/m². This observation suggests the presence of a dose-response effect.[37,40]

To date, the best results have come from the Fox Chase Cancer Center study,[36] which reported an impressive 62% response rate and 54% 1-year survival rate from a regimen involving intrapatient escalation of the paclitaxel dose between 135 and 215 mg/m² and carboplatin dosed to achieve an AUC of 7.5 mg/mL · min. Based on the reported phase I and II study results, recommended doses for the combination of paclitaxel/carboplatin call for paclitaxel to be given as a 24-hour infusion at 175 mg/m² or, in shorter infusions of 1 or 3 hours, at 200 to 225 mg/m², with carboplatin doses generally targeted to attain an AUC of 6 or 7.

The first large, randomized study of paclitaxel/carboplatin for advanced or metastatic non-small-cell lung cancer compared this combination with the standard cisplatin/etoposide regimen (Table 5). The study accrued 369 patients over 15 months. The median survival is 8.25 months, and the 1-year survival is 35%. The number of events required to perform a survival analysis by arm has not occurred.

Paclitaxel/Carboplatin in NSCLC: Future Directions

The paclitaxel/carboplatin combination has elicited a great deal of interest among oncologists. The encouraging improvements in 1-year survival from 10% to approximately 50% seen with paclitaxel/carboplatin have prompted evaluations of this combination in large, randomized studies of patients with advanced and metastatic non-small-cell lung cancer (Table 6) in combined-modality programs for unresectable and potentially resectable disease, in earlier stages of disease, and in patients with minimal tumor burden . In hopes of achieving further improvements and developing an optimal means of managing non-small-cell lung cancer, however, development of new agents and treatment approaches remain important goals of research. The development of three-drug combination regimens, for example, is currently under way and includes studies in which agents active in non-small-cell lung cancer, eg, gemcitabine (Gemzar), vinorelbine (Navelbine), or irinotecan (Camptosar), are being combined into the paclitaxel/carboplatin combination.

Paclitaxel/carboplatin is also being investigated in a number of combined-modality programs, including an induction regimen for patients with early stage disease and a trial of paclitaxel/carboplatin with either sequential or concurrent radiation. A large, multicenter randomized study (locally advanced multimodality protocol, or LAMP) will evaluate the efficacy of paclitaxel and carboplatin given either sequentially or concurrently with radiation therapy for patients with potentially unresectable disease (Figure 1). Other evaluation approaches include use of the paclitaxel/carboplatin combination as adjuvant therapy for resected non-small-cell lung cancer and in dose-dense weekly schedules for patients with metastatic disease.

Conclusions

The future of non-small-cell lung cancer management will incorporate strategies that combine these active chemotherapeutic regimens with selective approaches like gene therapy (adenovirus p53 gene), antiangiogenic agents, and monoclonal antibodies. With the use and efficacy of these regimens in earlier stages of non-small-cell lung cancer, most patients diagnosed with non-small-cell lung cancer will be offered chemotherapy as a part of the overall management.

References:

1. Grilli R, Oxman AD, Julian JA: Chemotherapy for advanced non-small-cell lung cancer: How much benefit is enough? J Clin Oncol 11:1866-1872, 1993.

2. Souquet PJ, Chauvin F, Boissel JP, et al: Polychemotherapy in advanced non-small-cell lung cancer: A meta-analysis Lancet 342:19-21, 1993.

3. Ellis PA, Smith IE, Hardy JR, et al: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 71:366-370, 1995.

4. Vogl SE, Bernzweig M, Camacho F, et al: Efficacy study of intensive cisplatin therapy in advanced non-small-cell bronchogenic carcinoma. Cancer 50:24-26, 1982.

5. Britell JC, Eagan RT, Ingle JN, et al: cis-Dichlorodiammineplatinum (II) alone followed by Adriamycin plus cyclophosphamide at progression versus cis-dichlorodiammineplatinum (II), Adriamycin, and cyclophosphamide in combination for adenocarcinoma of the lung. Cancer Treat Rep 62:1207-1210, 1978.

6. Casper ES, Gralla RJ, Kelsen DP, et al: Phase II study of high-dose cis-dichlorodiammineplatinum (II) in the treatment of non-small-cell lung cancer. Cancer Treat Rep 63:2107-2109, 1979.

7. Samson MK, Comis RL, Baker LH, et al: Mitomycin C in advanced adenocarcinoma and large cell carcinoma of the lung. Cancer Treat Rep 62:163-165, 1978.

8. Costanzi JJ, Morgan LR, Hokanson J: Ifosfamide in the treatment of extensive non-oat cell carcinoma of the lung (suppl 1). Semin Oncol 9:61-65, 1982.

9. Morgan LR, Posey LE, Rainey J, et al: Ifosfamide: A weekly dose fractionated schedule in bronchogenic carcinoma. Cancer Treat Rep 65:693-695, 1981.

10. Harrison EF, Hawke JE, Hunter HL, et al: Single-dose ifosfamide: Efficacy studies in non-small-cell lung cancer (suppl 1). Semin Oncol 9:56-60, 1982.

11. Furnas BE, Williams SD, Einhorn LH, et al: Vindesine: An effective agent in the treatment of non-small-cell lung cancer. Cancer Treat Rep 66:1709-1711, 1982.

12. Luedke SL, Luedke DW, Petruska P, et al: Vindesine (VDS) monochemotherapy for non-small-cell lung cancer: A report of 45 cases. Cancer Treat Rep 66:1409-1411, 1982.

13. Schulman P, Budman DR, Vinciguerra V, et al: Phase II study of divided-dose vinblastine in non-small-cell bronchogenic carcinoma. Cancer Treat Rep 66:171-172, 1982.

14. Ruckdeschel JC, Finkelstein DM, Ettinger DS, et al: A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol 4:14-22, 1986.

15. Bitran JD, Desser RK, DeMeester TR, et al: Cyclophosphamide, adriamycin, methotrexate, and procarbazine (CAMP)—Effective four-drug combination chemotherapy for metastatic non-oat cell bronchogenic carcinoma. Cancer Treat Rep 60:1225-1230, 1976.

16. Ruckdeschel JC, Finkelstein DM, Mason BA, et al: Chemotherapy for metastatic non-small-cell bronchogenic carcinoma: EST 2575, GENERATION V—A randomized comparison of four cisplatin-containing regimens. J Clin Oncol 3:72-79, 1985.

17. Eagan RT, Ingle JN, Frytak S, et al: Platinum-based polychemotherapy versus dianhydrogalactitol in advanced non-small-cell lung cancer. Cancer Treat Rep 61:1339-1345, 1977.

18. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer—Report of a Canadian multicenter randomized trial. J Clin Oncol 6:633-641, 1988.

19. Weick JK, Crowley S, Natale RB, et al: A randomized trial of five cisplatin containing treatments in patients with metastatic non-small-cell lung cancer. A South West Oncology Group study. J Clin Oncol 9:1157-1162, 1991.

20. Mason BA, Catalano RB: Mitomycin, vinblastine and cisplatin combination chemotherapy in non-small-cell lung cancer (abstr). Proc Am Soc Clin Oncol 21:A477, 1980.

21. Bonomi PD, Finkelstein DM, Ruckdeschel JC, et al: Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: A study of the Eastern Cooperative Oncology Group. J Clin Oncol 7:1602-1613, 1989.

22. Bunn PA Jr: Review of therapeutic trials of carboplatin in lung cancer(suppl 5). Semin Oncol 16:27-33, 1989.

23. Johnson DH, Paul DM, Hande KR, et al: Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: A phase II trial. J Clin Oncol 14:2054-2060, 1996.

24. Calvert AH, Newell DR, Grumbell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989.

25. Murphy WK, Fossella FV, Winn RJ, et al: Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer. J Nat Cancer Inst 85:384-388, 1993.

26. Chang AY, Kim K, Glick J, et al: Phase II study of taxol, merbarone, and piroxantrone in stage IV non-small-cell lung cancer: The Eastern Cooperative Oncology Group Results. J Natl Cancer Inst 85:388-394, 1993.

27. Gatzemeier U, Heckmayer M, Neuhauss R, et al: Chemotherapy of advanced inoperable non-small-cell lung cancer with paclitaxel: A phase II trial (suppl 5). Semin Oncol 22:24-28, 1995.

28. Millward MJ, Bishop JF, Friedlander M, et al: Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol 14:142-148, 1996.

29. Ramanathan RK, Belani CP: Chemotherapy for advanced non-small-cell lung cancer: Past, present, and future. Semin Oncol 24:440–454, 1997.

30. Rowinsky EK, Citardi MJ, Noe DA, et al: Sequence-dependent cytotoxic effects due to combinations of cisplatin and the antimicrotubule agents Taxol and vincristine. J Cancer Res Clin Oncol 119:727-733, 1993.

31. Rowinsky EK, Gilbert MR, McGuire WP, et al: Sequences of Taxol and cisplatin: A phase I and pharmacologic study. J Clin Oncol 9:1692-1703, 1991.

32. Klastersky J, Sculier JP: Cisplatin plus taxol in non-small-cell lung cancer: A dose finding trial (abstr). Proc Am Assoc Cancer Res 36:A1423, 1995.

33. Pirker R, Krajnik G, Zochbauer S, et al: Paclitaxel/cisplatin in advanced non-small-cell lung cancer (NSCLC). Ann Oncol 6:833-835, 1995.

34. Belli L, Le Chevalier T, Gottfried M, et al: Phase I-II trial of paclitaxel (Taxol) and cisplatin in previously untreated advanced non-small-cell lung cancer (NSCLC) (abstr). Proc Am Soc Clin Oncol 14:A1058, 1995.

35. Bonomi PD, Kim K, Chang A, et al: Phase III trial comparing etoposide (E) cisplatin versus Taxol (T) with cisplatin-G-CSF (G) versus cisplatin in advanced non-small-cell lung cancer: Eastern Cooperative Oncology Group (ECOG) (abstr). Proc Am Soc Clin Oncol 15:A1145, 1996.

36. 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.

37. Belani CP, Aisner J, Hiponia D, et al: Paclitaxel and carboplatin with and without filgrastim support in patients with metastatic non-small-cell lung cancer (suppl 9). Semin Oncol 22:7-12, 1995.

38. Langer C, Kaplan R, Rosvold E, et al: Paclitaxel (P) by 1 hour (hr) infusion combined with carboplatin (C) in advanced non-small-cell lung carcinoma (abstr). Proc Am Soc Clin Oncol 15:A1200, 1996.

39. Vafai D, Israel V, Zaretsky S, et al: Phase I/II trial of combination carboplatin and Taxol in non-small-cell lung cancer (NSCLC) (abstr). Proc Am Soc Clin Oncol 14:A1067, 1995.

40. Bunn PA Jr, Kelly K: A phase I study of carboplatin and paclitaxel in non-small-cell lung cancer: A University of Colorado Cancer Center study (suppl 9). Semin Oncol 22:2-6, 1995.

41. Rowinsky EK, Sartorious SE, Bowling MK, et al: Paclitaxel on a 3-hr schedule and carboplatin in non-small-cell lung cancer: Use of maximally tolerated and clinically relevant single agent doses in combination is feasible (abstr). Proc Am Soc Clin Oncol 14:A1075, 1995.

42. Giaccone G, Huizing M, Postmus PE, et al: Dose-finding and sequencing study of paclitaxel and carboplatin in non-small-cell lung cancer (suppl 9). Semin Oncol 22:78-82, 1995.

43. Schutte W, Bork I, Sucker S: Phase II trial of paclitaxel and carboplatin as firstline treatment in advanced non-small-cell lung cancer (NSCLC) (abstr). Proc Am Soc Clin Oncol 15:A1208, 1996.

44. Roa V, Conner A, Mitchell RB: Carboplatin and paclitaxel for chemotherapy-naive patients with advanced non-small-cell lung cancer (abstr). Proc Am Soc Clin Oncol 15:A1231, 1996.

45. Evans WK, Stewart DJ, Tomiak E, et al: Carboplatin (C) and paclitaxel (P) by one hour infusion for advanced non-small-cell lung cancer (NSCLC) (abstr). Proc Am Soc Clin Oncol 14:A1156, 1996.

46. Kearns CM, Belani CP, Erkmen K, et al: Reduced platelet toxicity with combination carboplatin and paclitaxel; Pharmacodynamic modulation of carboplatin associated thrombocytopenia (abstr). Proc Am Soc Clin Oncol 14:A364, 1995.