Chemoradiation in NSCLC: Focus on the Role of Gemcitabine
Chemoradiation in NSCLC: Focus on the Role of Gemcitabine
The discovery that chemotherapy
and radiation therapy separately
improve response rates
and survival in patients with non-
small-cell lung cancer (NSCLC) has
spurred considerable interest in determining
the optimal use of these treatment
modalities. Initial research
demonstrated that sequential chemoradiation
therapy consistently improves
survival in locally advanced
NSCLC compared with either radiation
therapy or chemotherapy alone.
Sequential vs Concurrent
In a series of clinical trials, the
2-year overall survival ranged between
19% to 25% in those receiving
sequential chemoradiation therapy
compared with 13% to 17% in patients
treated with radiotherapy
alone.[1-4] Similarly, phase II studies
conducted in Japan showed a 2-year
survival rate of 36% for patients receiving
chemoradiation therapy compared
with 9% for chemotherapy
alone; by 3 years, the respective survival
rates were 30% and 3%. There
is no role for chemotherapy alone in
stage III disease.
Subsequently, six clinical trials
conducted in Europe, Asia, and the
United States addressed the key issue
of determining the optimal sequence
of chemotherapy and radiation therapy.[
6-10] Regardless of what drug was
given or where the study was done,
results consistently demonstrated that
concurrent chemoradiotherapy provided
longer mean survival than sequential
average median survival was about
14 months for sequential chemoradiotherapy
and approximately 17
months for concurrent radiochemotherapy
(P < .05) (Figure 1; unpublished
data). The survival benefits
have been maintained for as long as
In one long-term study, a chemotherapy
regimen of cisplatin (80 mg/m2
on days 1 and 29), vindesine (3 mg/m2
on days 1, 8, 29, and 36), and mitomycin
(8 mg/m2 on days 1 and 29)
was administered either before or at
institution of radiotherapy (28 Gy) in
323 patients with NSCLC. The 5-year
overall survival rate was 9% for patients
receiving sequential chemoradiation
therapy vs 19% for concurrent
Similarly, in a study involving 610
patients with NSCLC who were treated
with either cisplatin (100 mg/m2
on days 1 and 29) plus vinblastine (5
mg/m2 on days 1, 8, 29, and 36) or
cisplatin (50 mg/m2 on days 1, 8, 29,
and 36) plus oral etoposide (50 mg
bid for 10 weeks) with radiation (60
to 69.6 Gy), the 5-year survival rates
were 12% and 21% for sequential and
concurrent chemoradiation therapy,
respectively. These findings
strongly suggest that synergy between
treatment modalities improves locoregional
control and survival. The disadvantage
is that enhanced toxicity
may restrict the ability to delivery full
doses of both modalities. For that reason,
may be indicated for patients whose
performance status is 0 or 1.
Research to identify the optimal
drugs for use in concurrent chemoradiotherapy
has lead to the development
of a number of new agents, such
as paclitaxel, irinotecan (Camptosar),
docetaxel (Taxotere), and vinorelbine
(Navelbine). Among the more promising
new options is the novel deoxycitidine
analog gemcitabine (Gemzar),
which has demonstrated excellent single-
agent activity in NSCLC.
In preclinical studies, gemcitabine
has exhibited cell phase specificity,
primarily by killing the radioresistant
cells undergoing DNA synthesis
(S-phase cells) and also by blocking
the progression of cells through the
G1/S-phase boundary.[13-17] The cytotoxic
effects of gemcitabine are attributed
to the active diphosphate and
triphosphate nucleosides. Diphosphate
gemcitabine facilitates incorporation
of triphosphate gemcitabine into
DNA, which ultimately inhibits DNA
synthesis and induces apoptosis.
These cytotoxic effects render
gemcitabine a potent radiosensitizer
for NSCLC. The sensitizer enhancement
ratio is ≥ 1.5.[13,14] Duration
of sensitization after exposure
exceeds 76 hours.[15,16] Sensitization
occurs at subcytotoxic doses and
is induced more rapidly with higher
Gemcitabine is indicated in combination
with cisplatin as first-line
therapy for locally advanced (stage
IIIA or IIIB) or metastatic (stage IV)
NSCLC. When administered
in dosages between 1,000 and
1,750 mg/m2, gemcitabine has been
associated with response rates ranging
from 57% to 68% (Table 1).[18-
24] A major advantage of gemcitabine
is its low toxicity when administered
sequentially as monotherapy or combined
with cisplatin, followed by radiation.
(It may be administered in
patients with low performance status
of 1 or 2.) However, gemcitabine
should be used with caution after radiotherapy,
because it has been associated
with radiation recall syndrome,
a rare but serious phenomenon.
A full dose of gemcitabine (1,000
mg/m2) can be used safely with cisplatin
as induction therapy followed
by radiation. In a potentially curative
setting, an interval of 1 to 4 weeks is
recommended between gemcitabine
and radiotherapy to minimize the risk
of radiation recall syndrome. In a palliative
setting, however, when radiotherapy
is used to treat bone
metastases, the interval between chemotherapy
and radiation therapy can
be reduced if necessary.
Gemcitabine and Concurrent
Phase I/II Trials
The activity of concurrent gemcitabine and radiation therapy in NSCLC was initially demonstrated in a multiinstitutional phase II pilot study conducted from October 1994 through August 1995. The treatment regimen included gemcitabine at 1,000 mg/m2/wk for 6 weeks, given together with radiation administered as a 2-Gy fraction 5 days/wk up to a maximum dose of 60 Gy. Seven of the eight patients had a > 50% reduction in the primary tumor, and four of five patients experienced a response in the nodes. The excellent activity of this regimen, however, was accompanied by serious toxicity. There were three treatment-related deaths, two due to pulmonary toxicity and one resulting from hemorrhage due to radiation necrosis. Three patients experienced pneumonitis or severe esophagitis, and another two patients experienced serious radiation-induced side effects. Two factors were believed to be primarily responsible for this toxicity. First was the large starting dose of gemcitabine, which had been chosen before results of phase I dose-escalation studies had been completed. Second was the large radiation treatment volume, which encompassed approximately 5,000 cm3 for the initial volume and 2,000 cm3 for the booster field. Those volumes are approximately twice the volumes that are recommended in the United States (personal communication, A. Turrisi A, H. Choy, 2003). Subsequent phase I studies have demonstrated that gemcitabine, in doses ranging from 100 to 600 mg/m2/wk, are well tolerated during radiation therapy.[27-30] The risk of serious toxicity increased substantially with the dose, and the maximum tolerated dose ranged from 190 to 350 mg/m2/wk. A recent randomized phase II study supports administration of gemcitabine with cisplatin during radiation therapy for NSCLC. Chemotherapy, consisting of cisplatin combined with gemcitabine, paclitaxel, or vinorelbine, was administered in two cycles of induction chemotherapy followed by two additional cycles of the same drugs with concomitant radiotherapy. All 175 patients received four cycles of cisplatin at 80 mg/m2 on days 1, 22, 43, and 65. Dosage schedules for the three different treatment arms were as follows: gemcitabine at 1,250 mg/m2 on days 1, 8, 22, and 29, and 600 mg/m2 on days 43, 50, 64, and 71; paclitaxel at 225 mg/m2 for 3 hours on days 1 and 22, and 135 mg/ m2 on days 43 and 64; and vinorelbine at 25 mg/m2 on days 1, 8, 15, 22, and 29, and 15 mg/m2 on days 43, 50, 64, and 71. Radiotherapy was instituted on day 43 at 2 Gy/d (total dose, 66 Gy). Response rates after completion of radiotherapy were 74%, 67%, and 73%, respectively, for the gemcitabine, paclitaxel, and vinorelbine arms. Median survival for all patients was 17 months. Median progression-free survival was 8.4 months with gemcitabine/ cisplatin, 9.1 months with paclitaxel/ cisplatin, and 11.5 months with vinorelbine/cisplatin. Rates were 68%, 37%, and 28% for 1-, 2-, and 3- year survival, respectively, for the gemcitabine arm; 62%, 29%, and 19% for the paclitaxel arm; and 65%, 40%, and 23% for the vinorelbine arm (Figure 2). The study was too small to show statistical significance in survival rates between treatment groups, although the numerically higher 3-year survival rate for the gemcitabine/ cisplatin arm appears to be encouraging. Toxicities during induction chemotherapy consisted primarily of grade 3 or 4 granulocytopenia. Grade 3 or 4 toxicities during concomitant chemoradiotherapy most frequently involved thrombocytopenia, granulocytopenia, and esophagitis. Of the group receiving the vinorelbine/cisplatin combination, 10 patients experienced grade 4 lung toxicity, and 1 patient died as a result of treatment-related respiratory failure. Dose-Escalation Trial
The optimal dosage of gemcitabine during radiation therapy for NSCLC is being assessed in an ongoing "Ping-Pong" trial (RTOG 0017), in which patients are recruited into treatment sequences involving escalating dosages of either gemcitabine plus carboplatin or gemcitabine plus paclitaxel (unpublished data). However, as of publication, sequence B- the "Pong" portion of the trial-has closed due to safety concerns about toxicities. The original design was as follows. In sequence A, there are five dosages of gemcitabine used in the six gemcitabine/carboplatin treatment arms: 300 mg/m2/wk (including one monotherapy and one combination therapy arm), 450, 600, 750, and 900 mg/m2/wk. Carboplatin will be given at an area under the concentration- time curve (AUC) of 2 in five treatment arms, but not used in the sixth. Sequence B was designed to include six treatment arms involving gemcitabine and paclitaxel, respectively, in dosages as follows: 300/30, 450/30, 450/40, 600/40, 600/50, and 750/50 mg/m2/wk. All arms would be followed by two cycles of consolidated chemotherapy, gemcitabine at 1,000 mg/m2 weekly 2 out of 3, and carboplatin at AUC 5.5. Patients will be recruited first into the lowest-dose arm of sequence A (300 mg/m2/wk gemcitabine monotherapy). After recruitment is completed in the first arm, toxicity will be assessed, while patients are being entered into the lowest dose arm of sequence B (gemcitabine at 300 mg/m2/wk plus paclitaxel 30 mg/m2/wk). While the toxicity of that regimen is being evaluated, patients are recruited into the second lowest dose arm in sequence A (gemcitabine at 300 mg/m2/wk plus carboplatin AUC 2). Recruitment will continue at escalating dosage levels until toxicity becomes unacceptable. Dose escalation continues as long as ≤ two of six patients experience dose-limiting toxicity. The estimated accrual is 36 patients, six per treatment arm. Preliminary toxicity data have been derived from the first 24 patients, seven each in the first three arms. Grade 3/4 hematologic toxicity occurred in four of seven patients in arm 1 (gemcitabine at 300 mg/m2/wk monotherapy), five of seven patients in arm 2 (gemcitabine at 300 mg/m2/wk plus paclitaxel at 30 mg/m2/wk), and four of seven patients in arm 3 (gemcitabine at 300 mg/m2/wk plus carboplatin at AUC 2). Pulmonary toxicity was noted only in two patients in arm 2. Since three patients in arm 2 had doselimiting toxicities, researchers concluded that the combination of gemcitabine plus paclitaxel is too toxic, and recruitment of patients to receive this combination has been discontinued. By contrast, recruitment into treatment arms involving esca- lating dosages of gemcitabine plus carboplatin is expected to continue. Conclusion The efficacy of gemcitabine as a radiosensitizer is strongly supported by accumulating clinical data. When administered together with radiation therapy, gemcitabine is associated with favorable overall survival and response rates, and may be used in patients with a low performance status. Although the safe weekly dose of gemcitabine has yet to be determined, it appears to be at least 300 mg/m2. An ongoing clinical trial may soon establish the maximum tolerated dose of gemcitabine to be used during radiation therapy. Toxicity may be minimized by using modern technology such as three-dimensional conformal radiotherapy. Additional clinical trials are needed to assess the long-term efficacy and safety of gemcitabine administration during radiotherapy.
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