NcXHF

SQUAMOUS, SMALL CELL, AND RARE LUNG CANCERS
SIDEBAR 4. Large Cell Neuroendocrine Variants
Large Cell Neuroendocrine Carcinoma: Tumor with histopathologic features of neuroendocrine tumor (e.g., trabecular pattern [ribbons of
malignant cells], rosettes) and tumor cells showing positive staining for neuroendocrine marker
Large Cell Carcinoma with Neuroendocrine Morphology or Pattern: Tumor with histopathologic features of neuroendocrine tumor but
lacking positive staining for neuroendocrine markers
Large Cell Carcinoma with Neuroendocrine Differentiation: Tumor does not have histopathologic features of neuroendocrine carcinoma but
stains positive with neuroendocrine marker
subgroup analysis of the 44 patients with bronchial carcinoid
(33 received everolimus plus octreotide; 11 received placebo
plus octreotide), median PFS was 13.6 months versus 5.6
months. 131 Almost 50% of patients treated with everolimus
had grade 3 or 4 adverse events (most commonly diarrhea,
stomatitis, and thrombocytopenia). In the ongoing follow-up
LUNA trial, 120 patients with lung or thymus NETs will be
randomly assigned to pasireotide (a long-acting somatostatin
receptor analog), 10 mg everolimus daily, or the combination.
In a phase II trial of the multitargeted kinase inhibitor
sunitinib enrolling 41 patients with metastatic NETs (of
whom 14 had foregut [lung or stomach] primary tumors),
the response rate was 2%, and 83% achieved SD. 132
Interferon alpha has demonstrated antitumor effects in advanced
carcinoid, but is usually not administered until failure
of somatostatin analogs because of adverse effects. 133-135 Radiolabeled
somatostatin analogs remain investigational but
trials have yielded encouraging initial fındings. 136-139 In a
phase II open-label trial, 1,109 patients with NETs (of whom
84 had bronchial carcinoid and 12 had SCLC) received 2,472
cycles of the somatostatin-based radiopeptide 90-yttriumlabeled
tetraazacyclododecane-tetraacetic acid modifıed
Tyr-octreotide ([ 90 Y-DOTA]-TOC). 136 Patients were required
to have visible tumor uptake on baseline SRS. The radiographic
response rate was 34%, 15% had biochemical
response, and 30% had improved symptoms related to the
hormonal syndrome. Notably, 9% of patients experienced
permanent grade 4 to 5 renal toxicity. Tumoral uptake on
baseline SRS predicted OS whereas initial kidney uptake
predicted severe renal toxicity. Hepatic-directed therapies
(surgery, radiofrequency ablation, arterial embolization,
chemoembolization, radioembolization) 140-143 may be associated
with prolonged survival if control of extrahepatic disease
is achieved. Prophylactic octreotide to prevent carcinoid
crisis during such procedures may be considered.
Large Cell Tumors
Historically, large cell tumors were considered to be NSCLCs
that lacked diagnostic features of small cell, adenocarcinoma,
or squamous cell tumors by light microscopy. With increasing
use of IHC to distinguish among histologic subtypes, the
proportion of cases designated large cell has decreased in
recent years and currently represents fewer than 5% of
NSCLCs. The large cell cancer category includes large cell
neuroendocrine cancer (LCNEC). Whether LCNEC should
be treated similarly to other NSCLC types or according to
small cell paradigms has been a subject of ongoing debate. 144
Although the National Comprehensive Cancer Network recommends
treating LCNECs as NSCLC, some experts group
and treat them as high-grade NETs together with SCLC. 145
Consistent with this approach, some SCLC clinical trials enroll
cases of large cell neuroendocrine tumors. Further complicating
these considerations is the nuanced and fluctuating
terminology describing these diseases (Sidebar 4). Retrospective
evidence supporting a SCLC-type approach to large cell
neuroendocrine tumors includes the following: (1) poor
prognosis, even for resected stage I tumors (33% 5-year survival)
145 ; (2) improved survival with adjuvant platinum/etoposide
compared to platinum with gemcitabine, vinorelbine,
or paclitaxel (44 months vs. 11 months; p 0.001) 146 ; (3)
substantially improved outcomes with adjuvant cisplatin/
etoposide versus historic controls (5-year disease-free survival
87% vs. 35%; 5-year OS 89% vs. 47%) 147 ; (4) rates of
brain metastases similar to those seen in SCLC 148 ; and (5)
gene expression and molecular profıling indistinguishable
from SCLC but clearly demarcated from other large cell tumors,
lung adenocarcinoma, and well-differentiated bronchial
NETs. 149-151 A proposed SCLC-based approach for
large cell neuroendocrine cancers includes (1) up to 4 cycles
of platinum/etoposide adjuvant chemotherapy for all resected
patients, (2) chemoradiation (up to 4 courses of platinum/etoposide
chemotherapy) for patients with positive
nodes post-resection or unresectable stage III disease, and (3)
4 to 6 cycles of platinum/etoposide chemotherapy for stage
IV disease. 145 For other cases of large cell tumors, numerous
clinical trials have shown a particular benefıt from pemetrexed
chemotherapy, perhaps even beyond the differential
effect seen in adenocarcinoma cases. 152,153
CONCLUSION
Although most recent advances in lung cancer advances have
been focused on adenocarcinoma tumors, new diagnostic
and treatment approaches are emerging for squamous cell,
small cell, and the rare lung cancer histologies. These developments
will hopefully improve the outcomes of patients
with these challenging diseases.
ACKNOWLEDGMENT
The authors thank Vincy Alex for assistance with manuscript
preparation.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK 157