Advances in treatment of
non-small-cell lung cancer
(NSCLC) and other
lung cancers over the
past year include demonstration
of the benefit
of adjuvant chemotherapy
in early NSCLC; new
indications for a number
agents and molecular
targeted agents; and continued progress not only
in efforts to identify early-stage disease through imaging,
but also in determining optimal use of targeted
for Early-Stage NSCLC
Two phase III trials reported last year have demonstrated
a significant benefit of adjuvant chemotherapy
in early-stage NSCLC, suggesting a new standard
of treatment. In the Cancer and Leukemia Group B
9633 trial (CALGB 9633), 344 patients with stage IB
NSCLC were randomized to paclitaxel (Taxol)/
carboplatin (Paraplatin) or no further treatment after
complete surgical resection (see report on page 5).
Adjuvant chemotherapy was associated with significant
38% and 49% reductions in risk for 4-year allcause
mortality and lung cancer mortality, respectively.
Chemotherapy was well tolerated; grade 3 or 4
neutropenia occurred in 36% of patients.
In the Canadian JBR.10 trial, 482 patients with
completely resected stage I or II disease were randomized
to adjuvant vinorelbine (Navelbine)/cisplatin
(Platinol) or observation (see report on page 6).
Adjuvant therapy was associated with a significant
30% reduction in risk for death over 5 years and a
significant prolongation of median overall survival (94 vs 73 months). Adjuvant therapy was well tolerated
in this trial, as well.
The U.S. Food and Drug Administration (FDA) approved
Tarceva (erlotinib) as treatment for patients
with locally advanced or metastatic NSCLC whose
disease has continued to progress despite other therapies,
including at least one prior chemotherapy regimen
(see report on page 5). In a phase III doubleblinded,
placebo-controlled trial in 731 patients from
17 countries, erlotinib treatment significantly improved
overall survival, progression-free survival, and tumor
response rate compared with placebo. Epidermal
growth factor receptor (EGFR) status was not part of
the study protocol, but was looked at retrospectively.
Among patients with known EGFR status, erlotinib
significantly improved overall survival in EGFR-positive
patients but did not appear to improve survival in
EGFR-negative patients. Adverse events were primarily
rash and diarrhea.
Interestingly, a significant survival benefit with
erlotinib treatment was seen in EGFR-positive patients
who had never smoked. While survival benefit was
seen in all groups, it was especially high in neversmokers.
The finding of survival benefit in never-smokers
was also made in a subset analysis
of the TRIBUTE trial of erlotinib in NSCLC; neversmokers
tended to be younger and female and to
have adenocarcinoma (see report on page 7).
Molecular studies indicate that patients who are neversmokers
have more mutations in the EGFR tyrosine
kinase domain and that such mutations may confer
sensitivity to treatment with EGFR inhibitors. A more
definitive analysis of this will await the final analysis of
the BR21 trial.
Other molecular studies have indicated that mutations
in the EGFR tyrosine kinase are significantly
associated with response to the EGFR inhibitor gefitinib
(Iressa), raising the possibility of screening for mutations
that can identify patients likely to benefit from
treatment (see report on page 8). Similar mutations
affect the response to erlotinib. In the meantime, the
post-accelerated approval clinical trial of gefitinib in
lung cancer patients failed to show survival benefit vs
placebo, despite an improved objective response rate;
AstraZeneca has cautioned patients currently taking
gefitinib to contact their physicians but to continue
taking the agent (see report on page 10).
EGFR inhibitors clearly provide benefit in some
patients, and it has become a major initiative to
identify markers that predict such benefit.
New Drug Findings and Approvals
The FDA approved Alimta (pemetrexed) for use in
combination with cisplatin in patients with malignant
pleural mesothelioma who are not candidates for curative
surgery, making this drug the first to be approved
in the treatment of this disease (see report on page
19). In a randomized, single-blind trial in 448 chemotherapy-
naive patients, pemetrexed plus cisplatin improved
median survival by 30% compared with cisplatin
alone (12.1 vs 9.3 months); 1-year survival was 50.3% vs 38%. It is now recognized that pemetrexed must be
given with folic acid and vitamin B12 supplementation;
among patients receiving supplementation throughout
the study, median survival was 13.3 months in the
pemetrexed group and 10.0 months in the cisplatinalone
group. Hematologic toxicity was more common
in patients receiving pemetrexed.
Pemetrexed has also been given accelerated approval
by the FDA for single-agent treatment of locally
advanced or metastatic NSCLC in previously treated
patients (see report on page 12). Approval was based
on a randomized, unblinded trial in 571 patients receiving
second-line treatment with pemetrexed plus vitamin
supplementation or docetaxel. In an as-treated analysis,
there were no significant differences between the Alimta
and docetaxel (Taxotere) groups with regard to response
rate (9.1% vs 8.8%) or stable disease (45.8% vs
46.4%) or rates of on-study death or drug-related death.
Pemetrexed treatment was associated with significant
reductions in a number of toxicities, including neutropenia,
diarrhea, and alopecia.
In other studies in NSCLC, an Italian phase II trial of
pemetrexed plus either carboplatin or oxaliplatin (Eloxatin)
showed good response rates and favorable toxicity profiles
for the combinations in chemotherapy-naive patients
with unresectable locally advanced or metastatic NSCLC
(see report on page 14). Response rates were 31.6% in
the pemetrexed/carboplatin arm and 26.8% in the
pemetrexed/oxaliplatin arm, and median survival was
10.5 months in both arms. Hematologic toxicities were
more common with pemetrexed/carboplatin.
Nonhematologic toxicities were minimal.
Investigation of inhalational therapy for lung cancer
continues (see reports on page 16). The Sustained
release Lipid Inhalation Targeting technology, or SLIT,
developed to improve injectable or inhaled products
by producing a targeted, prolonged effect that can
reduce systemic and local toxicity and permit dose
reduction, has been examined in a phase I study using
cisplatin. No dose-limiting toxicity was observed in the
study participants up to a maximum inhaled liposomal
dose of 48 mg/m2 every 2 weeks or 24 mg/m2 every
week. Preclinical studies using inhalational p53 indicate
reduced tumor growth and longer survival in
Screening and Treatment Planning
The National Lung Screening Trial has completed
enrollment of 50,000 smokers or former smokers,
who will be assessed to determine whether spiral
computed tomography (CT) or chest x-ray to detect
cancer prior to onset of symptoms can improve treatment
outcome and reduce mortality (see page 20).
The Early Lung Cancer Action Program (ELCAP)
has tested CT screening over the last decade and has
reported substantially improved cure rates when cancers
are detected early. CT is capable of identifying
tumors of much smaller size than are x-rays. Most
recently, the technique of volume CT has been
examined, which represents an improvement in resolution
over that achieved with spiral or helical CT. Of
cancers detected since 1993 in ELCAP, 80% were
stage I disease, a marked improvement in diagnosis
at this early stage compared with usual care, and the
8-year case fatality rate for all patients undergoing
resection was 4%.
Researchers in Germany found that fused positron
emission tomography (PET)/CT scanning was more
accurate in defining TNM stage in NSCLC than PET
alone, CT alone, or side-by-side PET and CT images.
Fused PET/CT resulted in modification of surgical
treatment plans in a substantial proportion of patients
compared with the other imaging approaches.
Gated 4D PET/CT scanning has been shown to
improve detection of tumor motion during respiration,
permitting determination of which patients may require
respiration-gated radiation therapy and improving
the accuracy of radiation treatment.
A working group of the National Cancer Institute
(NCI) released "Women, Tobacco, and Cancer:
An Agenda for the 21st Century," a series of recommendations aimed at stimulating scientific research
into tobacco-related cancers in women and developing
evidence-based interventions to prevent the cancers
worldwide (see page 23).
The American Society of Clinical Oncology is
setting up a commission comprising representatives
from government, educational and scientific organizations,
advocacy groups, and the private sector to
assess tobacco-related social, medical, legal, and economic
The National Institutes of Health is funding seven
new centers participating in the NCI's Transdisciplinary
Tobacco Use Research Center program, designed to
improve understanding of tobacco-related diseases and
their control, as well as psychosocial factors that influence
In less hopeful news, a House-Senate conference
committee dropped a provision that would have given
the FDA regulatory powers over tobacco products, a
provision the Senate had passed by a large margin as
part of the 2004 Foreign Sales Corporation tax cut bill.
Taken together, however, the research developments
of the past year have been quite promising on several
fronts, in terms of improvements in screening, diagnosis,
staging, and treatment, and 2005 will likely
continue to see further refinement in our understanding
of how to optimize management of our patients with
lung cancer through these state-of-the-art technologies
and therapies. In all, 2004 was a very good year for
lung cancer research.
Roy S. Herbst, MD, PhD
Associate Professor of Medicine
Chief, Section of Thoracic Medical Oncology
Department of Thoracic/
Head and Neck Medical Oncology
University of Texas M. D. Anderson Cancer Center