Trimodality Therapy for Non–Small-Cell Lung Cancer

Trimodality Therapy for Non–Small-Cell Lung Cancer

ABSTRACT: Prospects for the multimodality treatment of non–small-cell lung cancer have improved substantially with the demonstration of fairly dramatic results, in terms of 5-year survival, in several phase III trials that employed neoadjuvant chemoradiotherapy prior to surgical resection in patients with locally advanced, resectable disease. Moreover, the combination of chemotherapy and radiation therapy has an established role in the treatment of unresectable stage III non–small-cell lung cancer. The history of the development of multimodality therapies will be reviewed and compared with postoperative adjuvant therapy. The role of trimodality therapy in patients with stage IIIB disease is discussed, along with future directions for improving the cure rates of advanced non–small-cell lung cancer. [ONCOLOGY 13(Suppl 5):101-106, 1999]


The role of neodajuvant chemotherapy in the
treatment of resectable stage IIIA non–small-cell lung cancer
was established in several trials. Rosell et al randomly allocated 60
patients with stage IIIA non–small-cell lung cancer to receive
either three cycles of chemotherapy followed by surgery and
postoperative mediastinal radiotherapy, or surgery followed by
radiotherapy.[1] At 3 years, there were no survivors in the surgery
plus radiotherapy group, but 30% of patients in the group treated
with neoadjuvant chemotherapy survived. The difference in median
survival (26 vs 8 months) was highly significant (P < .001).

Pass et al randomized 27 patients to receive either preoperative
chemotherapy, surgery, and postoperative chemotherapy or surgery and
postoperative mediastinal irradiation.[2] A trend toward increased
overall and median survival was observed in the group that received
chemotherapy, but at the time of the report, it had not yet reached
statistical significance (P = .095).

Finally, Roth et al studied a group of 60 patients who were staged
with mediastinoscopy and allocated to receive either six cycles of
perioperative chemotherapy and surgery or surgery alone.[3] The
estimated 3-year survival rate was 56% in the neoadjuvant
chemotherapy group compared to 15% for those who had surgery alone.
In an update of the results after a median follow-up of 82 months,
the survival increase in the perioperative chemotherapy group was
maintained.[4] Taken together, these trials found roughly a 30%
improvement in median survival when neoadjuvant chemotherapy was
combined with surgery.

These findings are in striking contrast to those obtained with
postoperative adjuvant chemotherapy. In general, chemotherapy given
after surgery has resulted in no survival benefit at 5 years in most
studies.[5-7] Some of these studies showed an increase in
recurrence-free survival that did not manifest as a prolongation of
overall survival. A few other studies showed a survival benefit,
although it was of relatively small magnitude.[8,9] Because of
persistent confusion about the benefits of postoperative
chemotherapy, a large meta-analysis of all available randomized
trials evaluating postoperative chemotherapy was conducted.[10] This
analysis suggested that chemotherapy given after surgery provided a
small benefit (approximately 5%) in long-term survival. In contrast,
the three trials described above identified an average improvement of
30% in long-term survival when chemotherapy was administered before surgery.

However, not all prospective trials have found a survival advantage
with the addition of neoadjuvant chemotherapy. The Cancer and
Leukemia Group B (CALGB) began a phase II comparison of “best
local-regional therapy” with or without neoadjuvant
chemotherapy. A total of 47 patients were randomized between the two
treatment arms. No difference in the rate of complete surgical
resection, failure-free survival, nor overall survival was
observed.[11] The study was ultimately closed because of an inability
to accrue patients. Nonetheless, it is important to realize that the
“standard” use of neoadjuvant chemotherapy is based on
studies involving fewer than 150 patients.

The remainder of this article will evaluate the available data on the
trimodality treatment of stage IIIA and IIIB non–small-cell lung
cancer, as well as developing data on the neoadjuvant treatment of
stage II lung cancer.

Surgery With or Without Radiotherapy for Stage
IIIA Disease

Before revision of the International System for Staging Lung Cancer
in 1997,[12] T3N0 lesions were considered stage IIIA
non–small-cell lung cancer. This review will include only those
results for patients with N2 disease. Table
summarizes the surgical results of representative large series
of patients with N2 nodal involvement who underwent resection.
Attention is drawn to the differences in survival for patients with
radiographic or clinically evident nodal involvement as opposed to
lesser nodal involvement identified only at surgery.

Martini and colleagues from Memorial Sloan-Kettering Cancer Center
(MSKCC, New York, NY) have collected the most extensive data.[13]
Their group operated on 404 patients with N2 disease, defined by
either radiographic or pathologic criteria (these patients rarely had
mediastinoscopy). Most of their patients also received postoperative
radiotherapy. Overall, the 5-year survival rate was 30%. For patients
with radiographically detectable N2 disease, the 5-year survival rate
was only 9%.

In contrast to MSKCC, Pearson and colleagues from Toronto performed
mediastinoscopy on 141 patients and demonstrated N2 nodal
disease.[14] For patients who had enlarged nodes visible on chest
x-ray and underwent resection, the survival rate at 5 years was 9%.
The survival rate was 24% after surgery in patients whose mediastinal
nodes were found to be involved at mediastinoscopy or at resection.
In another study, Mountain found 5-year survival rates of 39% for
patients with N2 squamous cell carcinoma and 14% for patients with N2
adenocarcinoma who had resection.[15] Most series show long-term
survival between 8% and 20% in patients who successfully undergo
surgical resection.[16]

Surgical Resection and Radiotherapy for N2 Disease

Adding radiotherapy, either adjuvant or neoadjuvant, to surgery adds
little to the results observed with surgery alone. In a large
Veteran’s Administration study, radiotherapy given after surgery
actually decreased long-term survival.[17] Kirsh et al found 5-year
survival rates of 30% for squamous cell carcinoma and 13% for
adenocarcinoma in patients who were resected and treated with
postoperative radiotherapy.[18] Warram studied preoperative
radiotherapy, treating patients with radiographically involved
mediastinal nodes with radiotherapy and then randomizing them to
surgery or observation.[19] Survival at 5 years was 8% for the
resected group and 6% for the radiotherapy-alone group.

In another study, patients who were resected and received
postoperative radiotherapy had a survival rate at 5 years of 11%.[20]
At the Dana Farber Cancer Institute (Boston, MA), Sherman et al found
a 5-year survival rate of 18% when patients received preoperative
irradiation followed by thoracotomy.[21] The survival rate of all
resectable patients was 27%. Hilaris et al obtained a 5-year survival
rate of 22% by combining aggressive resection with intraoperative
brachytherapy and postoperative external radiotherapy.[22] Finally, a
recent large meta-analysis of randomized trials evaluating
postoperative radiotherapy found a 21% increase in the relative risk
of dying that was greatest for patients with N0 or N1 disease.[23]
There was no demonstrable benefit of postoperative radiotherapy for
patients with stage IIIA non–small-cell lung cancer, including
those with N2 disease.

Chemotherapy and Radiotherapy in
Unresectable Stage III Disease

While the role of chemotherapy in stage IV non–small-cell lung
cancer has only recently been established, the combination of
chemotherapy and radiotherapy has an established role in the
treatment of unresectable stage III disease based on the results of
large randomized studies (Table 2).
Fram et al studied six cycles of CAP (cyclophosphamide, doxorubicin
[Adriamycin], and cisplatin [Platinol]) chemotherapy and 57 Gy
radiation in patients with histologically proven N2 disease.[24] The
group found a response rate of 66% and a median survival of 9 months;
there were no 5-year survivors. Dillman et al for CALGB reported a
significant improvement in long-term survival when patients with
stage IIIA disease were treated with the combination of chemotherapy
(cisplatin and vinblastine [Velban]) and radiotherapy (60 Gy)
compared with radiotherapy alone.[25] Median survival improved from
9.6 to 13.7 months (P = .012) and the 5-year survival rate improved
from 6% to 17% with the combination of chemotherapy and radiotherapy.[26]

These data were confirmed in subsequent studies.[27-29] Thus,
combined- modality therapy, whether sequential chemotherapy and
radiotherapy or concurrent radiotherapy and radiosensitizing
chemotherapy, is now the standard of care for patients with
unresectable stage III non–small-cell lung cancer, yielding
3-year survival rates between 0% and 23%.


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