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Chemoradiation for Locally Advanced, Unresectable NSCLC

Chemoradiation for Locally Advanced, Unresectable NSCLC

ABSTRACT: The optimal therapy for locally advanced, unresectable, stage III non–small-cell lung cancer (NSCLC) continues to evolve. The critical determinants of overall survival include local tumor control and the eradication of subclinical micrometastatic disease. Historically, standard radiation therapy resulted in a median survival of 7 to 10 months. In a randomized trial, the Cancer and Leukemia Group B (CALGB) established the superiority of induction cisplatin (Platinol) and vinblastine chemotherapy followed by radiation therapy. Additional studies revealed that induction chemotherapy improved survival rates by decreasing metastatic disease progression. Three independent meta-analyses confirmed the survival benefit afforded by cisplatin-based induction chemotherapy followed by radiotherapy, and helped to establish this as the new standard of care. Other investigators have demonstrated improvements in local tumor control and survival with either concurrent chemoradiotherapy or hyperfractionated radiotherapy. Most recently, attention has focused on radiation dose intensity and the utilization of newer, highly active chemotherapeutic agents with concurrent or sequential radiation therapy. These newer drugs, including paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine (Gemzar), vinorelbine (Navelbine), and irinotecan (Camptosar), enhance radiation cytotoxicity and, when administered in systemically active dosages, may also control micrometastatic disease. Phase I and II studies of novel chemoradiation regimens continue to demonstrate encouraging results, and several large randomized clinical trials are currently enrolling patients. [ONCOLOGY 13(8):1075-1088, 1999]

Introduction

Lung cancer is the leading cause of
cancer-related death in men and women in the United States. In 1998,
an estimated 171,500 new cases were diagnosed and 160,100 patients
died from the disease.[1]

Non–small-cell lung cancer (NSCLC) is diagnosed in approximately
80% of patients with primary lung cancer.[2] Although patients with
malignant pleural effusion (T4) have a prognosis similar to those
with metastatic disease, other patients with locally advanced,
unresectable, stage III NSCLC represent a unique therapeutic
challenge. Their tumors may have invaded into mediastinal organs (T4)
or may have spread to mediastinal or supraclavicular lymph nodes (N2, N3).

Although such tumors may not be amenable to curative resection, the
lack of overt metastatic disease allows for some optimism, and a
small number of patients may be cured by definitive nonsurgical
therapy. Historically, this definitive therapy was single-modality
standard-fractionation thoracic radiotherapy, which resulted in a
median survival of 7 to 10 months.[2]

Over the past 2 decades, several trials of combined-modality
chemotherapy and radiotherapy have led to an improved outcome and a
new standard of care.[3] Although the American Society of Clinical
Oncology (ASCO) practice guidelines state that “chemotherapy in
association with definitive thoracic radiation is appropriate for
selected patients with unresectable, locally advanced non–small
cell lung cancer,” no specific regimen is defined. Relevant
questions include the timing of chemotherapy (sequential and/or
concurrent), the specific chemotherapeutic drugs, and the dose and
intensity of the radiation therapy.

This review chronicles the relevant trials that led to the change in
the standard of care, as well as the more recent investigations of
novel radiation schedules and new chemotherapeutic agents.

Induction Chemotherapy Followed By
Conventional Radiation

Several studies of cisplatin (Platinol)–based induction
chemotherapy followed by definitive radiation therapy (Table
1
) have reported improvements in survival for patients with
stage III, unresectable NSCLC.[4-12] In theory, induction
chemotherapy may improve survival by decreasing the local tumor
burden prior to definitive radiation and by eradicating sites of
subclinical micrometastatic disease.

Randomized Trials

In 1990, Dillman et al published the results of a pivotal randomized
study of induction chemotherapy followed by radiation vs radiation
alone in stage III NSCLC.[4] This study, conducted by the Cancer and
Leukemia Group B (CALGB), included 155 patients with stage IIIA/B
disease. Patients had a CALGB performance status of 0 or 1 and less
than a 5% loss in body weight.

Induction chemotherapy consisted of cisplatin (100 mg/m² on days
1 and 29) and vinblastine (5 mg/m² on days 1, 8, 15, 22, and
29). Conventional radiation therapy (60 Gy given in daily 200-cGy
fractions, 5 days per week for 6 weeks) was started on day 50 for the
patients in the induction chemotherapy group and immediately for
patients assigned to radiation alone.

The response evaluation after induction chemotherapy revealed 3
complete responses and 17 partial responses (response rate, 26%). An
equal percentage of patients in both arms completed all radiation
therapy, and a significant survival advantage among patients who
received induction chemotherapy led to the early closure of the study.[4]

The updated, 7-year follow-up results of this study, published in
1996, revealed a median survival duration of 13.7 months for patients
who received induction chemotherapy vs 9.6 months for those treated
with standard radiation alone (P = .012).[5] The percentages of
patients surviving at 2 and 5 years were 26% and 17%, respectively,
in the induction chemotherapy group, as compared with 13% and 6%,
respectively in the radiation alone group.

Although toxicity, including serious infection, nausea, and severe
weight loss, was greater in the induction chemotherapy arm, there
were no treatment related fatalities. Also, the frequency of severe
esophagitis and pneumonitis was only 1% in both treatment arms.[4]

Sause et al published the results of the confirmatory intergroup
study in 1995.[6] As in the CALGB study, patient enrollment in the
intergroup trial was limited to those with an excellent performance
status and minimal weight loss. A total of 452 patients were eligible
for enrollment and analysis.

Two of the treatment arms were identical to the CALGB trial. Patients
in a third arm received hyperfractionated radiation (1.2-cGy
fractions twice daily 5 days per week, for a total dose of 69.6 Gy)
without induction chemotherapy. The rationale for this third arm was
that increased radiation dose intensity could lead to greater local
control and survival.

Updated survival analyses, published in 1997 and 1998, indicated
median survival times of 11.4 months for the patients given standard
radiation, 13.7 months for those treated with induction chemotherapy,
and 12.2 months for those who received hyperfractionated radiation
therapy.[7,8] Survival rates at 2 and 5 years were 20% and 5%,
respectively, for the standard radiation group, 31% and 8%,
respectively, for the induction chemotherapy group, and 24% and 6%,
respectively, for the hyperfractionated radiation group. Like the
CALGB, the overall survival figures of the intergroup trial favored
the induction chemotherapy arm (P = .04).

Both the intergroup and CALGB studies established a role for
induction chemotherapy. Furthermore, the intergroup trial found that
hyperfractionated radiation could also lead to improved long-term survival.

In 1994, LeChevalier et al reported the updated results of a
randomized French trial of induction chemotherapy followed by
sequential radiotherapy and adjuvant chemotherapy vs radiotherapy
alone.[9,10] Previously, this group had described the encouraging
results, including a median survival of 15.9 months, of a phase II
study of vindesine, CCNU (lomustine), Platinol (cisplatin), and
cyclophosphamide (VCPC). This combination was given for three cycles
prior to and after definitive radiation therapy (65 Gy in 26
fractions given over 45 days).[11]

In a follow-up study, 353 patients were randomized to this combined-
modality treatment vs the same radiation without chemotherapy.[9]
Median survival was 10 months for the patients in the radiation
therapy arm and 12 months for those in the combined-therapy arm. The
survival rates at 2 and 5 years were 14% and 3%, respectively, in the
radiation therapy group and 21% and 6%, respectively, in the
combined-modality group (P = .02).[9,10,12]

Although distant metastatic progression was significantly decreased
(P < .001) and survival was increased in patients treated with
combined-modality therapy, local failure occurred in 92% of patients
in both arms at 5 years. This accounted for the limited absolute
survival benefit observed in the combined-modality group.[12] The
authors of this study concluded that increased local tumor control
was essential in order to “take full advantage of the effect of
cisplatin-based chemotherapy on reducing metastasis.”[12]

Meta-Analyses

Although several smaller randomized trials did not show a survival
advantage of induction chemotherapy in patients with NSCLC,[13-17]
these studies may have lacked statistical power and/or utilized
suboptimal chemotherapy. Also, three large meta-analyses recently
assessed the role of induction chemotherapy.[18-20]

As part of a larger study, the Non-Small Cell Lung Cancer Cooperative
Group (NSCLCCG) reviewed 22 randomized trials and updated individual
data for 3,033 patient records in order to evaluate the role of
chemotherapy added to definitive radiation therapy.[18] Of these
trials, 11 (1,780 patients) used cisplatin-based sequential
chemotherapy, whereas many of the older trials used alkylating agents
or anthracycline-based therapy. The results showed a significant
overall benefit for the use of chemotherapy. Trials using
cisplatin-based therapy provided the greatest benefit: a 13%
reduction in the risk of death and an absolute benefit of 4% (95%
confidence interval [CI], 1% to 7%) at 2 years and 2% (95% CI, 1% to
4%) at 5 years.

Reporting on the results of meta-analyses based on data extracted
from published studies, Marino et al and Pritchard et al found
similar benefits in favor of cisplatin-based therapy.[19,20] The
analysis by Pritchard et al concluded that the addition of
chemotherapy to radiotherapy improved median survival from 10.3 to 12 months.[20]

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