Patterns of Recurrence

The predominant sites of relapse for all stages of NSCLC after resection are distant metastases.

Approximately 30% of recurrences are locoregional with tumors of both squamous and nonsquamous

histology.81 For all stages of disease, the brain is the single most common site of relapse, and brain

metastases occur more frequently with nonsquamous tumors. Other common metastatic sites include

bone, ipsilateral or contralateral lung, liver, and the adrenal glands.81,82

At least 60% of recurrences develop in the first 2 years after operation, and virtually all recurrences

related to the original primary tumor occur within 5 years after surgery. Even the small proportion of

patients with stage II or III disease who survive 5 years are likely to survive 10 years or more

postoperatively. Recurrences of the original primary tumor are uncommon after 5 years, and after that

time the occurrence of new pulmonary cancers becomes the dominant problem. The risk for

development of a second lung cancer in patients with a prior history of cancer resection for NSCLC is

estimated to be 2% to 3% per patient per year,83 with a second lung cancer developing rarely in neversmokers at the time of initial resection, and at rates of 1.8% per patient-year in former smokers and

2.7% per patient-year in current smokers.84 Patients also face a consistent risk for the development of

new, nonpulmonary primary cancers during the first 5 years after operation and thereafter. New,

nonpulmonary malignancies develop in a wide variety of sites, most commonly breast, colon, and

prostate cancers.81

These data underscore the importance of long-term follow-up after resection of early-stage NSCLC.

Guidelines provided by the American College of Chest Physicians

85 and the National Comprehensive

Cancer Network support regular oncologic surveillance after curative-intent lung resection. In

coordination with the primary or referring physician, recommended surveillance includes directed

clinical assessment, every 6 to 12 months the first 2 years and then annually thereafter. Although there

is no single modality to detect recurrence, follow-up should include a combination of history, physical

examination, serial chest radiographs, and low-dose spiral chest CT. Neither PET scan nor MRI studies

are recommended as part of routine surveillance.85,86

Adjuvant Therapy for NSCLC

The risk for recurrent disease, even after resection of early-stage NSCLC, has led to efforts to improve

overall survival rates through the use of adjuvant therapy, even though no specific method is available

to identify which patients will relapse. Various types of adjuvant therapy have been tested, including

immunotherapy,87–89 radiation, chemotherapy, and combined chemotherapy and radiation.

Radiation has been evaluated extensively as adjuvant therapy. Although early retrospective series

suggested that postoperative radiation therapy (PORT) potentially improved overall survival,90–92

subsequent relatively small randomized trials comparing adjuvant radiation with no further treatment

failed to demonstrate any significant difference in overall survival.93–97 Distant metastases remained the

most common form of recurrent disease and were not affected by postoperative radiation to the

mediastinum. Several of these trials

93,94,96,97 showed that radiation significantly decreased the risk for

locoregional recurrence in tumors of all histologic types (Table 79-8). A meta-analysis of several

randomized controlled studies of postoperative radiation therapy suggested an adverse effect on

survival, particularly among patients treated with PORT with early-stage (I or II) lung cancer.98

Postoperative thoracic radiation appears to be appropriate for patients who are at high risk for

locoregional recurrence such as those found to have unexpected mediastinal (N2 or N3) nodal disease or

those with evidence of residual tumor (R1 resection) at surgical margins.99

RESULTS

Table 79-8 Summary of Representative Randomized Trials Comparing Resection

with or Without Adjuvant Radiation for Early-Stage Non–Small Cell

Lung Cancer

2245

RESULTS

Table 79-9 Summary of Representative Randomized Trials Testing the Benefit of

Adjuvant Chemotherapy after Resection of Early-Stage Non–Small

Cell Lung Cancer

Because distant metastases are the predominant mode of relapse after resection of early-stage NSCLC,

multiple randomized trials (Table 79-9) have been performed to determine if postoperative adjuvant

chemotherapy improves survival. Early trials evaluated agents, including nitrogen mustards, cytoxan,

methotrexate, and nitrosourea, now known to have no activity in NSCLC.100–103 More recently, several

studies have demonstrated that cisplatin-based chemotherapy regimens appear to provide a modest

survival benefit. A meta-analysis of 9,387 patients entered into 52 randomized clinical trials showed a

5% survival benefit at 5 years for adjuvant cisplatin-based chemotherapy in comparison with surgery

alone. Trials comparing adjuvant radiation with radiation plus chemotherapy showed an absolute

survival benefit of 4% at 2 years in favor of combined-modality treatment.104

Recent trials of adjuvant chemotherapy in patients with completely resected NSCLC appear to indicate

a therapeutic benefit. The multicenter International Adjuvant Lung Cancer Trial evaluated the effect of

cisplatin-based adjuvant chemotherapy on survival after complete resection of NSCLC. A total of 1,867

patients with resected stage I, II, or III NSCLC were randomized to receive cisplatin-based

chemotherapy, cisplatin-based chemotherapy and radiation, radiation alone, or no adjuvant treatment.

Individual institutions administered additional chemotherapeutic agents at their discretion (“open-choice

design”), with nearly half of the treated patients receiving cisplatin (100 mg/m2) and etoposide for 3 or

4 cycles. The total dose delivered of cisplatin was greater than 240 mg/m2 for 73.8% of treated

patients. Additional agents used were vinorelbine, vinblastine, or vindesine. Cisplatin dosing varied

from 80 to 120 mg/m2/cycle, for a total expected dose of 300 to 400 mg/m2. Statistically significant

benefits were observed for both overall (absolute difference, 4.1%) and disease-free (absolute

difference, 5.1%) survival at 5 years, for patients treated with cisplatin-based chemotherapy, with or

2246

without adjuvant radiation.4 Planned radiotherapy did not appear to provide any added benefit. In

subgroup analysis, the benefits of cisplatin-based adjuvant chemotherapy appeared to confer the

greatest benefit upon patients with stage III NSCLC. In longer-term follow-up, disease-free survival HR

remained improved at 0.88 (95% CI 0.78 to 0.98, p = 0.02) for patients receiving adjuvant therapy

over 7 years following operation, but the previously observed improvement in overall survival was no

longer statistically significant with HR 0.91 (95% CI 0.81 to 1.02, p = 0.10).115

Several subsequent studies support the use of adjuvant chemotherapy, particularly in stage II and III

lung cancer. These studies are summarized in recent meta-analyses of combined modality therapy in the

treatment of resectable lung cancer,116,117 which confirm the benefit of adjuvant chemotherapy

following lung cancer resection for curative intent, with an absolute improvement in survival of 4% to

5.4% at 5 years of follow-up or beyond.

Notably, clinical trials evaluating adjuvant treatment for resected NSCLC have shown that

approximately half of all patients actually received the planned dose of chemotherapy.105,109 It remains

to be determined whether patients undergoing minimally invasive approaches to pulmonary resection

can tolerate adjuvant chemotherapy better than similar patients recovering from open operations.

Thoracoscopic lobectomy, for example, may facilitate subsequent adjuvant chemotherapy.118 In a series

of 100 patients, 43 underwent thoracotomy and 57 had pulmonary resection performed by

thoracoscopy. Those undergoing thoracoscopic resection were found to have a higher compliance rate

with adjuvant treatment. Chemotherapy doses were delayed in significantly fewer patients in the

thoracoscopic group (18% vs. 58%). Chemotherapy doses were reduced in only 26% of subjects

undergoing thoracoscopy compared with 49% in the thoracotomy group. In addition, a significantly

higher percentage of thoracoscopy patients received 75% or more of the planned regimen. There was no

significant difference in the time to initiation of chemotherapy or toxicity.

Treatment of Stage III Disease

Stage III NSCLC indicates locoregionally advanced disease that encompasses several anatomic subsets

which vary considerably in the likelihood that resection will provide durable oncologic benefit. Stage

IIIB is generally considered unresectable. There is no role for resection for patients with T4 (stage IIIB)

disease due to malignant pleural or pericardial effusion, infiltration of the heart, or those with

contralateral or supraclavicular nodal metastases (N3). Several small series from specialized centers

have demonstrated that curative intent operation can be considered for selected patients with invasion

of mediastinal structures such as the superior vena cava, left atrium, carina, vertebrae or aorta, with

consideration for induction chemoradiation, to “downstage” such tumors.119–121 These series indicate

that complete resection is essential to obtain survival benefit from this approach.

Stage IIIA includes patients with extrapulmonary disease involving the ipsilateral hemithorax, that is,

T3N1 and T1–3N2. The management of patients with stage IIIA disease due to mediastinal nodal

involvement (N2) has evolved considerably over the last several decades. Local therapy alone for

curative intent, that is, pulmonary resection or definitive-dose radiation therapy is not recommended.

Role of Resection

The most controversial and complex part of the treatment of stage IIIA NSCLC is the management of

patients with N2 disease. Reported 5-year survival rates after resection for N2 disease are usually 20%

to 30% but range from zero to 40%. This variation reflects the extent of mediastinal nodal involvement,

the T status of the primary tumor, and the ability to perform a complete resection. With respect to

mediastinal nodal involvement, adverse prognostic factors include the presence of extracapsular nodal

disease, multiple levels of involved lymph nodes and superior mediastinal nodal metastases.122,123

Rationale for Neoadjuvant Therapy

Although some patients with “minimal” N2 disease survive for long periods of time after resection, most

have more extensive nodal involvement and do not benefit from either surgery or radiation therapy

alone as their primary treatment. Efforts to improve outcomes following local control strategies have

been limited by relapse at distant sites. Two early, randomized clinical trials challenged the concept of

resection as the primary treatment for any patient with N2 disease. Rosell and colleagues

124,125

randomized 60 patients with stage IIIA NSCLC (16 of whom did not have N2 disease) to undergo

resection or to receive three cycles of cisplatin-based chemotherapy followed by resection. The median

survival of the patients who received preoperative chemotherapy was significantly longer (26 vs. 8

months) than the survival of patients who underwent only resection. A study of similar design from the

2247

M. D. Anderson Cancer Center corroborated these results.126,127 Both trials were stopped early because

of highly significant differences between the two study arms. These two studies suggested that it is

appropriate to consider all patients with N2 disease diagnosed at mediastinoscopy for induction

chemotherapy. Since pretreatment mediastinoscopy was not mandated in either trial, some patients who

did not have N2 disease were included. The results of these trials are not universally accepted because

of the small numbers of patients enrolled, the lack of systematic pretreatment staging, and the

unusually poor survival of the patients in the control (surgery-only) arms.

Early Trials of Neoadjuvant Therapy

The concept of preoperative therapy followed by resection (neoadjuvant therapy) dates back to 1955,

when Bromley and Szur128 used radiation (at an average dose of 47 Gy) to treat 66 patients before

resection. At operation, no viable tumor was found in 29 of 62 (47%) patients, but 10 patients died of

complications in the first month, and only two patients survived to 5 years after operation. At the time,

the natural history of NSCLC was not well understood, the methods of staging before resection not very

accurate, and the risk for distant metastases not fully recognized. Effective chemotherapy did not exist

and it was hoped that an approach that increased resectability might lead to better long-term survival.

Thus, early neoadjuvant trials focused on the use of preoperative radiation.

Several subsequent studies further explored this approach.129 All these trials were flawed by a lack of

pretreatment staging, by the use of widely varying amounts of radiation, and by excessively long

intervals between irradiation and resection. Nonetheless, it became apparent that aggressive local

treatment did not improve long-term survival, even though radiation provided local control in a

significant number of patients. The development of distant metastases in 50% to 80% of patients during

or shortly after treatment underscored the need for systemic therapy in stage III NSCLC.

Recent Trials of Neoadjuvant Therapy

Because of a better understanding of the natural history of early-stage lung cancer and more universal

adoption of the UICC/AJCC TNM staging system, recent trials have defined more uniform patient

populations, so that it has been easier to interpret trial results. Although many different treatment

regimens have been used in neoadjuvant trials, they can be grouped into three major categories: (a)

chemoradiation without resection, (b) chemotherapy followed by resection, and (c) chemoradiation

followed by resection.

Trials of Chemoradiation without Resection

These trials cannot be equated with trials of neoadjuvant therapy that include resection because patients

entered into nonsurgical trials are staged clinically without tissue confirmation of mediastinal lymph

node involvement. Therefore, nonsurgical trials include a mix of patients with stage IIIA and IIIB

cancers, and might even include some patients with earlier-stage disease who were thought erroneously

to have stage III disease because of benign mediastinal adenopathy diagnosed only by axial chest

imaging.

With the acceptance of chemotherapy and radiation as standard treatment, attention has focused

recently on the optimal means to deliver both modalities.130 Several studies have demonstrated that

concurrent treatment is superior to sequential chemoradiotherapy. A cochrane database systematic

review identified fourteen randomized studies comparing concurrent chemoradiation and radiation

therapy alone. In this meta-analysis of 2,393 subjects, concurrent therapy was associated with a

reduction in risk of death at 2 years (RR 0.93; 95% CI 0.88 to 0.98; p = 0.01) and improved 2-year

progression-free survival, locoregionally (RR 0.84; 95% CI 0.72 to 0.98; p = 0.03) or distant (RR 0.90;

95% CI 0.84 to 0.97; p = 0.005). Concurrent chemoradiotherapy also had improved survival compared

with sequential chemotherapy and radiation (RR 0.86; 95% CI 0.78 to 0.95; p = 0.003). In a separate

meta-analysis of studies evaluating the addition of sequential or concurrent chemotherapy to radiation

therapy in over 1,200 patients, a substantial overall survival benefit was observed for patients receiving

concurrent treatment, with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5

years (from 10.6% to 15.1%).131 Although concurrent chemoradiation was associated with less

locoregional disease progression, no significant differences were observed between these two

treatments, concurrent or sequential therapy, in terms of distant disease progression.131 Toxicities,

particularly esophagitis, also were greater for patients receiving concurrent chemoradiation.131,132

Trials of Neoadjuvant Therapy with Resection

2248