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Lung Cancer: Multimodal Therapy
Although long regarded as the best chance for cure, surgery alone has significant shortcomings in the management of non–small cell lung cancer (NSCLC). Even in the most favorable of circumstances (stage I), failure of therapy is anticipated in 20% to 40% of patients. Moreover, because most patients do not have localized disease at time of initial diagnosis, surgical resection is offered to only a minority of all patients with NSCLC.
Considerable effort has been directed toward developing preoperative (induction or neoadjuvant) and postoperative (adjuvant) strategies to improve long-term outcome after surgery and to increase the total number of resectable patients. These strategies use chemotherapy and radiation singly, sequentially, or concurrently.
Predicting which patients will not be cured by resection alone would clearly permit identification of appropriate candidates for multimodality treatment. To this end, locoregional lymph node involvement is a powerful predictor of cancer recurrence and should be thoroughly investigated during treatment planning. Tumor histology and size also affect cancer-related and overall survival of resected patients. Numerous genetic markers are being discovered that may further refine outcome prediction when combined with current imaging modalities (e.g., positron emission tomography). Recent reports have proposed systems using histologic and molecular criteria to stratify predicted survival of resected patients.
In developing strategies for combined therapies, patterns of failure must be considered. Locoregional recurrence after resection of stage I cancers is rare, but it is fairly common when regional lymph nodes are involved. The impact of improving local control with adjuvant radiotherapy may not translate to a survival advantage because patients seldom die from local recurrence. Even in the presence of local lymph node involvement, completely resected patients with stage II cancers are still twice as likely to fail systemically as locally. Moreover, patients (stage IB-IIIA) who recur after resection with curative intent show distant sites of disease in up to 75% of cases. Consequently, effective adjuvant systemic therapy (chemotherapy) would be favored to adjuvant local therapy (radiotherapy) for resected cancers at high risk for recurrence.
Adjuvant Therapy
Despite enthusiasm for 35 years of promising clinical trials of multimodality treatment of NSCLC, it has only recently become apparent that there is a clear and consistent benefit of adjuvant therapy for resected lung cancer. This ambiguity may have been partly because chemotherapy and radiation protocols are changed frequently, resulting in large numbers of studies that cannot be compared. Also, few studies have been designed to critically examine treatment effects on specific NSCLC stages, as most studies tend to group stages I through III in their treatment arms. This shortcoming has been compounded by lack of accurate, sophisticated staging in most trials.
Unfortunately the promising results generated at high-volume academic centers do not, for a number of reasons, easily translate to less specialized, smaller institutions. Regardless, all patients with the diagnosis of NSCLC should be evaluated by a multidisciplinary team or physician adept in the care of patients with lung cancer in order to recommend and coordinate the optimal therapeutic approach. It is also essential that treated patients are carefully followed.
Adjuvant Chemotherapy
Early randomized trials of adjuvant chemotherapy focused on the use of nitrogen mustard, cyclophosphamide, and a combination of lomustine and hydroxyurea. Cumulatively, these trials demonstrated that treated patients had more postoperative complications without survival benefit. In fact, patients treated with adjuvant cyclophosphamide experienced a worse long-term survival rate than untreated patients. This was independently confirmed by meta-analysis. Findings from these early studies have since been discounted because histologic type and pathologic stage were not considered during trial design and chemotherapeutic agents used in these trials have since been demonstrated to be ineffective, if not detrimental, for patients with NSCLC.
As several studies began documenting the efficacy of platinum-based agents for advanced (stage IV) NSCLC, platinum-based adjuvant regimens were trialed with resected patients. Initial enthusiasm was generated when the Lung Cancer Study Group trial suggested a disease-free and overall survival benefit in the adjuvant treatment arm. Although the survival advantage was not considered statistically significant, sufficient optimism was generated to continue investigations of platinum-based chemotherapeutic protocols. However, several subsequent trials continued to demonstrate minimal efficacy, even though continued trial design flaws were identified.
A randomized study of cyclophosphamide, doxorubicin, and cisplatin adjuvant therapy for resected stage I to II NSCLC did not demonstrate treatment efficacy. This trial suffered from inability to deliver the prescribed chemotherapeutic regimen over the prescribed time and also the toxicity and limited usefulness of doxorubicin in the treatment of NSCLC. Less than 30% of patients in the treatment arm actually received chemotherapy as intended. Other randomized studies have been similarly plagued by incomplete delivery of prescribed postoperative therapies, which in part contributes to the negative findings. Additionally, the dose of cisplatin (40 to 60 mg/m 2 /cycle) used in most previous trials is substantially lower than currently recommended (80 to 120 mg/m 2 /cycle).
Although all of these early platinum trials were considered statistically negative, subtle survival differences were noted between control and treated patients in essentially every study. Not surprisingly, a 1995 meta-analysis of several randomized adjuvant platinum-based trials demonstrated a 13% reduction in the risk of death ( P = 0.08) for treated patients. This finding fueled continued interest in this platinum-based adjuvant treatment and spawned several modern trials. Platinum dosage was adjusted so that patients were scheduled to receive 300 to 400 mg/m 2 (total dose). Adjuvant radiation therapy was often left to the discretion of participating centers. Two such studies demonstrated trends favoring a survival benefit in treated patients, but neither was considered to be a positive trial. However, the International Adjuvant Lung Cancer Trial demonstrated a clear survival benefit of adjuvant platinum-based chemotherapy. This study included resected stage I to III patients and found a survival advantage, 5% benefit after 5 years ( P = 0.003), favoring the adjuvant chemotherapy arm versus surgery alone. This survival advantage is similar in magnitude to that achieved by adjuvant chemotherapy for resected breast and colon cancers.
The Lung Adjuvant Cisplatin Evaluation (LACE) pooled data from the five largest randomized trials at the time and reanalyzed this collective. This study amassed information from more than 4500 patients and concluded that postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC. Trials contributing to LACE were heterogeneous with regard to stage (I to III), and subsequent subgroup analysis of pooled data provided insight into the differential effect of adjuvant therapy on specific stages of resected cancer. Based on results from LACE, there is little doubt that resected stage II and III patients experience a meaningful survival advantage from adjuvant chemotherapy—at least 5% for overall survival and 6% for disease-free survival. Patients with resected stage IB disease, however, have much less benefit, although there is a trend toward some advantage in much the same way as in Cancer and Leukemia Group B (CALGB) 9633, a trial of adjuvant carboplatin and paclitaxel for resected stage IB patients only. An important finding of CALGB 9633 was that patients with resected tumors larger than 4 cm do, indeed, benefit from adjuvant chemotherapy. Current guidelines recommend that patients with stage IIA-B and IIIA (with occult N2 disease) receive a platinum-based postoperative chemotherapy regimen. Stage IA-B NSCLC patients who have been completely resected (R0) are advised not to receive postoperative chemotherapy at this time.
The application of molecular inhibitors as adjuvant therapy in lung cancer is an area of intense current interest. However, a recent phase III adjuvant clinical trial of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), versus placebo in resected NSCLC was closed early as interim analyses demonstrated either no benefit or potential detrimental impact.
Adjuvant Radiotherapy
Studies of the efficacy of adjuvant radiotherapy are confounded by many of the same factors that have plagued, and continue to plague, chemotherapy trials. Many randomized adjuvant radiotherapy trials are composed of patients from all stages of resected NSCLC. Consequently, the expected negligible (or deleterious) effects on patients with early-stage cancer may obscure small beneficial effects for patients with more advanced disease. Also, because the field of radiation oncology has evolved so quickly, many early randomized studies became obsolete before their data had matured. Moreover, most early randomized trials were underpowered. Consequently, it is not surprising that, although feasibility and retrospective studies often yield promising results, no randomized data exist to suggest a survival benefit of postoperative radiotherapy (PORT).
At this time, there is no justification to include adjuvant radiotherapy for resected stages I and II NSCLC. Three randomized trials, as well as meta-analyses of trials (PORT studies), document a deleterious effect on survival of adjuvant radiotherapy for early-stage NSCLC. Postulated reasons for this include poor radiotherapy planning, larger fraction sizes, greater total radiation dosage, outdated equipment, and poor quality control.
Although there was some optimism that hilar lymph node (N1)–positive patients (stage II) would provide a good substrate for adjuvant radiotherapy, this does not appear to be the case. Based on subgroup analysis of several randomized trials, radiotherapy has no significant effect on either local control or overall survival for these patients.
Finally, there are insufficient data to defend use of adjuvant radiotherapy for resected stage III (N2/N3) disease, as well. Even though improved local control has been reported, this has not translated into a meaningful survival benefit. The strongest argument to support adjuvant radiotherapy for resected stage III NSCLC comes from a nonrandomized, single-institution, retrospective study. Investigators in this study found that PORT was the strongest independent predictor of survival for resected N2-positive disease. This study, however, has been widely criticized, and PORT meta-analyses consistently fail to demonstrate efficacy for adjuvant radiotherapy for stage III disease. Yet, controversy remains over radiotherapy used in this setting, as one recent trial of adjuvant chemotherapy demonstrated improved 5-year overall survival when patients received thoracic radiation (after their chemotherapy) for resected stage III disease.
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