Trial Information

A Pilot Study: Phase II Study of Histology-based Consolidation Chemotherapy Following Concurrent Chemo-radiotherapy for Inoperable Stage III Non-small Cell Lung Cancer

Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer related mortality in US
(1). About 22% of patients diagnosed with NSCLC have locally advanced or stage III disease
at the time of diagnosis (2). 5 years survival for stage III lung cancer is 23% which is
much less than survival in similar stage breast and Colon Cancers (2). Current standard of
care for inoperable stage III NSCLC is concurrent chemo-radiotherapy as established by a
study SWOG 9019 (3). Surgery following concurrent chemo-radiotherapy has been evaluated in a
large Phase III clinical trial in patients with Stage III (N2) disease which did not show
any improvement in overall survival from surgery as compared to concurrent
chemo-radiotherapy alone.(4). These two studies demonstrated that the most common site of
cancer relapse in patients with stage III disease was distant metastasis, 65% (3) and 57%
(4) respectively.

These observations have led to the idea that perhaps giving additional chemotherapy
following definitive concurrent chemo-radiotherapy may prevent distant relapse in stage III
NSCLC.

This idea was evaluated in a Phase II study SWOG S9504 in which patients with stage III
NSCLC were treated with concurrent chemo-radiotherapy followed by 4 cycles of docetaxel
consolidation (5). Four cycles of docetaxel consolidation showed an impressive improvement
in median OS to 26 months.

This idea of docetaxel consolidation was subsequently evaluated in a large phase III trial
in which patients inoperable stage III NSCLC after receiving concurrent chemo-radiotherapy
were randomized to docetaxel consolidation versus observation (6). However, this study
showed no improvement in OS between the docetaxel arm and the observation arm. Many patients
in docetaxel arm developed pneumonitis and febrile neutropenia.

Histology based selection of chemotherapy is now standard of for stage IV metastatic NSCLC.
A large randomized Phase III trial from Europe showed that a combination of Cisplatin and
Pemetrexed is more effective in patients with non-squamous histology and a combination of
Cisplatin and Gemcitabine showed efficacy in patients with squamous cell histology (7).
Recently maintenance Pemetrexed was evaluated in advanced NSCLC and showed improvement in
PFS and OS in patients with non-squamous histology (8). Similarly maintenance gemcitabine
has also been evaluated in large Phase III clinical trial after initial chemotherapy with
Cisplatin and Gemcitabine (9).

Since most patients with inoperable stage III NSCLC develop distant metastasis following
definitive concurrent chemo-radiotherapy there clearly is a need to give addition treatment
for these patients. Docetaxel consolidation has not been shown to be successful as noted
above. Perhaps tailoring chemotherapy according to histology may result in improvement in
PFS and OS in these patients.

Based on this hypothesis the investigators intend to do a pilot phase II study of histology
based consolidation chemotherapy in patients with inoperable stage III NSCLC following
concurrent chemo-radiotherapy. Patients with inoperable stage III NSCLC would be treated
with standard concurrent chemo-radiotherapy and subsequently those with non-squamous
histology would be offered 4 cycles of consolidation pemetrexed and those with squamous
histology 4 cycles of consolidation with gemcitabine.