Cisplatin (Platinol)-based chemotherapy
has been the foundation of the treatment of lung cancer for over 2 decades.
Several new classes of agents, or analogs of existing drugs, that have
single-agent activity comparable to cisplatin have recently been introduced. Two
classes of new drugs that have significant activity in both small-cell and non-small-cell
lung cancer are the camptothecins and the taxanes.
Taxanes preferentially bind to microtubules, inhibiting dynamic
reorganization of the microtubular network, leading to the arrest of cells in
G2/M phase of the cell cycle. Both paclitaxel (Taxol) and docetaxel
(Taxotere) are drugs active against non-small-cell lung cancer, and each
produces a single-agent response rate of approximately 20%.
The Eastern Cooperative Oncology Group (ECOG) performed a
randomized study comparing cisplatin/etoposide to cisplatin/paclitaxel.
Patients were randomized to three arms: control (cisplatin/etoposide),
paclitaxel 135 (cisplatin and paclitaxel as a 24-hour infusion at 135 mg/m2 per
cycle), and paclitaxel 250 (cisplatin and paclitaxel as a 24-hour infusion at
250 mg/m2 per cycle with granulocyte colony-stimulating factor [G-CSF] support).
Survival was better in both paclitaxel-containing arms than in the control arm,
but the difference reached standard levels of statistical significance only if
results of the two paclitaxel-containing groups were combined (1-year survival
of 39% vs 32%, P = .048).
Patient tolerance and preservation of quality of life were
fairly comparable with the different regimens. Preliminary results of a study
comparing the combination of carboplatin (Paraplatin)/paclitaxel to
cisplatin/etoposide reported comparable survival. Febrile neutropenia
developed less frequently in the patients treated with carboplatin/paclitaxel,
but myalgia and neuropathy were more common.
The Southwest Oncology Group (SWOG) has reported the preliminary
results of a study that compared carboplatin/paclitaxel to cisplatin/vinorelbine
(Navelbine). No difference in survival was noted. However, fewer patients
dropped out of the carboplatin/paclitaxel arm due to toxicity, suggesting that
this regimen was better tolerated. The ECOG has also conducted a large study
(E1594) comparing four of the newer platinum-containing regimens. This study
compared the combinations of cisplatin/paclitaxel to cisplatin/gemcitabine
(Gemzar) to cisplatin/docetaxel to carboplatin/paclitaxel.
A total of 1,163 patients were treated, and survival was
comparable in the four arms. The median survival ranged from 7.4 to 8.2 months,
and 1-year survival ranged from 31% to 36%. Taken together, these studies
suggest that platinum-containing chemotherapy regimens that include one of the
newer drugs, such as a taxane, offer advantages to regimens that contain older
agents (ie, etoposide). Whether or not there are clinically important
differences if a platinum drug is combined with a taxane or with another one of
the newer drugs, such as gemcitabine, has not been established.
For patients who have received prior platinum-containing
chemotherapy, docetaxel is one of the few agents that have demonstrated
activity. Shepherd and colleagues randomized previously treated patients (one or
more regimens) to docetaxel or to best supportive care. Overall, both
survival (time to progression and median survival) and quality of life were
better in the patients who received treatment with docetaxel. A study by
Fossella and coworkers randomized 373 previously treated patients to docetaxel
100 (docetaxel at 100 mg/m2 per cycle), docetaxel 75 (docetaxel at 75
cycle), or a control arm of vinorelbine or ifosfamide (Ifex). Previous
treatment with paclitaxel was permitted, and 37% of the patients had received
this drug as part of their prior therapy.
Based on an intention-to-treat analysis, survival at 1 year in
the docetaxel 75 group (32%) was superior to the other two arms (21% and 19% in
the docetaxel 100 and control group [P = .025 vs control], respectively). In
both docetaxel arms progression-free survival and quality of life were
improved. An analysis attempting to adjust for the effects of poststudy
treatment suggested a survival advantage for both docetaxel arms.
Two phase II studies have examined the role of single-agent
paclitaxel in patients with previously untreated extensive-stage small-cell lung
cancer.[10,11] The ECOG reported a response rate of 34%, but life-threatening
grade 4 leukopenia occurred in 56% of the patients. A second trial,
conducted by the North Central Cancer Treatment Group (NCCTG), administered
paclitaxel on a similar schedule, but with the addition of G-CSF. The
response rate was similar (53%), and the incidence of severe leukopenia was
reduced to 14%.
One study has examined the activity of paclitaxel in patients
refractory to chemotherapy, defined as a relapse within 3 months of the
completion of previous therapy. Nearly half of the patients enrolled in this
study had received prior platinum-containing chemotherapy. In 21 assessable
patients, 7 achieved a partial response, for an objective response rate of 29%.
There were two early deaths and two toxic deaths in the trial, and the median
survival of assessable patients was 100 days. This study suggests that
paclitaxel is a useful, active drug in the management of refractory small-cell
When combined with cisplatin, paclitaxel has shown substantial
activity in small-cell lung cancer. A phase II study by Nair et al in
chemotherapy-naive patients assessed paclitaxel at an initial dose of 135 mg/m2,
later escalated to 175 mg/m2, with cisplatin at 75
mg/m2. Patients that
developed progressive disease were crossed over to cisplatin and etoposide.
Fifteen of 21 (71%) evaluable patients in the lower paclitaxel arm and 39 of 44
(89%) evaluable patients in the higher paclitaxel arm demonstrated a response to
Docetaxel has been evaluated in small-cell lung cancer in a
small number of phase II trials. The National Cancer Institute of Canada
evaluated docetaxel in chemotherapy-naive patients with extensive disease at a
dose of 75 mg/m2 every 3 weeks. Twelve patients were evaluable for response,
of which only one demonstrated a partial response (12-week duration), resulting
in a disappointing response rate of 8%. A subsequent SWOG study utilized a
higher dose of docetaxel at 100 mg/m2 every 3 weeks. In 46 eligible patients
with untreated extensive-stage small-cell lung cancer, a response rate of 26%,
with a median survival of 9 months, was reported. In 34 previously treated
patients, a European Organization for Research and Treatment of Cancer (EORTC)
study reported a response rate of 25%.
In previously untreated patients, irinotecan (Camptosar, CPT-11)
has demonstrated a single-agent response rate of 15% to 32%. Response rates
in previously treated patients have been comparable to other chemotherapy drugs
and ranged from 0% to 14%. The main toxicities were neutropenia and diarrhea.
Pulmonary toxicity, presumably due to a hypersensitivity reaction, occurred in
8% of patients in one phase II study. Similar to the results in studies of
colorectal cancer, both the weekly schedule of administration of irinotecan and
the single dose every 3 weeks appear to yield comparable activity and side
The combination of irinotecan and cisplatin has been reported to
show significant antitumor activity in untreated patients, with response rates
ranging between 31% and 55%.[17,19,20] Dose reductions are common when
irinotecan is given on a weekly schedule and cisplatin is administered once
every 4 weeks. Schedules in which cisplatin is given in divided doses weekly
together with irinotecan may be better tolerated and are equally effective.
Two randomized phase III studies from Japan have compared the
combination of cisplatin and irinotecan to a standard regimen in patients with
previously untreated non-small-cell lung cancer. In the study by Masuda and
colleagues, 398 patients were randomized to cisplatin/irinotecan, irinotecan
alone, or a control arm consisting of cisplatin and vindesine; 378 were
evaluable for response, survival, and toxicity. In a study by Niho and
coworkers, 203 eligible patients were evaluated for responses and toxicity to
cisplatin/irinotecan or cisplatin/vindesine regimens. Although no
differences in survival were detected individually in these studies, an analysis
that combined the data showed that patients treated with cisplatin/irinotecan
had a significantly better survival at 1 year than patients treated with the
1. Rowinsky EK, Donehower RC: Paclitaxel (Taxol). New Engl J Med
2. 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 trial. J Clin Oncol
3. Belani CP, Natale RB, Lee JS, et al: Randomized phase III
trial comparing cisplatin/etoposide versus carboplatin/paclitaxel in advanced
and metastatic non-small cell lung cancer (NSCLC) (abstract 1751). Proc Am Soc
Clin Oncol 17:455a, 1998.
4. Kelly K, Crowley J, Bunn PA, et al: A randomized phase III
trial of paclitaxel plus carboplatin (PC) versus vinorelbine plus cisplatin (VC)
in untreated advanced non-small cell lung cancer (NSCLC): A Southwest Oncology
Group (SWOG) trial (abstract 1777). Proc Am Soc Clin Oncol 18:461a, 1999.
5. Schiller JH, Harrington D, Sandler A, et al: A radomized
phase III trial of four chemotherapy regimens in advanced non-small cell lung
cancer (NSCLC) (abstract 2). Proc Am Soc Clin Oncol 19:1a, 2000.
6. Shepherd FA, Dancey J, Ramlau R, et al: Prospective
randomized trial of docetaxel versus best supportive care in patients with
non-small-cell lung cancer previously treated with platinum-based chemotherapy.
J Clin Oncol 18:2095-2103, 2000.
7. Dancey J, Shepherd F, Ramlau R, et al: Quality of life (QOL)
assessment in a randomized study of taxotere (TAX) versus best supportive care
(BSC) in non-small cell lung cancer (NSCLC) patients (pts) previously treated
with platinum-based chemotherapy (abstract 1896). Proc Am Soc Clin Oncol
8. Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III
trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced
non-small-cell lung cancer previously treated with platinum-containing
chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J
Clin Oncol 18:2354-2362, 2000.
9. Miller VA, Fossella FV, DeVore R, et al: Docetaxel (D)
benefits lung cancer symptoms and quality of life (QoL) in a randomized phase
III study of non-small cell lung cancer (NSCLC) patients previously treated with
platinum-treated therapy (abstract 1895). Proc Am Soc Clin Oncol 18:491a, 1999.
10. Ettinger DS, Finkelstein DM, Sarma RP, et al: Phase II study
of paclitaxel in patients with extensive-disease small-cell lung cancer: An
Eastern Cooperative Oncology Group study. J Clin Oncol 13:1430-1435, 1995.
11. Kirschling RJ, Grill JP, Marks RS, et al: Paclitaxel and
G-CSF in previously untreated patients with extensive stage small-cell lung
cancer: A phase II study of the North Central Cancer Treatment Group. Am J Clin
Oncol 22:517-522, 1999.
12. Smit EF, Fokkema E, Biesma B, et al: A phase II study of
paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J
Cancer 77:347-351, 1998.
13. Nair S, Marschke R, Grill J, et al: A phase II study of
paclitaxel and cisplatin in the treatment of extensive stage small cell lung
cancer (abstract 1629). Proc Am Soc Clin Oncol 16:454a, 1997.
14. Latreille J, Cormier Y, Martins H, et al: Phase II study of
docetaxel (Taxotere) in patients with previously untreated extensive small cell
lung cancer. Invest New Drugs 13:343-345, 1996.
15. Burris HA, Crowley JJ, Williamson SK, et al: Docetaxel
(Taxotere) in extensive stage small cell lung cancer: A phase II trial of the
Southwest Oncology Group (abstract 1737). Proc Am Soc Clin Oncol 17:451a, 1998.
16. Smyth JF, Smith IE, Sessa C, et al: Activity of docetaxel
(Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the
EORTC. Eur J Cancer 8:1058-1060, 1994.
17. Argiris A, Murren JR: Clinical use of the camptothecins at
year 2000. PPO Updates 14:1-15, 2000.
18. 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 [see comments]. J Clin Oncol 10:16-20, 1992.
19. De Vore R 3rd, Johnson D, Crawford J, et al: Irinotecan plus
cisplatin in patients with advanced non-small-cell lung cancer. Oncology
20. 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.
CPT-11 Lung Cancer Study Group [see comments]. Br J Cancer 78:251-256, 1998.
21. Kobayashi K, Shinbara A, Kamimura M, et al: Irinotecan
(CPT-11) in combination with weekly administration of cisplatin (CDDP) for
non-small-cell lung cancer. Cancer Chemother Pharmacol 42:53-58, 1998.
22. Masuda N, Fukuoka M, Negoro S, et al: Randomized trial
comparing cisplatin (CDDP) and irinotecan (CPT-11) versus CDDP and vindesine
(VDS) versus 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,
23. Niho S, Nagao K, Nishiwaki Y, et al: Randomized multicenter
phase III trial of irinotecan (CPT-11) and cisplatin (CDDP) versus CDDP and
vindesine (VDS) in patients with advanced non-small cell lung cancer (NSCLC)
(abstract 1897). Proc Am Soc Clin Oncol 18:492a, 1999.
24. Fukuoka M, Nagao K, Ohashi Y, et al: Impact of irinotecan
(CPT-11) and cisplatin (CDDP) on survival in previously untreated metastatic
non-small lung cancer (NSCLC) (abstract 1938). Proc Am Soc Clin Oncol 19:495a,
25. Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A new
derivative of camptothecin for the treatment of refractory or relapsed
small-cell lung cancer. J Clin Oncol 10:1225-1229, 1992.
26. Negoro S, Fukuoka M, Niitani H, et al: A phase II study of
CPT-11, a camptothecin derivative, in patients with primary lung cancer. CPT-11
Cooperative Study Group. Gan To Kagaku Ryoho 18:1013-1019, 1991.
27. Noda K, Nishiwaki Y, Kawahara M, et al: Randomized phase III
study of irinotecan (CPT-11) and cisplatin in extensive-disease small-cell lung
cancer: Japan Clinical Oncology Group Study (JCOG9511) (abstract 1887). Proc Am
Soc Clin Oncol 19:483a, 2000.
28. Bissery MC, Vrignaud P, Lavelle F: In vivo evaluation of the
docetaxel-irinotecan combination (abstract 2578). Proc Am Assoc Cancer Res
29. Chou T-C, Motzer RJ, Tong Y, et al: Computerized
quantitation of synergism and antagonism of taxol, topotecan, and cisplatin
against human teratocarcinoma cell growth: A rational approach to clinical
protocol design. J Natl Cancer Inst 86:1517-1524, 1994.
30. Pei XH, Nakanishi Y, Takayama K, et al: Effect of CPT-11 in
combination with other anticancer agents in lung cancer cells. Anti-Cancer Drugs
31. Madden T, Newman RA, Antoun G, et al: Low-level taxane
exposure increases the activity of topoisomerase I targeted agents (abstract
3583). Proc Am Assoc Cancer Res 39:527, 1998.
32. Murren JR, Peccerillo K, DiStasio SA, et al: Dose escalation
and pharmacokinetic study of irinotecan in combination with paclitaxel in
patients with advanced cancer. Cancer Chemother Pharmacol 46:43-50, 2000.
33. Asai G, Yamamoto N, Sakai S, et al: Paclitaxel (Taxol)
affects pharmacokinetics of irinotecan and its metabolites (abstract 773). Proc
Am Soc Clin Oncol 19:199a, 2000.
34. Rich RS, Argiris A, Peccerillo K, et al: Weekly chemotherapy
with irinotecan plus a taxane in advanced non small cell lung cancer (NSCLC).
Lung Cancer 29(suppl 1):6, 2000.
35. Socinski MA, Kies M, Unger P, et al: Second-line (SL) weekly
paclitaxel (P) in patients (pts) with advanced non-small cell lung cancer
(NSCLC) failing first-line (FL) carboplatin/paclitaxel (C/P) (abstract 15). Lung
Cancer 29(suppl 1):6, 2000.
36. Akerley W, Glantz M, Choy H, et al: Phase I trial of weekly
paclitaxel in advanced lung cancer. J Clin Oncol 16:153-158, 1998
37. Hainsworth JD, Burris HA 3rd, Erland JB, et al: Phase I
trial of docetaxel administered by weekly infusion in patients with advanced
refractory cancer. J Clin Oncol 16:2164-2168, 1998.
38. Rushing DA: Phase I/II study of weekly irinotecan and
paclitaxel in patients with SCLC. Oncology 14(suppl 5):63-66, 2000.
39. Masuda N, Negoro S, Kudoh S, et al: Phase I and
pharmacologic study of docetaxel and irinotecan in advanced non-small-cell lung
cancer. J Clin Oncol 18:2996-3003, 2000.