State of the Art - Cleveland Clinic

State of the Art 1177
The role of induction therapy has been addressed only in Most of the patients in the earlier studies, particularly the Phase
RCTs for early-stage or minimal N2 disease (negative CT of II studies, would have been fitter, more motivated, often
the mediastinum with either no or minimal N2 involvement at younger, with minimal comorbidity compared with the average
mediastinoscopy). These patients would be eligible for surgery patient currently undergoing routine resection for lung cancer.
alone, and have less bulky disease than those in the Phase II studies We may never have a clear picture of the real value of neoadju-
described above. The five studies are summarized in Table 3. The vant treatment, or for which cell type or disease stage it may
two positive studies by Roth and coworkers (156, 168) and Rosell have a clear-cut benefit compared with surgery alone.
and coworkers (157, 169) closed early because of disparity in
survival between the two arms, a statistical hazard when applying Adjuvant Chemotherapy and Surgery
early closure rules to small studies. However, the median survival The place of chemotherapy after surgery is likely to emerge
differences have become smaller at 5 years (0 versus 17% in the clearly within the next 2 to 3 years. In 1995, the NSCLC Collabostudy
by Rosell and coworkers, and 15 versus 36% for Roth and rative Group meta-analysis (170) reported 14 trials (4,357 pacoworkers),
although still clearly favorable for the combined tients) in which patients were randomized to receive or not
modality treatment. These studies have been criticized because receive chemotherapy after surgery. Five trials used long-term
the surgery-alone arms have fared badly, particularly in the study alkylating agents and showed a significant disadvantage for the
by Rosell and coworkers, in which there was a higher rate of addition of chemotherapy (HR, 1.15; confidence interval [CI],
tumor K-ras mutation and DNA aneuploidy, which are indica- 1.04–1.27). Eight studies incorporated cisplatin, at a relatively
tors of poor prognosis, than in the chemotherapy arm. low dose (40–80 mg/m2 ). The HR for the eight cisplatin-con-
The much larger French study just published (155) included taining regimens was 0.87 (CI, 0.74–1.02) and the absolute benefit
355 patients with clinical Stage I (except T1N0), II, and IIIA for chemotherapy was 3% at 2 years and 5% at 5 years. The metadisease
randomized to surgery or two courses of MIC followed by analysis did not derive a significant advantage for the addition of
surgery with an option for two further courses postoperatively. chemotherapy after surgery (p 0.08) and, therefore, several
Patients with T3 and N2 disease received postoperative irradia- studies are now in progress, or have recently completed, that
tion. A pathologic CR was seen in 11% of patients receiving will be expected to answer this question, either as a single study
neoadjuvant chemotherapy, but the survival data for the entire or, more probably, as a new meta-analysis. These studies include
study were not significantly different at 3 years (p 0.15; the International Adjuvant Lung Cancer Trial (IALT), which
Table 3). There was no difference in the postoperative mortality randomizes completely resected patients to three or four cycles
rates: 6.7% in the chemotherapy arm and 4.5% in the surgery- of cisplatin-based chemotherapy after surgery, or to no further
only arm. The median survival was 37 months with neoadjuvant treatment; the Adjuvant Lung Project, Italy, which also randomchemotherapy
and 26 months with surgery alone. There was a izes completely resected patients to cisplatin, mitomycin, and
significant survival advantage with neoadjuvant chemotherapy vindesine for three cycles or to control. The National Cancer
for patients with N0 and N1 disease, but not for those with N2 Institute of Canada is randomizing patients with completely redisease.
It is suggestive, therefore, that there may be an added sected Stage IB and II disease to observation or treatment with
advantage for chemotherapy for survival with Stage I and II cisplatin and vinorelbine. The North American Cancer and Leu-
NSCLC. However, there was no evidence of added benefit with kemia Group B is using carboplatin plus paclitaxel versus control
chemotherapy for Stage IIIA disease. in completely resected Stage IB NSCLC. The Big Lung Trial in
Thus, valuable information is emerging to define the role of the UK will contribute about 400 patients randomized to control
neoadjuvant chemotherapy in patients with resectable disease. or to one of four cisplatin-containing regimens after surgery.
This population of NSCLC patients includes those most likely Together, these studies will accrue in excess of 5,000 patients
to respond to chemotherapy (good performance status, small- and should clarify whether the precise role of adjuvant chemovolume
disease, and normal biochemical values) and, clearly, a therapy is after surgery in NSCLC.
small percentage improvement in overall survival data as a result
of adding chemotherapy to surgery would affect a large number Chemotherapy and Radiotherapy in Locally Advanced Disease
of patients with this common disease and would be an important With the lack of any clear advantage for adjuvant chemotherapy
step forward. or PORT in resected N2 lung cancer, the possible benefits of
There are other studies in progress to assess this question. combining chemotherapy with radiotherapy after resection have
The UK MRC LU22 study is a pragmatic study of randomization been studied. The logic is that radiotherapy decreases local rates
to neoadjuvant chemotherapy, which is open to any patients of recurrence and chemotherapy may both add to this and treat
deemed operable. However, patient refusal was high in a pilot distant occult disease. There have been four randomized confeasibility
study (162) and some surgeons are reluctant to enter trolled trials of surgery plus adjuvant chemotherapy–irradiation
patients because of the risks of tumor progression during chemo- versus surgery and radiation alone (131, 171–173).
therapy and belief that there are risks of increased perioperative All these studies failed to show an advantage in overall surmorbidity,
making recruitment slow. vival, with the most recent failing to demonstrate any improve-
The other question, concerning whether neoadjuvant treat- ment in disease-free survival or overall survival with the addition
ment is of value in downstaging locally advanced inoperable of chemotherapy to radiotherapy (131).
disease, appears more difficult to resolve. RCTs are in progress The median survival of patients with locally advanced, inoperin
which patients with bulky N2 disease, after induction chemo- able NSCLC after radical radiotherapy is about 12 months. Both
therapy or chemotherapy–radiotherapy, are randomized to sur- local and distant recurrence rates are high, explaining the logic
gery or completion radiotherapy or radical radiotherapy. These of adding chemotherapy to radiotherapy to treat not only the
studies hope to recruit about 500 patients each and are prog- primary tumor but distant micrometastatic disease as well. There
ressing slowly. have been many studies addressing this issue (174–180), with
Although neoadjuvant chemotherapy appears to be widely either no benefit or a small benefit for the combined treatment.
practiced outside clinical trials in some countries, the data for The meta-analysis by the NSCLC Collaborative Group of indiimproved
survival are more tenuous than for almost any other vidual data from all 22 RCTs in which patients were randomized
treatment policy in the management of lung cancer, and these to radiation alone or chemotherapy and radiotherapy (170) in-
studies appear to have particular difficulty in recruiting patients.
cluded 3,033 patients. There were two groups: older studies using