Treatment options for patients with advanced nonsmall-cell lung
cancer (NSCLC) have greatly improved during the last decade. A number
of new agents have shown activity both when administered alone or in
combination, most commonly with cisplatin (Platinol) or carbo-platin
(Paraplatin). These agents include paclitaxel (Taxol), docetaxel
(Taxotere), gemcitabine (Gemzar), irinotecan (CPT-11 [Camptosar]),
topotecan (Hycamtin), and vinorelbine (Navelbine).[1-6]
A large meta-analysis showed that compared with supportive care
alone, cisplatin-based chemotherapy increased median survival by more
than 6 weeks.  The newer agents alone or in combination have
yielded median survivals of 8 to 10 months in large multicenter,
phase II and III trials. These results represent an increase in
absolute improvement in median survival of approximately 2 to 3
months, and in 1-year survival of about 25% to about 40%.
The combination of paclitaxel and carboplatin has proven to be well
tolerated and active in the treatment of advanced NSCLC.[8,9] Studies
have shown reproducible median survivals of > 8 months and 1-year
survival rates of about 40%. Paclitaxel plus carbo-platin has become
the community standard throughout much of the United States.
Gemcitabine, alone and in combination with cisplatin, has shown
promising response rates, with a median survival of approximately 9
months. [10,11] Gemcitabine is very well tolerated by most patients,
and as a single agent, it appears to be as useful as the older
Designing a three-drug regimen for treating NSCLC includes combining
agents that are potentially synergistic, with non-overlapping
toxicity profiles, and with unique mechanisms of action. The
incorporation of a third agent may lead to even greater improvement
in median survival. Gemcitabine is an attractive agent to consider
because of its demonstrated single-agent activity, favorable toxicity
profile, and unique mechanism of action.
We conducted a phase I trial to confirm the feasibility of combining
gemcitabine, paclitaxel, and carboplatin in a single regimen. A
total of 15 patients were treated at two dose levels (7 patients with
paclitaxel 200 mg/m², day 1; carboplatin, area under the curve
(AUC) 6.0, day 1; gemcitabine 800 g/m², days 1 and 8; 8 patients
with paclitaxel 200 g/m², day 1; carboplatin, AUC 5.0;
gemcitabine 1,000 mg/m², days 1 and 8). In this trial,
leukopenia was the most common toxicity, with a moderate degree of
thrombocytopenia. The myelosuppression reversed rapidly and did not
delay the administration of subsequent cycles.
Furthermore, the lack of severe nonhematologic toxicity with
gemcitabine (including the lack of neuropathy and arthralgia/myalgia)
resulted in no difference in the nonhematologic toxicity profile of
the triple regimen in comparison to the paclitaxel/carboplatin
Phase II dose levels of gemcitabine 1,000 mg/m² on days 1 and 8;
paclitaxel 200 mg/m² on day 1; and carboplatin at an AUC of 5.0
on day 1, were selected for further study.
Patients and Methods
Between December 1996 and September 1997, 69 patients were enrolled
in the phase II portion of this triplet combination study. Entry
criteria were the same as for the phase I portion. Therefore, a total
of 77 patients were entered and treated at the recommended dose
levels (including the 8 patients from the phase I trial). Patients
had previously untreated, pathologically confirmed stage IIIB or IV
Previous radiation therapy was permitted as long as the evaluable
disease was outside the radiation therapy field. Other requirements
were as follows: measurable disease; an Eastern Cooperative Oncology
Group (ECOG) performance status of 0 to 2; age > 18 years; life
expectancy of ³ 12 weeks; a white
blood cell (WBC) count > 3,000/µL; a platelet count > 100,000/µL;
and normal creatinine and bilirubin levels.
Exclusion criteria were brain metastases, active cardiac disease, or
other serious, ongoing medical problems. Informed consent was
obtained from all patients.
Dosage and Administration
Chemotherapy was administered on day 1 of each 21-day cycle as
follows: paclitaxel 200 mg/m² was given first, followed by
gemcitabine 1,000 mg/m², and then carboplatin (AUC = 5.0).
This administration sequence was chosen because other phase I
studies[13,14] of gemcitabine and members of the taxane family have
reported an acceptable toxicity profile and antitumor efficacy when
the taxane was administered before gemcitabine. Additionally, with
short paclitaxel infusions, there has been no obvious
sequence-related toxicity with carboplatin.
Premedications included oral dexamethasone 20 mg administered 12 and
4 hours prior to paclitaxel dosing; dexamethasone 20 mg; cimetidine
(Tagamet) 300 mg; diphenhydramine 50 mg (30 minutes prior to
paclitaxel); and a serotonin antagonist antiemetic.
The gemcitabine dose was repeated on day 8, based on a day-8 blood
count. Carboplatin dosing was calculated using the Calvert formula:
carboplatin = target AUC × glomerular filtration rate (GFR) +
25. The GFR was calculated using the Cockcroft-Gault formula.
Cytokines were not routinely administered as part of this therapy.
Blood counts were measured weekly during therapy and were used to
modify dosages on the day of therapy. On day 1 of each cycle, full
doses were administered if the WBC count was > 3,000/µL, and
if the platelet count was > 100,000/µL.
When the WBC count was between 2,000/µL and 3,000/µL, or
the platelet count was between 75,000/µL and 100,000/µL,
75% of all three drugs were administered. If the WBC count was <
2,000/µL or a platelet count was < 75,000/µL, the course
was delayed 1 week, and the full dose was administered if the counts
For day 8 of gemcitabine dosing, full doses were administered if the
WBC was > 3,000/µL and the platelet count was >
If the WBC was > 2,000/µL to 3,000/µL, and the platelet
count was between 75,000/µL and 100,000/µL, 75% of the
planned dose was administered. Day-8 doses were omitted if the WBC
was < 2,000/µL or if the platelet count was < 75,000/µL.
Patients requiring hospitalization for the treatment of fever and
neutropenia had subsequent doses reduced to 75% of all three drugs
for the remainder of treatment. For patients developing grade 3 and 4
nonhematologic toxicity, doses were held until the toxicity had
recovered to grade 1 or less, and then 75% of planned doses were
administered with future cycles.
Patients were evaluated for response after two treatment courses.
Those patients with stable disease or response continued treatment,
with responses reassessed after each additional two cycles. A minimum
of four and a maximum of ten courses of treatment were given to
responding or stable patients.
Responses were defined by standard criteria. Complete response
required the absence of all clinical evidence of tumor for a minimum
of 4 weeks. Partial response required a > 50% decrease in tumor
size (a perpendicular sum of the products of measurable lesions) for
at least 4 weeks, with no new lesions developing and evaluable
lesions remaining stable or improved.
Progressive disease was defined as those patients showing an increase
of at least 25% of the product of the measured lesions or the
appearance of any new lesions. Patients not meeting partial response
definitions and not having developed progressive disease were
considered to have stable disease.
Patients for the phase II study were enrolled at 13 sites in the
Minnie Pearl Cancer Research Network. All 77 patients treated at the
phase II doses of gemcitabine, paclitaxel, and carboplatin are
included in the survival analysis (8 patients from the phase I
portion and 69 patients subsequently accrued).
Patient characteristics are shown in Table
1. Of the 77 enrolled patients, 56 (73%) had stage IV disease,
and 23 (30%) patients were treated at the Sarah Cannon Cancer Center,
Nashville, Tennessee. A total of 67 (87%) patients received at least
two courses of therapy and were fully evaluable for assessment of
response. An additional 4 patients who were included in the response
analysis experienced rapid progressive disease prior to completing
two treatment cycles and were categorized as nonresponders.
A total of 6 other patients received fewer than two courses of
therapy for the following reasons: 2 patients reported a severe
hypersensitivity reaction to paclitaxel; 2 patients requested
withdrawal from the study because of therapy intolerance; 1 patient
suffered sepsis (treatment-related death); and 1 patient died from a
cerebral vascular accident (nontreatment related). All 77 patients
were both evaluable for treatment-related toxicities and included in
the survival analysis.
A total of 291 courses were administered (median, four courses). Full
doses were administered in 77% of the courses on day 1, compared with
50% of the full doses given on day 8. Patients received a mean of 92%
paclitaxel, 85% gemcitabine, and 94% carboplatin during their first
two courses of therapy. More than six cycles were administered to 10 patients.
Table 2 shows
intent-to-treat response rates, tumor response, response duration,
and survival. A response rate of 48% (34 patients) was documented,
including 2 patients with complete responses in the 71 fully
evaluable patients. A total of 25 (35%) patients reported stable
disease or minor regressions of tumor as their best response to
therapy, and 12 patients (17%) progressed.
Median duration of response was 6 months, with a range of 3 to 14
months. Among the 21 patients with stage IIIB disease, 11 (52%)
responded, including two complete responses. Median survival of all
77 patients was 9.9 months. The minimum follow-up was 24 months
(range, 24 to 36 months). At 1 year, the actual survival was 47%, and
at 2 years, the survival rate was 21%.
Tables 3 and 4
show the toxicities reported in this phase II trial. Myelosuppression
was the most commonly noted toxicity, with 16% of patients
experiencing febrile neutropenia. Although 44% (34 of 77) of patients
experienced grade 3 or 4 thrombocytopenia (platelet count <
50,000/µL), no bleeding complications were noted and only 9
patients received platelet transfusions. Red blood cell transfusions
were administered to 17 (22%) patients.
The addition of gemcitabine to the paclitaxel and carboplatin regimen
did not seem to greatly affect the observed nonhematologic
toxicities. Fatigue and asthenia were the most common toxicities.
Arthralgia/myalgia occurred in approximately one-half (53%) of
patients, while severe peripheral neuropathy (grades 3 or 4) was
noted in only 8% of patients. Mucositis, dermatitis, nausea, and
edema were infrequently reported.
Use of the triple-drug combination of
gemcitabine/paclitaxel/carboplatin for patients with advanced NSCLC
is feasible. The results of this multi-institutional trial are
encouraging. Of the 71 fully evaluable patients, 34 (48%) showed
documented responses. Also impressive is the fact that only 12 (17%)
patients reported progressive disease as their best response to
treatment. The actual 1-year survival rate for this group approaches
50%, and the 2-year survival rate is 21%, which is the next threshold
to surpass in designing effective NSCLC regimens.
Myelosuppression observed in this trial was brief and quickly
reversible. The vast majority of patients received their subsequent
cycles of therapy on time. The overall toxicity of this triplet
combination was only modestly increased compared to that experienced
with paclitaxel plus carboplatin.
Results of the triplet combination with gemcitabine as reported
herein compare favorably with recent results from paclitaxel and
carboplatin phase II trials, including those from our own center.
Prospective, randomized comparisons are now warranted. In addition,
this triplet combination may be particularly useful in neoadjuvant
and adjuvant settings for patients with earlier stage disease.
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