A Phase II Study of Single-Agent Gemcitabine as a Second-Line Treatment in Advanced Non-Small Cell Lung Cancer

http://jjco.oxfordjournals.org/cgi/content/full/36/1/50
Japanese Journal of Clinical Oncology Advance Access originally published
online on January 17, 2006

A Phase II Study of Single-Agent Gemcitabine as a Second-Line Treatment in
Advanced Non-Small Cell Lung Cancer
Keun-Hyok Cho, Young-Bong Song, Ik-Sung Choi, Eun-Hee Cho, Jae-Won Choi,
Young Mi Ahn, Yong Ho Roh, Seung-Hyun Nam and Bong-Seog Kim

Department of Internal Medicine, Seoul Veterans Hospital, Seoul, Korea

For reprints and all correspondence: Bong-Seog Kim, Department of Internal
Medicine, Seoul Veterans Hospital, (134-791) 6-2 Dunchon-Dong,
Kangdong-Gu, Seoul, Korea. E-mail: seog@xxxxxxxxxxxxx

Received April 17, 2005; accepted November 17, 2005

Objective: To evaluate the efficacy and safety of the single-agent
gemcitabine in advanced non-small cell lung cancer (NSCLC) as second-line
chemotherapy.

Methods: Between February 2002 and November 2004, a total of 27 patients,
who had previously been treated with paclitaxel and platinum as first line
chemotherapy, were enrolled in the study. Patients were treated with
gemcitabine (1000 mg/m2) on days 1, 8 and 15 in a 28 day cycle. The
response was assessed every two cycles. Toxicities were evaluated
according to common toxicity criteria (CTC).

Results:
The median age was 62 (range, 46?79) years old.
Among the 27 patients, 26 were male.

Twenty-three patients had an ECOG performance status of 0 or 1 and four
patients had a status of 2.

Pathologically, 24 patients had squamous cell carcinoma and 3 had
adenocarcinoma.

Parrtial responses were observed in 15 patients. All patients were
evaluated for response and toxicity. The overall response rate was 18.5%
(95% confidence interval, 5?33%) and the median response duration was 17
(range, 7.4 to 49+) weeks. The median time to progression was 10 (range, 7
to 34+) weeks. The median overall survival for all patients was 38 (range,
10 to 122+) weeks. During a total of 87 cycles, granulocytopenia greater
than CTC grade 2 occurred in 7%, thrombocytopenia in 1% and anemia in 24%
of case. Non-hematologic toxicities were minor and easily controlled.
Conclusion: This study confirms the activity and safety of the
single-agent gemcitabine as a second-line therapy in pretreated patients
with advanced NSCLC.

Key Words: gemcitabine ? second-line treatment ? non-small cell lung
cancer


INTRODUCTION
TOP
Abstract
INTRODUCTION
PATIENTS AND METHODS
RESULTS
DISCUSSION
CONCLUSION
References

Lung cancer is currently the leading cause of death from malignant disease
in Korea (1). The results of a large meta-analysis of 52 randomized
clinical trials showed conclusively that the administration of
chemotherapy offers a modest but significant survival benefit compared
with the best supportive care (2). Use of chemotherapy for advanced
non-small cell lung cancer (NSCLC) has recently become more customary.
Randomized studies showed that cisplatin-based chemotherapy and new
chemotherapeutic agents result in improved quality of life compared with
the best supportive care (3). Consequently, for advanced NSCLC patients
with a good performance score, a platinum-based regimen is now advised.

Virtually all patients who respond initially will eventually relapse.
Because of improved therapeutic results with newer agents, a growing
number of patients experience a longer disease-free interval compared with
the older regimens. At relapse, the patients are likely to have a good
performance status and be eligible for further treatment. The role of
second-line chemotherapy after initial treatment with a platinum-based
regimen remains largely undefined. Results from a number of recent studies
on second-line chemotherapy are challenging this view (4).

One of the most active new drugs in NSCLC is gemcitabine (2'-2'
difluorodeoxycytidine) a nucleoside analog that, as a single-agent, has
shown a response rate of ~20% in previously untreated patients (5,6). As a
first line treatment, single-agent gemcitabine has been shown to have
anti-tumor activity equal to that of cisplatin/etoposide with less
toxicity and slightly better quality of life resulting (7). In vitro
gemcitabine still shows activity in platinum resistant cell lines (8).

In view of the promising data about gemcitabine, we started a phase II
study of the single-agent gemcitabine as a second-line therapy in advanced
NSCLC with the aim to assess response and evaluate toxicity.


PATIENTS AND METHODS
TOP
Abstract
INTRODUCTION
PATIENTS AND METHODS
RESULTS
DISCUSSION
CONCLUSION
References

PATIENT SELECTION
Patients were included in the study if they had a relapse or progression
of proven advanced NSCLC during or prior to therapy. Radiotherapy was
allowed as long as it had been completed at least 4 weeks prior to
inclusion in the study, to allow the patients to recover from any side
effects, and the disease had progressed outside the radiation field. All
patients had to have an ECOG performance status of 0?2, one or more
lesions that could be measured from each side, and adequate baseline organ
function, defined as a WBC count of at least 4000/µl, a platelet count of
at least 100 000/µl, a total bilirubin level of <3.0 mg/dl, serum
transaminases levels of less than three times the upper limit of normal,
and a serum creatinine value of <1.5 mg/dl or a creatinine clearance of
50 ml/min.

Patients with symptomatic brain metastases or other severe illnesses were
excluded from the study. Written informed consent was required from each
patient prior to inclusion. The protocol was approved by the institutional
review board (IRB) at the Seoul Veterans Hospital of Korea.

PATIENT EVALUATION
A complete history, physical examination, recording of performance status
according to ECOG criteria, complete blood cell count with differential,
serum biochemistry, urinalysis and ECG were obtained at baseline for each
patient. Chest radiographs and CT scans were routinely performed in all
patients. Other radiographic examinations, e.g. isotope bone scans, brain
CT scan, abdominal ultrasonography and abdominal CT scan, were performed
if clinically indicated.

TREATMENT AND DOSE ADJUSTMENTS
Single-agent gemcitabines was administered on an outpatient basis.
Gemcitabine (1000 mg/m2) was administered as a 30 min intravenous infusion
on days 1, 8 and 15 of each 28 day cycle. Prophylactic antiemetics were
administered on the day of chemotherapy with 5-HT3 receptor antagonists.
Drug administration was delayed to a maximum of 2 weeks if there was
incomplete hematological recovery on day 29 (WBC < 3000/µl and/or platelet
<75 000/µl) or in the case of persistent NCI common toxicity criteria
(CTC) grade 2 or more non-hematological toxicity. The dose of gemcitabine
was reduced to 75% in cases where the WBC was between 3000 and 4000/µl or
platelet count was between 75 000/µl and 100 000/µl, and reduced to 50% in
cases where the WBC was between 2000 and 3000/µl or platelet count was
between 50 000/µl and 75 000/µl. Doses were omitted in cases where the WBC
had dropped to <2000/µl, platelets <50 000/µl or in cases where there was
CTC grade 3 non-hematological toxicity. The cycle was repeated a maximum
of six times and was stopped earlier if there was evidence of progressive
disease, unacceptable toxicity or by the patient's wish. No other
chemotherapy or experimental medication was permitted while the patients
were on this study.

RESPONSE AND TOXICITY ASSESSMENT
Physical examinations, complete blood counts and biochemistry profiles
were repeated every 4 weeks. Complete blood counts were measured before
each gemcitabine infusion. Toxicities were graded according to CTC
(version 3.0). Radiographic evaluations for tumor response, including
isotopic bone scan and CT scan, were performed every two courses of
chemotherapy. Tumor response was measured according to standard WHO
criteria.

The response duration was measured from the date of confirmation of at
least partial tumor response to the date of disease progression.
Progression-free survival was measured from the commencement of therapy
until the date of confirmation of disease progression. Survival was
measured from the commencement of therapy until the date of death or last
follow-up evaluation. After the discontinuation of treatment, patients
were evaluated every 8 weeks to assess disease progression.

RESPONSE AND SURVIVAL
All of the patients completed at least two cycles and were evaluated for
response and toxicity. After a median two cycles of chemotherapy, there
were no complete responses and five partial responses, for an overall
response rate of 18.5% (95% confidence interval, 5?33%). The median
response duration was 17 weeks (range, 7.4 to 49+ weeks).

The median follow-up period was 9 months. At the time of this analysis, 17
patients were reported dead. The median progression-free survival was 10
weeks (range, 7 to 34+ weeks). The median survival time was 38 weeks
(range, 10 to 122+ weeks) and 1 year survival rate was 37% (Fig. 1). The
median survival duration was not reached in responding patients and was 33
weeks in non-responding patients, however the difference between the two
groups was not statistically significant (P = 0.15).

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