Patients with non-small-cell lung cancer (NSCLC) represent an extremely
heterogeneous group with respect to several factors, including age, gender,
performance status, histologic type, stage, presence of other major comorbid
conditions, and degree of enthusiasm about therapy. It is necessary to
evaluate all these factors and to appreciate the most recent treatment
data before a management plan is recommended for an individual patient.
With regard to curability, we define potentially curable NSCLC patients
as those surgically/pathologically staged patients with stage I and II
disease and a small minority (about 15% of the entire group) of stage IIIA
patients, a group that will be more specifically defined later in this
Historically, treatment of stages I, II, and certain subsets of stage
IIIA NSCLC has consisted of surgical resection.[1-4] The majority of patients
with stages IIIA and IIIB disease are not resectable and have been treated
with radiation therapy [5-7]; patients with stage IV disease generally
have received either symptomatic care alone or various types of chemotherapy.
The idea of combined-modality therapy for various subsets of patients
is not new. The rationale has been present for many years and is based
on the fact that micrometastases are usually present at the time of diagnosis,
except in patients with stage I disease. We will review the current status
of combined-modality therapy for patients with potentially curable NSCLC.
Risk of Micrometastasis
Assessment of the risk of micrometastasis in patients with NSCLC is
similar in many ways to risk assessment in patients with breast carcinoma.
The size of the primary lesion and the presence, number, size, and location
of local nodal metastases are fairly accurate predictors of the presence
of other distant micrometastatic tumors. Adequate surgical-pathologic staging
for carcinoma of the breast includes removal of the primary tumor and axillary
nodes. This is equally true for patients with NSCLC, but hilar and mediastinal
node sampling or dissection has been practiced less rigorously and with
little enthusiasm by many thoracic surgeons, in no small part due to the
questionable therapeutic value of these procedures and the poor or ineffective
systemic therapy available.
Accurate final staging and therapy for patients with clinical stages
I and II disease (no enlarged nodes seen in the mediastinum on chest radiograph
and CT scan) usually require thoracotomy with complete excision of all
known tumor either by lobectomy or pneumonectomy with concomitant extensive
node sampling or, ideally, a complete node dissection to identify N1, N2,
or N3 disease. These surgical-pathologic data provide an accurate assessment
of the degree of risk for distant micrometastatic tumors and, therefore,
accurate staging and classification of patients. The success of curative
resection can be predicted from these data, and potential candidates for
adjuvant therapy can be identified.
The majority of patients do not present with clinical stages I and II
disease, but rather, have either clinical stage III (enlarged nodes in
the mediastinum on chest radiograph or CT scan) or stage IV disease. Patients
with stage III disease are a heterogeneous group. Histologic documentation
of N2 or N3 disease (stage IIIB) is desirable and can be performed by transbronchial
biopsy, fine-needle aspiration, mediastinoscopy, or mediastinotomy before
definitive therapy is planned. Occasionally, it is necessary to perform
staging and therapy (resection) at the same time during thoracotomy.
Disease Classification by Prognosis
There are several distinct groups or subsets of patients with stage
IIIA disease. It has been recognized for years that patients with chest
wall involvement, parietal pleural involvement, and superior sulcus tumors
without local node involvement (T3 N0) are potentially curable with resection
(about 30% to 40%). Involvement of N1 nodes decreases the cure rate to
approximately 15%, and involvement of N2 nodes makes cure unlikely following
Furthermore, the amount of ipsilateral mediastinal node involvement
is an important determinant of prognosis following resection. Patients
with either clinical stages I or II disease (normal mediastinum on chest
radiograph, CT scan, and/or preoperative biopsy) who are found to have
minimal N2 disease (stage IIIA) at either thoracotomy (microscopic involvement
of one node station/level) or by preoperative biopsy have curative potential
(about 15% to 30%) after surgical resection. In contrast, patients with
bulky N2 disease ( 2 cm or more nodes in several node stations or levels)
cannot be cured, even after radical resection. Patients with smaller amounts
or nonbulky but multiple N2 disease (ranging from mi- croscopic involvement
of multiple node levels to macroscopic involvement 2 cm or less) have a
small chance of cure following resection, with or without postoperative
radiation therapy (about 5% to 10%). The T-status is also important; considering
the same N status, patients with T2 and T3 lesions are cured less often
than are patients with T1 lesions.
Subsets of Stage IIIA Disease--Given the variable possibility
of cure following surgical resection, with or without radiation therapy,
for patients with stage IIIA disease, and the evolving data favoring multimodality
therapy, it is now reasonable to divide these patients into several subsets.
This division is particularly appropriate for planning and evaluating multidisciplinary
therapy. Precise staging is necessary to design and interpret clinical
trials. In addition, knowledge of these data allows for a more logical
decision regarding management for these patients.
We propose a division of patients with stage IIIA disease as outlined
in Table 1 (subsets IIIA1-IIIA7). This
definition was proposed, in part, by Ruckdeschel and associates. These
subsets are listed in order from the best to worst prognosis (following
surgical resection and/or definitive radiation therapy). It appears that
the outcome of multimodality therapy differs among patients in these subsets
of stage IIIA disease, making their distinction relevant both prognostically
Although stage IIIB disease is not included here, groups of patients
with stage IIIB disease appear to have a similar prognosis to that of patients
in the worst subsets of stage IIIA disease. These patients with stage IIIB
disease include some with T4 N0 disease, as well as those with mediastinal
and/or hilar N3 disease only (without pleural/pericardial effusions or
supraclavicular node involvement). These patients are also candidates for
Even patients in the most favorable subsets with stage IIIA (IIIA1-IIIA4)
disease have distant micrometastases nearly 60% to 90% of the time. Nearly
all patients with stage IIIA disease with either bulky ( 2 cm or less)
multiple levels of N2 (IIIA5, IIIA7) or T3 N2 (IIIA6) involvement have
distant micrometastasis, and the prospect of curative resection or radiation
therapy is very unlikely. These patients are common, representing the largest
subgroups of patients with stage IIIA disease. Therefore, from a historical
perspective, patients with potentially curable NSCLC represent those patients
with surgical-pathologic staged I and II disease (approximately 75% and
50% cure rates) and the small minority (nearly 15% of the entire group)
of patients with substages IIIA1-IIIA4 disease (cure rates of 5% to 40%).
When considering multimodality therapy, it is essential to define the
patient population and prognosis. Furthermore, the performance status and
physiologic status of the heart, lungs, liver, and kidneys are important
considerations. Medically inoperable patients generally are not candidates
for multimodality therapy. With a few exceptions, nearly all the clinical
multimodality trials have included patients with bulky, unresectable stage
IIIA (N2) or IIIB disease (mediastinal and/or hilar N3 involvement) easily
seen on plain radiographs or CT scans of the chest. In our opinion, the
results observed in several recent trials with these patients are also
applicable to patients who have surgically resectable, potentially curable
Chemotherapy is now the preferred therapy for ambulatory patients with
stage IV disease. Once systemic therapy is "effective," it will
also serve as the primary therapy for the majority of patients with stages
IB, II, and III disease. Local therapy will then be "adjuvant therapy."
Chemotherapy has developed slowly for NSCLC; many agents active against
several other neoplasms have been ineffective in treating NSCLC. We refer
to the era of single-agent and combination chemotherapy before the development
of cisplatin (Platinol) (1965-1980) as first-generation chemotherapy (Table
2). First-generation chemotherapy was essentially inactive against
NSCLC, with no effect on the survival of patients with stage IV disease
and no apparent additive effect when combined with surgery or radiation
therapy for patients with stage III disease.
Cisplatin became the cornerstone of second-generation chemotherapy (1981-1992).
When used usually in combination with other agents, it was capable of prolonging
survival, as well as often providing useful palliation for patients with
stage IV disease who had a good performance status. The less toxic platinum
analog, carboplatin (Paraplatin), has proven to be as useful as, if not
more useful than, cisplatin. Cisplatin-based therapy has also prolonged
the survival of patients with stage III disease when used in concert with
sequential and probably concurrent radiotherapy. Preoperative chemotherapy
for patients with resectable stage III disease also looks more promising
than resection alone.
The present era (1993-?) of third-generation chemotherapy has essentially
just begun with the evaluation of several new, relatively active single
agents, including paclitaxel (Taxol), vinorelbine (Navelbine), docetaxel
(Taxotere), irinotecan (Camptosar), gemcitabine (Gemzar), and topotecan
(Hycamtin). These agents are rapidly being tested both as single agents[9-18]
and in various combinations with other drugs, including cisplatin, carboplatin,
and etoposide (Etopophos, VePesid) (Table
3).[19-40] Other phase II studies have also evaluated many of these
new agents in concert with radiation therapy.[34-36] Although paclitaxel
has demonstrated only about a 20% to 25% objective response rate, it has
consistently been associated with a 1-year survival rate of 35% to 40%,
which is superior to that of other single agents and most combinations
for patients with stage IV disease.
Recently, a large, randomized comparison of paclitaxel and cisplatin
has shown them to be superior to standard cisplatin and etoposide.
These results are particularly impressive in light of the prolonged survival.
Several series also have studied paclitaxel and carboplatin, and findings
have shown quite impressive 1-year survival rates, in addition to response
rates ranging from nearly 30% to 60%.[16-21] The Cancer and Leukemia Group
B (CALGB) is currently comparing paclitaxel plus carboplatin vs paclitaxel
alone. A randomized comparison performed by the Southwest Oncology Group
(SWOG) has shown the superiority of cisplatin and vinorelbine over cisplatin
alone. The current SWOG trial is comparing paclitaxel and carboplatin
vs cisplatin and vinorelbine. The Eastern Cooperative Oncology Group (ECOG)
has prepared a four-arm study of patients with stage IV disease; the regimens
being compared are paclitaxel/carboplatin, paclitaxel/cisplatin, docetaxel/cisplatin,
With these recent encouraging findings, additional refinements are likely
to continue. The combined-modality therapies reported with second-generation
chemotherapy for patients with stage III disease (see Table
4, Table 5, and Table
6) and the current ongoing trials must be interpreted in light of the
evolving and improved third-generation chemotherapy. Based on the results
seen with these newer, active third-generation combinations, a case can
be made for their immediate incorporation into combined-modality programs
for patients with stages II and III disease.
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