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Limited Small-Cell Lung Cancer: A Potentially Curable Disease

Limited Small-Cell Lung Cancer: A Potentially Curable Disease

ABSTRACT: Patients with limited-stage small-cell carcinoma of the lung are treated with combined-modality therapy with the intent to cure. Standard therapy consists of platinum-based combination chemotherapy, thoracic irradiation, and for responders, prophylactic cranial irradiation. Despite this aggressive approach, too few patients achieve 5-year survival. In the past several years, new chemotherapeutic agents, including the taxanes and the topoisomerase I inhibitors, have demonstrated substantial activity against small-cell carcinoma. These agents are now being incorporated into clinical trials for patients with limited-stage disease. The best combination of these agents with platinum-based regimens is yet to be determined, and data supporting increased survival are awaited. Other studies are exploring thoracic radiation issues. Questions remain regarding optimal timing, dose, volume, and fractionation schemes. The most effective combination of thoracic irradiation and the newer chemotherapy agents also remains to be determined. The current approach to limited-stage small-cell carcinoma is reviewed, ongoing trials are described, and future directions are explored. [ONCOLOGY 14(10):1395-1409, 2000]

Introduction

During the past 3 decades, progress has inched forward in the
management of limited small-cell carcinoma of the lung. Prior to the
1970s, patients were managed largely with surgery alone or radiation
therapy alone. In 1969, the British Medical Research Council reported
5-year survival rates of only 1% with surgery and 4% with
radiotherapy.[1]

In the early 1970s, the ability of small-cell carcinoma to
disseminate early prompted clinical trials focusing on systemic
management with chemotherapy.[2] Initial results with chemotherapy,
yielding a four- to fivefold increase in median survival, generated
great enthusiasm and the hope that outcomes similar to those achieved
with other chemosensitive tumors would be forthcoming.[3] Now, almost
30 years later, high rates of local and distant relapse, including
central nervous system relapse, continue to thwart efforts to achieve
this elusive goal.

Nevertheless, real progress has been made, and the use of combination
chemotherapy, concurrent thoracic radiotherapy, and prophylactic
cranial irradiation have led to 5-year survival rates as high as
26%.[4] New chemotherapeutic agents with significant activity against
small-cell carcinoma are emerging, and refinements in
radiotherapeutic technique are producing not only improvements in
local control, but survival benefits as well.[4] This article will
review the current approach to limited small-cell carcinoma of the
lung, and will explore unanswered questions and future directions.

Staging/Definition of Limited Disease

The overwhelming tendency of small-cell carcinoma of the lung is to
disseminate early. This has taught us that even when a rigorous
search fails to find distant metastases, the best approach is to
treat limited small-cell carcinoma of the lung as a systemic disease,
with chemotherapy as the cornerstone of treatment. As a result, there
is less emphasis on the TNM classification, which is more appropriate
when surgery is being considered. Instead, a simplified staging
system of “limited disease” vs “extensive disease”
is used.

The limited-disease category includes patients whose disease may be
encompassed within a radiation portal. Ambiguities about pleural
effusion and nodal stations cause some confusion in categorizing
small-cell lung cancer as limited or extensive. The presence of an
ipsilateral pleural effusion frequently, though not uniformly,[5]
excludes patients from limited-disease protocols, although
technically this is considered limited disease. Some investigators
include within the limited-disease category patients with minimal
pleural effusions not felt to be easily accessible for cytologic
diagnosis; this includes those with blunting of the costophrenic
angle on chest radiographs, as well as those with effusions seen only
on chest computed tomography (CT).[6] Many investigators,[7-9]
however, exclude all patients with demonstrated pleural effusions by
any study, including chest CT.

Similar variability in the definition of limited disease occurs with
reference to the extent of lymphadenopathy. Some studies include
patients with bilateral supraclavicular adenopathy in the
limited-disease category[10]; others[4,6] include only those with
ipsilateral adenopathy. Likewise, some investigators include patients
with contralateral hilar adenopathy in the limited-disease
category[9]; others exclude them.[4] These variations reflect a
change in approach from a time when all nodal stations were targeted
by radiotherapy ports to the more recent policy of including only
nodes with obvious involvement radiographically.

In addition to the variability in the definition of limited-stage
disease, current imaging techniques detect more extrathoracic disease
than did planar images. In many of the older studies, thoracic
imaging consisted only of chest radiographs.[7,11,12] Current staging
minimally includes chest CT extending through the liver and adrenals (Table
1
). Because the brain is a common site of metastatic disease in
small-cell lung cancer, imaging of the brain by CT or magnetic
resonance imaging (MRI) remains sensible. A radionuclide bone scan is
also frequently performed. However, bone marrow aspiration and
biopsy—once a routine staging procedure—is no longer
required. Bone marrow involvement as the sole manifestation of
extensive disease is quite rare, occurring in only 1.7% of
patients.[13] Thus, this invasive procedure, and the associated
discomfort, may be omitted.

At present, positron-emission tomography (PET) has no defined role in
the routine staging evaluation of small-cell carcinoma patients.
However, use of this highly sensitive imaging modality is
increasingly being explored in a variety of oncologic settings. It
has the potential to become a very useful staging procedure for
small-cell carcinoma patients and may prove beneficial in terms of
monitoring their response to therapy.[14] The precise role of PET
scanning in small-cell carcinoma will emerge in the next decade.

As imaging modalities continue to improve, the ability to detect
disease outside of what might be “encompassed within a radiation
portal” will continue to increase. Patients who would previously
have been classified as having limited-stage disease will be found to
have extensive-stage disease. This stage migration will appear to
improve the outcome of both limited- and extensive-disease patients,
another example of the Will Rogers phenomenon.[15]

Chemotherapy

In the 1970s, chemotherapy regimens consisted of single-agent
alkylators and then combinations based on alkylating agents (mainly
cyclophosphamide [Cytoxan, Neosar]). One of the most commonly
prescribed regimens throughout the 1980s was CAV (cyclophosphamide,
doxorubicin [Adriamycin], and vincristine [Oncovin]). Doxorubicin was
considered highly effective—“the paclitaxel (Taxol) of the
1970s.” This regimen produced excellent response rates, but the
majority of patients relapsed both locally and systemically. Also,
the inclusion of doxorubicin created havoc in regimens combining
chemotherapy with radiation therapy, because doxorubicin potentiated
radiation-induced toxicity and caused radiation recall.

Cisplatin and Etoposide

In the late 1970s, a regimen consisting of cisplatin (Platinol) and
etoposide was developed.[16,17] Preclinical studies suggested a
marked synergy with this combination, whereas single-agent therapy
with cisplatin had produced a response rate of only 10%.[18] The
combination was studied as salvage therapy for patients with
recurrent or refractory small-cell carcinoma and was associated with
response rates as high as 52%.[19] Cisplatin/etoposide was
investigated as first-line therapy, and was found to be highly active
and amenable to combination with concurrent thoracic irradiation. The
regimen proved to be equivalent or superior to all previous
combinations[20] and in the 1980s became the treatment of choice for
limited small-cell carcinoma.

A prospective, randomized trial of standard-dose cisplatin/etoposide
(cisplatin, 80 mg/m² IV on day 1, and etoposide, 80 mg/m²
IV on days 1 to 3, repeated every 3 weeks) compared to high-dose
cisplatin/etoposide (cisplatin, 27 mg/m² IV on days 1 to 5, and
etoposide, 80 mg/m² IV on days 1 to 5, repeated every 3 weeks)
showed no improvement in efficacy and a substantial increase in
toxicity in the high-dose arm.[21] Even standard-dose cisplatin
regimens, however, produce significant toxicity, most notably nausea,
vomiting, nephrotoxicity, and neuropathy.

Carboplatin

Carboplatin (Paraplatin) may have a more favorable toxicity profile,
and has been used instead of cisplatin. The carboplatin/etoposide
combination has also demonstrated excellent activity in small-cell
carcinoma, and in a prospective randomized phase III trial conducted
by the Hellenic Cooperative Oncology Group, carboplatin/etoposide was
associated with equal efficacy and less toxicity than the
cisplatin/etoposide combination.[22]

Because of the equivalent efficacy and favorable toxicity profile of
carboplatin, many clinicians prefer carboplatin/etoposide over
cisplatin/etoposide. The combination of a platinum compound with
etoposide remains standard therapy for small-cell carcinoma. Over the
past few years, however, several new cytotoxic agents with
substantial activity in this disease have been developed.

Paclitaxel

Paclitaxel was introduced in 1993, and phase II studies demonstrated
considerable single-agent activity in previously untreated and
treated small-cell lung cancer patients (Table
2
).[23-25] Greco and Hainsworth added paclitaxel as a 1-hour
infusion to a commonly used combination of carboplatin/etoposide.[26]
Hainsworth et al started with modest doses of paclitaxel (135 mg/m²)
and carboplatin (area under the concentration-time curve [AUC in
mg/mL · min] = 5), but because the myelosuppression that
developed with this regimen was manageable, the investigators
subsequently treated a larger number of patients with increased doses
of paclitaxel (200 mg/m²) and carboplatin (AUC = 6).[27]
This study included previously untreated small-cell carcinoma
patients with limited or extensive disease. Limited-disease patients
received thoracic irradiation at 1.8 Gy/d to a total dose of 45 Gy
over 5 weeks, beginning concurrently with cycle 3 of the
chemotherapy. While response and toxicity data were promising, this
three-drug combination is costly, and whether it will prove superior
to the combination of carboplatin/etoposide chemotherapy awaits the
results of a prospective, randomized trial.

Paclitaxel has also been combined with the cisplatin/etoposide
regimen. This combination has produced a response rate of 94% in
extensive-disease patients.[28] Recently, a multi-institutional phase
I/II study of this regimen administered with concurrent thoracic
irradiation to limited-disease small- cell carcinoma patients was
published.[29] In this trial, four 21-day cycles of chemotherapy were
administered, concurrently with thoracic irradiation given at a total
dose of 45 Gy over 5 weeks, beginning on day 1 of cycle 1. Cisplatin,
60 mg/m², was given on day 2 of all cycles. Etoposide was
given at a lower dose, 60 mg/m²/d, on days 1 to 3 of cycles 1
and 2 (with concurrent radiation), and at a higher dose, 80
mg/m²/d, on days 1 to 3, during cycles 3 and 4.
Granulocyte-colony stimulating factor (G-CSF [Neupogen]) was added
during cycles 3 and 4.

During the phase I portion of the trial, the paclitaxel dose during
cycles 1 and 2 was escalated to determine the maximum tolerated dose
with concurrent radiation. This was found to be 135 mg/m²,
administered intravenously over 3 hours on day 1; grade 4 neutropenia
was the dose-limiting toxicity. During cycles 3 and 4, paclitaxel was
given at 170 mg/m². The overall response rate for this regimen
was 96%, with 39% complete responses. Again, the question of whether
this active, but costly, three-drug regimen is superior to standard
cisplatin/etoposide in terms of survival cannot be answered without a
prospective, randomized trial.

Topoisomerase I Inhibitors

The topoisomerase I inhibitors, topotecan (Hycamtin) and irinotecan
(Camptosar), have also been shown to have significant activity
against small-cell carcinoma. Topotecan (Table
3
) has been studied in the salvage setting, where it yielded
response rates of 14% to 38% in patients with sensitive
disease—ie, those who responded to first-line chemotherapy and
subsequently relapsed more than 3 months after their chemotherapy was
discontinued.[30-33] Topotecan was noted to be considerably less
effective in patients with refractory small-cell carcinoma, where
response rates ranged from 2% to 11%.[30-32,34] In previously
untreated extensive-disease patients, a response rate of 39% has been reported.[35]

An ongoing phase I trial is being conducted to determine the maximum
tolerated systemic exposure of topotecan when combined with
carboplatin/etoposide in extensive-disease patients.[36] Preliminary
results show an 81% response rate.

The combination of topotecan and paclitaxel has been shown to be
active by several investigators (Table 4).[37-39]
A study in limited-disease patients is currently being conducted by
the Cancer and Leukemia Group B (CALGB). In this protocol, patients
initially undergo two cycles of induction chemotherapy with the new
combination of topotecan/paclitaxel with G-CSF support. They
subsequently receive the standard regimen of carboplatin/etoposide
for three cycles. Thoracic irradiation is given starting with the
first cycle of carboplatin/etoposide: A 60-Gy total dose is being
administered to the first 10 patients; then, if well tolerated, a
70-Gy total dose. Prophylactic cranial irradiation is required for
those who achieve complete or very good partial remissions.

Irinotecan has also shown substantial activity in previously treated
small-cell carcinoma patients (Table 5).[40-42]
A phase II study, including both limited-disease and
extensive-disease patients, evaluated the combination of irinotecan,
60 mg/m² on days 1, 8, and 15, with cisplatin, 60 mg/m² on
day 1, every 28 days.[43] Patients with limited disease received four
cycles of chemotherapy followed by thoracic irradiation to a dose of
50 Gy. The response rate in limited-disease patients was 83%, with
30% complete remissions; median survival was 14.3 months. The major
toxicities were myelosuppression and diarrhea.

This chemotherapy regimen has also been explored with concurrent
thoracic irradiation in limited-disease small-cell lung cancer
patients.[44] In this setting, the dose-limiting toxicity was
fatigue, and the recommended regimen for future study is irinotecan,
40 mg/m² on days 1, 8, and 15, with cisplatin, 60 mg/m² on
day 1, every 28 days. Whether this combination will prove to be
superior to standard therapy for limited-disease patients awaits
further study.

Recently, however, a randomized phase III study in extensive-disease
patients compared cisplatin/irinotecan to the standard regimen of
cisplatin/etoposide.[45] The response rate was 89% with
cisplatin/irinotecan; 67% with cisplatin/etoposide. Median survival
and 1-year survival rate were 420 days and 60%, respectively, with
cisplatin/irinotecan; 300 days and 40% with cisplatin/etoposide. The
survival benefit was statistically significant (P = .0047;
log-rank test).

Irinotecan has also been combined with etoposide in the salvage
setting. Masuda et al[46] treated 25 patients with relapsed or
refractory small-cell carcinoma, all of whom had received prior
platinum-based combination chemotherapy. Treatment was administered
with G-CSF support. The major toxicities were myelosuppression and
diarrhea. This highly active regimen achieved a 71% response rate and
a median survival of 271 days.

Thus, the last several years have brought new chemotherapeutic agents
with novel mechanisms of action into the therapy of small-cell
carcinoma. Encouraging results obtained in both the salvage and
extensive-disease settings have paved the way for using these new
agents in the treatment of limited disease. The results of ongoing
trials exploring various ways of combining or sequencing these agents
with each other, with standard regimens, and with thoracic
irradiation are anxiously awaited.

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