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MARTINS, REYNOLDS, AND RIELY
Beyond “Second-Line” in Non–Small Cell Lung Cancer: Therapy
and Supportive Care
Renato G. Martins, MD, Craig H. Reynolds, MD, and Gregory J. Riely, MD, PhD
OVERVIEW
Although there once was a single algorithm for the treatment of patients with advanced lung cancer, the modern treatment of advanced
lung cancer has multiple treatment pathways that depend on multiple factors, including histology and molecular subtype of disease.
New molecular targets, targeted agents, and modes of therapy for patients, including immunotherapy, are being identified at an
accelerating pace. These advances are changing outcomes and the treatment landscape, but they also highlight situations with
inadequate data to support the use of cytotoxic chemotherapy. In this article, we provide an overview of data regarding cytotoxic
chemotherapy and targeted therapy and their value after second line, review the critical role of supportive care and palliative care,
and emphasize the importance of advance care planning with our patients. Although this article focuses primarily on NSCLC, the
comments about palliative care and advanced care planning also apply to patients with small cell lung cancer.
Although there once was a single algorithm for the treatment
of patients with advanced lung cancer, the modern
treatment of advanced non–small cell lung cancer
(NSCLC) has multiple treatment pathways that depend on
many factors including histology and molecular subtype of
disease. In addition, new molecular targets, targeted agents,
and modes of therapy, including immunotherapy, are being
identifıed at an accelerating pace. These advances are changing
outcomes and the treatment landscape, but the rapid
introduction of many new therapies may be somewhat bewildering
for the practicing oncologist. In this context, a discussion
of therapy’s role beyond second line is outdated.
However, more relevant than ever is the medical oncologist’s
role in advocating for patients to have access to these advances,
discerning the patient’s care goals, and sparing them
from the toxicities of unproven therapies. 1 This article will
review critical factors for decision making in this changing
treatment environment.
THE ROLE OF CHEMOTHERAPY IN THIRD-LINE AND
BEYOND
Unlike the data establishing the role of docetaxel in the
second-line treatment of advanced NSCLC, 2 there are no
randomized trials evaluating chemotherapy in the third- and
fourth-line treatment of advanced NSCLC. There are multiple
single-institution and retrospective analyses (selected
data is presented in Table 1). The results of chemotherapy in
the third and fourth line are strikingly variable across these
studies. This may reflect different patient characteristics or
underlying tumor biology. Results from Asia—which are
generally more favorable than those from the West—are consistent
with previous observations that Asians have a better
prognosis. There clearly is some heterogeneity in progressive
lung cancer, and some patients will respond better than others
to further treatment. There is a suggestion that response
to previous treatment and continued good performance status
are predictors of benefıt from third- and fourth-line chemotherapy,
but these conclusions must be viewed with
caution given the absence of randomized data.
TARGETED THERAPIES FOR PATIENTS WITH A
TARGET
Today broad molecular profıling is the standard of care for
patients with lung adenocarcinomas, 3 and the identifıcation
of actionable molecular targets in squamous NSCLC is an
area of active investigation. 4 Furthermore, the number of effective
therapies has expanded. As an example, for patients
with ALK-positive lung cancers, four lines of therapy have
shown meaningful clinical benefıt (two “targeted” and two
“conventional”). Survival for some molecular subtypes of
NSCLC is now measured in years rather than weeks.
Although evidence supporting the use of third- and fourthline
standard cytotoxic chemotherapy is largely retrospective
and of poor quality, prospective data support the use of targeted
therapies in patients with defıned molecular targets,
even when patients have had multiple prior lines of therapy.
From Seattle Cancer Care Alliance, University of Washington, Seattle, WA; US Oncology Research, Ocala, FL; Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Craig Reynolds, MD, US Oncology Research, 433 SW 10th St., Ocala, FL; email: craig.reynolds@usoncology.com.
© 2015 by American Society of Clinical Oncology.
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