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Evolution of Combined Modality Therapy for Stage III Non–Small-Cell Lung Cancer

Evolution of Combined Modality Therapy for Stage III Non–Small-Cell Lung Cancer

ABSTRACT: A number of randomized clinical trials and meta-analyses now support the conclusion that combined modality regimens that include cisplatin (Platinol)-based chemotherapy improve survival in stage III non–small-cell lung cancer (NSCLC) more effectively than radiotherapy or surgery alone. Depending on the therapy, chemotherapy may play a cytoreductive role by eradicating distant micrometastases, a radiosensitizing role by improving local control, or do both. In general, sequential therapies in which platinum-based chemotherapy precedes thoracic radiation or surgery have improved outcome by affecting distant metastases. In contrast, concurrent chemoradiotherapy utilizing low-dose cisplatin improves survival by reducing local recurrence without an effect on distant failure rates. In view of these observations, chemoradiotherapy strategies that integrate both radiosensitizing agents and dose levels of chemotherapy that are effective against micrometastases may prove to be most efficacious. Since distant metastases remain the major site of failure, it is also likely that more effective chemotherapy or other systemic antitumor agents are necessary to increase the current level of response and survival. Fortunately, several new chemotherapeutic agents are highly effective against NSCLC as well as potent radiosensitizers. [ONCOLOGY 14(Suppl 5):35-41, 2000]

Introduction

Non–small-cell lung cancer (NSCLC) is the most common cause of
cancer-related death in both men and women in the United States each
year. As the recently revised international staging system
indicates,[1] patient survival is directly related to stage. Survival
rates with surgical resection of early stage disease (stage I and II)
have improved. However, this subgroup accounts for only a small
fraction of the 140,000 new cases of NSCLC each year. Even in this
favorable category, 20% to 40% of patients develop recurrence, which
typically manifests as distant metastases.

Locally advanced (stage III) disease, which represents approximately
50,000 cases annually, is more common. This category of tumors is
heterogeneous and, for treatment planning purposes, can be divided
into several patient subgroups (Table
1
): stage IIIA without mediastinal node involvement (T3 N1),
IIIA N2 (minimal bulk), IIIA N2 (bulky)/IIIB (T4 or N3 without
malignant pleural effusion), and stage IIIB (malignant pleural
effusion). All of these subgroups are now candidates for combined
modality therapy with curative intent—except in those patients
with malignant pleural effusion (whose natural history and treatment
options mimic those of stage IV [metastatic] disease).

A multidisciplinary clinical research effort that integrates
combinations of chemotherapy, radiotherapy, and/or surgery into the
therapeutic approach against advanced NSCLC has evolved within the
past 10 years.[2] In a number of phase III clinical trials, cisplatin
(Platinol)-based chemotherapy—either in combination with
thoracic radiation or administered before surgery—has improved
survival more effectively than radiotherapy or surgery alone.[3-9] In
addition, a number of new chemotherapeutic agents are now
incorporated into combined modality regimens. These recent advances,
including the rationale and design of ongoing clinical research
studies investigating new treatment regimens, are reviewed on the
following pages.

Combined Modality Approaches

A variety of approaches that integrate chemotherapy, radiation,
and/or surgery into combined modality treatment of NSCLC are
illustrated in Table 2. Each
has potential advantages and disadvantages. Both bimodality
(chemotherapy plus radiotherapy, or chemotherapy plus surgery) and
trimodality (chemotherapy plus radiotherapy plus surgery) options are
under investigation.

In both options, NSCLC is considered to be a two-compartment model
consisting of a combination of local-regional disease and distant
micrometastases in which thoracic irradiation or surgical resection
addresses the issue of local control, while the use of chemotherapy
(or other systemic antineoplastic agents) addresses occult distant
spread.[2] Additionally, chemotherapy may play a cytoreductive role
locally or a radiosensitizing role, as described above.

For the purpose of this discussion, these approaches to combined
modality therapy can be divided into two avenues: (1) definitive
chemoradiotherapy (nonsurgical combined modality therapy), and (2)
preoperative (neoadjuvant or induction) chemotherapy with or without
radiotherapy followed by surgical resection. A third avenue,
postoperative adjuvant therapy, is not detailed in this review.

Definitive Chemoradiotherapy Studies

Sequential therapy, in which chemotherapy is completed prior to the
administration of radiotherapy, is the most widely recognized
approach to chemoradiotherapy for locally advanced NSCLC. Because
sequential chemoradiation avoids overlapping toxicities, full doses
and optimal schedules of both modalities may be used, but the
duration of therapy is prolonged. In addition, the potential for
chemotherapeutic radiosensitization is lost. By comparison,
concurrent chemoradiation optimizes both the radiosensitizing and
local cytoreductive potential of chemotherapy. There is no delay in
use of either modality, but concurrent therapy entails the risk of
overlapping toxicity. Conceptually, enhanced toxicity with concurrent
therapy may preclude delivery of full doses of either modality,
depending on the chemotherapeutic regimen and radiation dose
schedule.

A number of phase III trials have compared sequential chemoradiation
to radiotherapy alone in stage III NSCLC and their overall results
have been subjected to meta-analysis.[3-7,10] In a landmark Cancer
and Leukemia Group B (CALGB) study, a limited 5-week course of
chemotherapy (100 mg/m² cisplatin during weeks 1 and 5 plus
vinblastine (Velban), 5 mg/m²/week during weeks 1–5)
followed by radiotherapy (60 Gy/30 fractions) was delivered in
clinical stage III patients who had good performance status (0–1)
and minimal weight loss (< 5%). Results were compared to patients
who received the same radiotherapy alone. Despite the brief duration
of exposure to this platinum-based chemotherapy, survival was
significantly greater in the combined modality treatment arm (P
= .006). Although median survival was modestly improved (13.8 vs 9.7
mo), survival at 2 years (26% vs 13%) doubled.[3] These results were
confirmed in a subsequent Intergroup trial (Radiation Therapy and
Oncology Group [RTOG] 88-08),[4] comparing identical radiotherapy and
sequential chemoradiotherapy arms with those of the previous CALGB
study.

A third treatment arm evaluated the role of hyperfractionated
radiotherapy. Median and 2-year survival in the chemoradiotherapy arm
(13.8 mo/31%) were significantly superior to both standard
radiotherapy (11.4 mo/20%) and hyperfractionated radiation (12.3
mo/24%) (log rank, P = .03). However, at 5-year follow-up,
survival was less than 10% in all three arms, which substantiates the
need for better chemoradiotherapy strategies.[11]

A French study in stage III disease by Le Chevalier compared a
control arm of radiotherapy alone (65 Gy) to three monthly cycles of
PCVC (cisplatin, lomustine [CeeNU], vindesine [Eldesine], and
cyclophosphamide [Cytoxan, Neosar]) followed by the same
radiotherapy.[5] At 3 years, 12% of patients treated with sequential
chemoradiotherapy were alive vs 4% of those treated with radiotherapy
alone (P = .02).[5,6] In this study, the rate of distant
metastasis was significantly lower in the combined modality group (P
< .001). With rigorous restaging that included bronchoscopy, local
control was less than 20% on either treatment arm, which demonstrates
one of the limitations of sequential chemoradiotherapy.

Several phase III trials have compared concurrent cisplatin-based
chemoradiotherapy to radiotherapy alone.[12-15] The hypothesis that
improved local control from chemoradiosensitization could improve
survival is supported by a study from the European Organization for
Research and Treatment of Cancer (EORTC), reported by Schaake-Koning
et al.[12]

Three treatment arms were evaluated: split-course radiotherapy alone,
split-course radiotherapy administered concurrently with either
weekly cisplatin (30 mg/m²/week), or daily cisplatin (6
mg/m²) on the days of radiotherapy. Both cisplatin-containing
arms showed superior results to radiation alone, with a statistically
significant survival advantage using daily cisplatin over
radiotherapy alone (P = .009).

Of particular interest, improved survival with cisplatin was entirely
due to increased control, with a significant difference in 2-year
freedom from local recurrence in those treated in the
radiotherapy-alone arm (19%) vs the chemotherapy treatment arm (30%).
There was no difference in time to development of distant metastasis.
These results suggest that low-dose cisplatin functioned primarily as
a radiosensitizer—leading to improved local control but proving
ineffective against occult systemic disease. Conversely, fully
cytotoxic doses of cisplatin-based chemotherapy, sequenced prior to
radiation in the Le Chevalier study, were effective in eradicating
distant micrometastases without an impact on local control.[5,6]

Concurrent vs Sequential Chemoradiotherapy

Most recently, the results of a Japanese study by Furuse et al
directly compared concurrent vs sequential chemoradiotherapy in stage
III NSCLC.[16] In this randomized study, median and long-term
survival were clearly superior in the concurrent arm (Table
3
). Patients on the sequential arm received two cycles of
mitomycin (Mutamycin)/vindesine/cisplatin (MVP) chemotherapy (56 Gy/2
Gy daily) prior to thoracic radiotherapy; patients on the second arm
received split-course thoracic radiotherapy (56 Gy) concurrent with
MVP. Median survival for the concurrent chemoradiotherapy arm was
16.5 months, significantly better than the 13.3 months observed in
the sequential arm (P = .05). At 3 years, survival was 27%
with concurrent therapy compared to 12.5% with sequential therapy.
Furthermore, toxicity profiles were acceptable in both of these
combined modality approaches, although esophagitis and
myelosuppression were more frequent in the concurrent arm. If these
data are confirmed by a recently completed RTOG trial, concurrent
chemoradiotherapy will become the standard of care for nonsurgical
therapy of stage III disease. Most ongoing clinical trials have
already incorporated concurrent chemoradiotherapy into the study design.

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