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Rationale and Dose-Finding Studies of the Combination of Irinotecan and a Taxane on a Weekly Schedule

Rationale and Dose-Finding Studies of the Combination of Irinotecan and a Taxane on a Weekly Schedule

ABSTRACT: Cisplatin (Platinol)-based chemotherapy has been the standard systemic therapy for both non-small-cell and small-cell lung cancer for the past 2 decades, though the efficacy and benefit remain modest. Recently, several novel agents have been introduced that have single-agent activity comparable to cisplatin and offer the possibility of improved therapy for lung cancer. Camptothecin and taxane derivatives are associated with both different mechanisms of action and nonhematologic toxicities, and have demonstrated additive or synergistic activity when used in combination in preclinical studies. We review pertinent clinical studies of these agents in lung cancer and present our experience in combining irinotecan (Camptosar, CPT-11) with taxanes on a weekly schedule in dose-finding and efficacy studies. When chemotherapy is delivered for 4 consecutive weeks followed by a 2-week rest, hematologic toxicity is dose limiting and most prominent during weeks 3 and 4. Dose intensification is feasible if the schedule is modified so the chemotherapy is given on days 1 and 8, with cycles repeated every 3 weeks. The most common nonhematologic toxicities remain asthenia, neuropathy, and diarrhea. Future studies will explore and better define the role of these drug combinations in the treatment of lung cancer. [ONCOLOGY 15(Suppl 1):25-30, 2001] Introduction 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.


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 in Non-Small-Cell
Lung Cancer

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.[1] 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.[2]
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.[3] 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).[4] 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.[5]

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.[6] Overall, both
survival (time to progression and median survival) and quality of life were
better in the patients who received treatment with docetaxel.[7] 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
mg/m2 per
cycle), or a control arm of vinorelbine or ifosfamide (Ifex).[8] 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.[9] An analysis attempting to adjust for the effects of poststudy
treatment suggested a survival advantage for both docetaxel arms.

Taxanes in Small-Cell
Lung Cancer

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.[10] 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.[11] 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.[12] 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
lung cancer.

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.[13] 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.[14] 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.[15] In 34 previously treated
patients, a European Organization for Research and Treatment of Cancer (EORTC)
study reported a response rate of 25%.[16]

Irinotecan in Non-Small-Cell Lung Cancer

In previously untreated patients, irinotecan (Camptosar, CPT-11)
has demonstrated a single-agent response rate of 15% to 32%.[17] 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.[18] 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.[21]

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.[22] In a study by Niho and
coworkers, 203 eligible patients were evaluated for responses and toxicity to
cisplatin/irinotecan or cisplatin/vindesine regimens.[23] 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
controlled regimen.[24]


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