Madison, WisThe largest randomized clinical trial ever
conducted in advanced nonsmall-cell lung cancer (NSCLC) has
shown that combination chemotherapy regimens extend survival in
The four different treatment regimens were equivalent in terms of
most of the outcomes studied, with no one combination emerging as
clearly superior to the reference regimen of paclitaxel
Results of the Eastern Cooperative Oncology Group (ECOG) trial 1594
were presented at the ASCO meeting by principal investigator Joan H.
Schiller, MD, professor of medicine, University of Wisconsin, Madison.
The study involved 1,163 patients and compared three different
treatment combinations with the standard paclitaxel/cisplatin
No Significant Differences
The analysis found no statistically significant differences between
four commonly used chemotherapy regimens, in terms of overall
response rate (18.7%), overall 1-year survival (33.5%), and overall
2-year survival (12%). The gemcitabine (Gemzar)/cisplatin arm,
however, offered a statistically significant 1-month advantage in
time to progression (4.5 months vs 3.5 months; P = .02) but
was more toxic than the other arms, Dr. Schiller reported.
The activity of all four regimens indicates that a number of
effective chemotherapy options are available to oncologists, and
their selection should be based on factors other than their activity
in NSCLC, Dr. Schiller said. The general message of ECOG 1594, she
said, was that chemotherapys benefit was confirmed.
Improved Survival Rate
Survival for advanced lung cancer patients has improved with
the use of chemotherapy as a treatment, Dr. Schiller said.
Patients now have a 35% to 40% chance of 1-year survival, up
from a 20% to 25% 1-year survival 5 years ago.
ECOG 1594 compared three platinum-based regimens containing
third-generation drugs active against NSCLC to a reference regimen of
24-hour paclitaxel/cisplatin in stage IIIB and IV patients. The
experimental arms were gemcitabine/cisplatin, docetaxel
(Taxotere)/cisplatin, and carboplatin (Paraplatin)/paclitaxel.
Patients received cisplatin 75 mg/m² on day 1 plus paclitaxel
175 mg/m²/24 hours; gemcitabine 1,000 mg/m² on days 1, 8,
and 15 plus cisplatin 100 mg/m² on day 1; docetaxel 75 mg/m²
on day 1 plus cisplatin 75 mg/m² on day 1; or paclitaxel 225 mg/m²/3
hours on day 1 plus carboplatin AUC 6 on day 1.
The trial was based on results of an earlier ECOG trial (Bonomi et
al: J Clin Oncol 18:623-631, 2000) that compared two dose
levels of paclitaxel and cisplatin to cisplatin and etoposide. The
lower-dose paclitaxel/cisplatin arm produced a higher response rate,
better survival, and fewer side effects than the other two arms, and
thus became the reference for this trial.
Reducing Side Effects
But todays standard in combination chemotherapy for NSCLC is
actually paclitaxel/carboplatin, according to Joseph Treat, MD,
medical director, Fox ChaseTemple University Cancer Center. He
said this regimen was compared to paclitaxel/cisplatin to put to rest
the suspicion that carboplatin may not be equivalent to cisplatin.
The studys primary objective was to determine which of
four different types of chemotherapy treatment is best for patients
with advanced lung cancer, Dr. Schiller noted. While all
of the chemotherapy regimens used today are effective, only the
paclitaxel plus carboplatin regimen has been shown to have
statistically fewer life-threatening side effects.
Indeed, in ECOG 1594, the regimen of paclitaxel/carboplatin had the
lowest rate of grades 3, 4, and 5 toxicities, including less nausea
and vomiting, less need for IV antibiotics, and fewer
If I had more advanced disease and was looking for a slightly
more gentle regimen, I would go with paclitaxel/carboplatin,
commented the discussant of the session, Frances Shepherd, MD,
professor of medicine, University of Toronto.
The docetaxel/cisplatin arm was associated with the most
hypersensitivity reactions. The gemcitabine/cisplatin arm was the
most toxic in general, including renal toxicity, but this regimen
included higher doses of cisplatin and was dosed more frequently than
the other arms. Other than the variations in toxicity, the results
were quite uniform across all treatment groups (see Table).
Time to Progression
The only statistically significant difference was the improved time
to progression with gemcitabine/cisplatin. Within the whole study
population, there was also a statistically significant difference in
survival by performance status (PS), with PS 0 patients achieving a
median survival of 10.7 months, compared to 4 months for PS 2 patients.
In discussing the study, Dr. Shepherd pointed out that many of the
outcomes (see Table, above) were lower than results seen in similar
trials of these combination regimens. The difference might be
attributed to the inclusion of patients with poor PS and to the
smaller proportion of stage IIIB patients in this study, compared
with several European trials achieving higher response rates.
She also suggested that the lack of benefit from one arm vs the
others in this study may have occurred because many patients crossed
over to second-line therapy, and therefore essentially received the
same treatment. This, unfortunately, will remain an unanswered
question, she said.
Dr. Shepherd concluded, This race has a photo finish . . .
Based on the results of this trial, do we have a new gold standard
for the treatment of NSCLC? No, but I think we have several
optionspaclitaxel/carboplatin, gemcita-bine/cisplatin, and,
based on last years SWOG trial, vinorelbine (Navelbine)/cisplatin.
A future Southwest Oncology Group trial will evaluate the standard
paclitaxel/carboplatin regimen vs a novel triplet of
paclitaxel/carboplatin/tirapazamine (Tirazone), which was developed
by Dr. Treat.
Tirapazamine has little activity as a single agent but works
synergistically with cisplatin, he explained. Also, a multicenter
coalition phase III trial chaired by Dr. Treat is evaluating
paclitaxel/gemcitabine, paclitaxel/carboplatin, and gemcitabine/carboplatin
in patients with metastatic stage IIIB or IV NSCLC.