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Role of Adjuvant Therapy in Resected Stage II/IIIA Non-Small-Cell Lung Cancer

Role of Adjuvant Therapy in Resected Stage II/IIIA Non-Small-Cell Lung Cancer

ABSTRACT: The role of adjuvant therapy following complete resection of node-positive (stage II/IIIA) non-small-cell lung cancer remains controversial. Five-year survival rates in pathologic stage II disease range from 30% to 50% and in resected stage IIIA disease from 10% to 30%. The majority of recurrences following surgery are distant metastases. This two-part review, which will conclude in the January 2002 issue, analyzes the role of adjuvant therapy in this setting, using an evidence-based approach and focusing primarily on randomized trials and meta-analyses. The key variables in evaluating these studies are elucidated, ranging from the extent of mediastinal, systemic, and "molecular" staging to the quality of the adjuvant treatments administered. Some of the potential flaws inherent in meta-analyses are reviewed. To date, there is no convincing evidence that any therapy consistently improves survival in the adjuvant setting. Postoperative radiotherapy has been associated with a significant improvement in local control, particularly in patients with pathologic N2 disease. Chemotherapy should be offered to patients in appropriate clinical trials, and active phase III trials are reviewed. Future strategies include novel chemotherapy, methods to reduce toxicity, the emerging role of neoadjuvant therapy, and the promise of new biologic agents. [ONCOLOGY 15:1549-1558, 2001]

For those who believe a role exists for adjuvant
therapy following resection of stage II or IIIA non-small-cell lung cancer (NSCLC),
the past few years have been disappointing. In 1998, the postoperative
radiotherapy (PORT) meta-analysis published in the Lancet demonstrated a
survival decrement with postoperative radiotherapy in patients with NSCLC.[1]
The controversial results of this trial received widespread coverage in the
media. In the Philadelphia area alone, headlines ranged from "Study
Questions Radiation Therapy" in the Philadelphia Inquirer to the
broad-based conclusion, "Radiation No Help in Lung Cancer," in the
Philadelphia Daily News
.

More recently, the Intergroup randomized trial (0115) published in the New
England Journal of Medicine
showed no survival advantage when adjuvant
chemotherapy was added to radiotherapy.[2] Is it simply time to "give
up" on adjuvant therapy in this setting?

This two-part review, which will conclude in next month’s issue, evaluates
the role of adjuvant therapy in completely resected (margin-negative) stage II/IIIA
(node-positive) NSCLC, using an evidence-based approach and primarily focusing
on randomized trials and meta-analyses.

Defining the Problem

Of all patients presenting with NSCLC, only about 30% are eligible for
complete resections.[3] Mountain and others have shown that patients with
pathologic stage I NSCLC (T1-2, N0) have 5-year survival rates ranging from
60% to 70%.[4-6] Patients with pathologic stage II (T1-2, N1; T3, N0) disease
have lower 5-year survival rates of 30% to 50%,[7] and for those with resected
stage IIIA (T1-3, N2; T3, N1) disease, 5-year survival rates range from 10% to
30%.[8,9]

The majority of recurrences are distant metastases to bone, liver, or brain.
Even in stage I NSCLC, Feld documented distant metastases as the first site of
recurrence in 65% to 77% of patients.[10] Patients with resected stage II or
IIIA tumors have a similar recurrence pattern, although with more locoregional
recurrences.[11,12] To decrease the incidence of recurrent disease following
curative resections, a variety of adjuvant therapies, including radiation and/or
chemotherapy, have been studied.

Key Variables

Surgical Staging

Detailed and consistent intraoperative surgical staging is essential for
accurately assessing the efficacy of adjuvant therapy. In 1997, the
tumor-node-metastasis (TNM) staging system was modified (Table 1 and
Table 2),[13]
and stages I and II were divided into two subsets (IA: T1, N0 vs IB: T2, N0; IIA:
T1, N1 vs IIB: T2, N1 or T3, N0). Any metastatic tumor deposits found in the
ipsilateral lung (other than the primary tumor lobe) are now defined as M1
(rather than T4). The anatomic definitions of some of the intrathoracic lymph
nodes were altered.[14] The minimum number of lymph node stations that should be
resected or sampled during a right thoracotomy are levels 4, 7, and 10, and for
a left thoracotomy, levels 5 or 6, and 7.

It is unclear whether mediastinal lymph node sampling vs a complete
lymphadenectomy affects survival. So far, only one randomized trial has compared
mediastinal lymph node sampling with complete lymphadenectomy and found no
difference in survival,[15] although this trial in 182 patients was underpowered
to show a small improvement in survival. The American College of Surgeons
Oncology Group (ACOSOG) has initiated a randomized trial of mediastinal lymph
node sampling vs complete lymphadenectomy during pulmonary resection in patients
with N0 or N1 (less than hilar) NSCLC (protocol Z0030). The accrual goal is
1,000 patients, and the primary end point is survival.

Patients with ipsilateral mediastinal lymph node involvement (N2) comprise a
heterogeneous group of patients, with 5-year survival rates after surgery alone
ranging from 6% to 35%.[16] Sawyer et al demonstrated that the number of N1 and
N2 lymph nodes, as well as the number of N2 nodal stations involved are
important prognostic variables.[17] In a recent analysis of over 700 patients
who underwent surgical resection of N2 NSCLC, Andre et al detected four negative
prognostic factors on multivariate analysis: clinical N2 status, involvement of
multiple lymph nodes, pathologic T3/T4 stage, and no preoperative
chemotherapy.[18]

Systemic Staging

Prior studies have demonstrated the value of positron-emission tomographic
(PET) scanning in staging the mediastinum, as well as for systemic disease.[19]
Van Tinteren et al [20] assessed the ability of PET to reduce futile
thoracotomies in 188 clinically staged I to III NSCLC patients randomized (prior
to mediastinoscopy or thoracotomy) to a conventional work-up vs conventional
work-up plus PET. Thoracotomy was considered futile in benign disease,
exploratory thoracotomy, pathologic stage IIIA (N2)/IIIB/IV disease, or
postoperative relapse within 12 months. After 1 year, there were 39 (41%) futile
thoracotomies in the conventional work-up arm vs 19 (21%) in the conventional
work-up plus PET arm—a relative reduction of 50%.

Many of the studies to be reviewed span a period of more than 30 years. PET
scans were unavailable at the beginning of that period, as were computed
tomography (CT) scans of the chest or brain. The potential benefit of adjuvant
therapy in the past may have been diluted by inadequate staging modalities.

Molecular Staging

A relative unknown in adjuvant therapy relates to underlying biologic or
molecular genetic prognostic factors, which simply are not available for most
patients. Molecular-clinical correlative studies in patients undergoing
resection for NSCLC have identified various markers with differing prognostic
significance, such as p53, K-ras, Bcl2, HER2, and Ki-67 among others.[21-23]
These studies suggest that profiles of multiple markers may be necessary to
obtain the greatest predictive value.

Recently, Cox et al demonstrated the potential of such "molecular
staging" in 168 patients with resected stage I-IIIA NSCLC.[24]
Multivariate analysis identified independent poor prognostic factors, including
high microvessel count (P = .002), matrix metalloproteinase (MMP)-9 (P = .009)—a
factor facilitating tumor invasion—nodal status (P = .01), and tumor grade
(P
= .05). The expression of both epidermal growth factor receptor (EGFR) and MMP-9
was associated with a poor prognosis (P = .0001). While prospective,
well-designed, studies are necessary to confirm the value of potential markers,
this type of "molecular fingerprinting" may pave the way for patients
at high risk for recurrence to be candidates for molecular-based therapies
targeting specific pathways.

Technical and Quality Variations

Many technical details of radiotherapy need to be evaluated, such as beam
energy, volume of tissue irradiated, total dose, dose per fraction, overall
treatment time, and timing of treatment in relation to surgery. Similarly,
important issues must be considered regarding the administration of chemotherapy—the
specific chemotherapy agents employed, their mechanisms of action, and potential
interaction with radiotherapy and compliance with the planned regimen. The
quality of each study itself must also be assessed.

Adjuvant Radiation

Unlike systemic therapy, the primary goal of radiotherapy is that of local
control. Most radiation oncologists consider a locoregional relapse rate of 15% high enough
or more to warrant a recommendation for postoperative
radiotherapy. The lack of a clear survival benefit does not necessarily negate
the importance of enhancing local control.

Locoregional failure in the mediastinum following surgery alone can have
devastating quality-of-life consequences, leading to airway obstruction,
hemoptysis, dysphagia, and/or chest pain. The potential benefit of postoperative
radiotherapy in the enhancement of local control must be weighed against its
side effects and possible complications. The main acute side effects include
fatigue, skin irritation, and radiation esophagitis. Subacute and chronic
complications primarily include radiation pneumonitis, lung fibrosis, and
possible cardiac damage.

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