Trial Information

Treatment of Stages IIIB and IV, Non Small Cell Lung Cancer With Alternating Cycles of Carboplatin/Taxol and Carboplatin/Gemcitabine.

Lung cancer is the leading cause of cancer death in men and women in the USA, and account
for 28% of all cancer deaths in 2002 (1). In stage IV and some patients with stage III
disease chemotherapy is widely used with the primary aim of prolonging survival and /or
palliating symptoms. A meta analysis of clinical studies that randomized patients between
the best supportive care and chemotherapy concluded that Cisplatin based chemotherapy
resulted in a potential gain in the median survival and an increase of the 1-year survival
rate compared to the supportive care alone (2). Combination chemotherapy regimens
(Platinum/Taxanes, Platinum/Gemcitabine, Platinum/Vinca alkaloids) have demonstrated a
response rate of 30-50% with median survival of approximately 10 months, one year survival
rates around 40%, and 2 year survival of only 10 % in patients with advanced Non Small Cell
Lung Cancer (NSCLC) (3,4). Therefore it is important to continue to search for new
agents/combinations that can be used to improve the overall prognosis of these patients.

Rationale for using alternating cycles of chemotherapies:

Emergence of progressive or recurrent disease is a consequence of selection and overgrowth
of pre-existent, drug resistant cells during treatment. Based on the mechanism of somatic
cell mutation, Goldie and Coldman (5,6) proposed a model for the emergence of drug
resistant cells in tumors. Their model proposed that alternating non-cross-resistant
combinations would prevent the overgrowth of resistant cancer cells and improve the
probability of tumor control or cure. Their recommendation assumed that the two
non-cross-resistant regimens were of equal or similar efficacy and that the drugs contained
in the two combinations could not be administered together in one single regimen.

There are few instances in Clinical Oncology where two regimens of similar efficacy exist
for the same tumor type. Since apparently equivalent chemotherapy regimens exist for the
treatment of NSCLC, the Goldie and Coldman hypothesis could also be tested in this tumor
type. Historically, SWOG conducted a phase III trial randomizing patients between FOMi
(5-Fluorouracil/Vincristine/MitomycinC), CAP (Cyclophosphamide/Doxorubicin/Cisplatin) and a
third arm FOMi/CAP, which alternated the two combinations. Response rates were 26%, 17% and
22%, respectively, and were not statistically significantly different (P=0 .247). Survival
was reported as 20, 24 and 23 weeks, respectively. Statistically survival of FOMi/CAP
treated patients was superior to FOMi treated (P=0.024) but not CAP treated (P=0.23)
patients (7). Since then, several studies have attempted to improve upon the response rate
and survival in advanced NSCLC by using regimens with alternating cycles of
non-cross-resistant therapy (8,9,10,11). These regimens yielded overall response rate of
21-49%, median survival of 20-48 wks with acceptable toxicity.

Though several studies have been done to evaluate clinical response in lung cancer using
alternating chemotherapies, none of these studies have evaluated clinical response with
alternating Paclitaxel and Gemcitabine based treatment which are two of the most effective
chemotherapy regimens in use currently. In studies of Platinum combinations that included
one of these agents, results were better than those achieved with Platinum alone or combined
with earlier generation agents such as Vindesine or Etoposide (12). Current evidence
suggests that combinations of Paclitaxel or Gemcitabine with Cisplatin or Carboplatin are
among the most active palliative treatments for advanced NSCLC. With combination of
Cisplatin and Gemcitabine a response rate in phase II trials ranged from 30-54%, with median
survival times of approximately 8-15 months and I year survival rates from 34-61% (13,14).
Myelosuppression was the major toxicity, while Cisplatin associated nonhematologic
gastrointestinal, renal and neurologic effects were also problematic. Attempts to reduce
toxicity associated with the Cisplatin/ Gemcitabine regimen have included replacing
Cisplatin with Carboplatin, a platinum analog possessing similar efficacy and hematologic
effects, but lacking the non hematologic toxicity commonly experienced with Cisplatin
therapy (15,16). Furthermore Carboplatin can be administered with no need for prehydration
to avoid renal toxicity.

In several phase II studies of the Carboplatin/Gemcitabine regimen in patients with stages
IIIB and IV NSCLC, objective response rate ranged from 25%-59%, with median survival of
10-16 months (17,18). In a phase II trial, Carrato et al (19) compared 21 day and 28-day
schedules of the Gemcitabine/Carboplatin regimen in 75 advanced NSCLC patients. Patients
received Gemcitabine 1000mg/m2 on days 1,8 and 15 with Carboplatin AUC 5 on day 1 every 28
days, or a modified regimen omitting the day 15 Gemcitabine dose and repeating cycles every
21 days. Incidence of grades 3 and 4 neutropenia were 52% and 38%, respectively with the 28
day regimen, and decreased to 39% and 23% with the modified regimen. Significant reductions
in rates of grades 3 and 4 thrombocytopenia were noted from 45% and 61%, respectively, in
the 28 day cohort to 24% (P=0.04) and 17% (P=0.002) respectively, in the 21 day group.
Response rate (46% and 37%, respectively) and median survival time (38 wks for both
schedules) were maintained in both groups of patients. Furthermore, higher dose intensities
of both Gemcitabine and Carboplatin were achieved every 3 wk vs every 4 wk schedules
(Gemcitabine 1,133 v 1,002 mg/wk: Carboplatin 162 v 124 mg/wk) (20). Results from current
phase III trials (21,22) are also consistent in showing good activity and tolerability of
the Carboplatin/Gemcitabine combination in advanced NSCLC, and establish this regimen as an
appealing approach for treating this disease. On the basis of above discussion we have
chosen Carboplatin/Gemcitabine as one of the doublets we will use in our study. The other
doublet we are using in our study is Carboplatin/Paclitaxel. Several studies have shown
response rate of approximately 30% with median survival 8-11 months (23,24,25). Toxicity was
mild. Grades 3,4 neutropenia, thrombocytopenia and anemia were seen in 15%, 2% and 5%
respectively (25). Dose finding studies (26,27) of Paclitaxel and Carboplatin in advanced
NSCLC have shown that doses of Paclitaxel higher than 175 mg/m2 prolongs the median time to
progression but causes more neurotoxicity and leucopenia. Also, better response rate, the
longer overall and better one-year survival seen with the higher dose of Paclitaxel were not
statistically significant.

Rationale for using Gemcitabine and Paclitaxel (alternatively in the same regimen) for NSCLC
is provided by their antitumor activity, different mechanism of cytotoxicity and different
toxicity profiles. In an in-vitro study (28) Jensen PB et al has shown collateral
sensitivity between Paclitaxel and Gemcitabine in seven resistant small cell lung cancer
cell lines.

The importance of evaluating the impact of any therapy on the quality of life (QOL) of
patients with malignancy has been demonstrated in recent literature (29). Patients with
advanced NSCLC suffer from a variety of treatment related challenges and do not have an
expectation of cure. Hence, it is particularly important to compare treatment alternatives
not only on survival endpoints but also on QOL. Therefore, we propose to incorporate QOL
evaluations in the proposed clinical trial. QOL instrument we are using is the FACT-L
(version 4). The FACT-L is a validated 36-item Likert instrument that combines both relative
frequency of symptomatic/quality of life problems with the patients perceived relative
importance of each issue (30).

Can we use Taxotere as second line agent if patient had received Paclitaxel as first line
agent?

In comparison with best supportive care, Docetaxel (Taxotere) has shown a benefit in overall
survival for the second line treatment of NSCLC (31,32). Patients with prior exposure to
paclitaxel were excluded from TAX 317 trial (29). But in TAX 320 trial (30) many patients
had received Paclitaxel prior to enrollment (31% of patients in Docetaxel 100 mg arm, 42% of
patients in the Docetaxel 75 mg arm and 41% of patients in the control arm. Authors were
able to evaluate retrospectively, what impact, if any, prior Paclitaxel exposure may have
had on response and survival with Docetaxel. Partial response rates were equivalent in the
cohort of 91 patients who had received prior Paclitaxel (10.5%) and the group of 157
patients who had not received prior Paclitaxel (8.5%). In a similar analysis of survival
data, prior Paclitaxel therapy had no bearing on the survival advantage seen with Docetaxel.