American Journal of Clinical Oncology:
ACR Appropriateness Criteria® Postoperative Adjuvant Therapy in Non-Small Cell Lung Cancer
Decker, Roy H. MD*; Langer, Corey J. MD†; Rosenzweig, Kenneth E. MD‡; Chang, Joe Yujiao MD, PhD§; Gewanter, Richard M. MD∥; Ginsburg, Mark E. MD¶; Kong, Feng-Ming MD, PhD, MPH♯; Lally, Brian E. MD**; Videtic, Gregory M. MD††; Movsas, Benjamin MD‡‡
*Yale University School of Medicine, New Haven, CT
†American Society of Clinical Oncology, Fox Chase Cancer Center, Philadelphia, PA
‡Mount Sinai School of Medicine
¶Society of Thoracic Surgeons, Columbia University, NY
∥Memorial Sloan-Kettering Cancer Center, Rockville Centre, NY
§MD Anderson Cancer Center, Houston, TX
♯VA Health Center, Ann Arbor, MI
**University of Miami, Miami, FL
††Cleveland Clinic Foundation, Cleveland, OH
‡‡Henry Ford Health System, Detroit, MI
As reported by Benjamin Movsas, MD. Research support funding from Varian, Inc., Resonant, Inc., Philips, Inc. to Department of Radiation Oncology, Henry Ford Health System. As reported by Corey Langer, MD. For participation in the Speakers Bureau and Advisory Boards: Lilly USA $25,000 per year. Bristol—Myers Squibb $12,500 per year.
The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply society endorsement of the final document. This article is a revised version of the American College of Radiology Appropriateness Criteria Postoperative Adjuvant Therapy in Non-Small Cell Lung Cancer excerpts of which are reprinted here with permission. Practitioners are encouraged to refer to the complete version at http://www.acr.org/ac.
Reprints: Roy Decker, MD, American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. e-mail: email@example.com.
Therapeutic options for postoperative adjuvant treatment for patients with non-small cell lung cancer (NSCLC) continue to evolve, and may include postoperative radiotherapy (PORT) and chemotherapy, alone or in combination. The use of platinum-based adjuvant chemotherapy has been demonstrated to confer an improvement in overall survival in patients with completely resected, stage N1 or N2 NSCLC, in several randomized trials and 2 meta-analyses. Consideration may also be given to adjuvant chemotherapy in patients with node-negative NSCLC, when the primary tumor is >4 cm, based on subset analyses of recent prospective studies. The precise role of PORT is less well defined. Older randomized studies indicated that the toxicity of PORT outweighed the potential improvement in local control, but studies using more modern radiation techniques show significantly reduced toxicity, inferring that select patients may benefit. Relative indications for PORT include the presence of mediastinal lymph nodes, positive surgical margins, and considerations with regard to the extent and type of resection. This study by the lung cancer expert panel of the American College of Radiology summarizes the recent evidence-based literature that addresses the use of postoperative adjuvant radiotherapy and chemotherapy in patients with NSCLC, illustrated with clinical scenarios. The sequencing of radiotherapy and chemotherapy is discussed, along with issues regarding radiotherapy dose and fractionation, and the appropriate use of intensity modulated radiation therapy and particle therapy.
Options in the postoperative setting for patients with non-small cell lung cancer (NSCLC) include observation, postoperative radiotherapy (PORT), chemotherapy, or combination treatment. The indications for PORT are subject to debate, but include both the T and N stage, the status of surgical margins, and consideration of the extent and type of surgery. The role of adjuvant systemic therapy has become more defined with the publication of multiple randomized trials and meta-analyses demonstrating a survival benefit to postoperative chemotherapy, especially in patients with N1 or N2 disease; ongoing trials are addressing the optimal combination therapy and molecular factors that may predict response and survival.
SURGICAL ISSUES AND PORT
The role of PORT in patients with NSCLC has been examined in retrospective studies, randomized trials, and a meta-analysis. The populations of patients studied have been heterogeneous with respect to histology, T and N stage, surgical staging, and treatment parameters. Within this group of patients, a number of important prognostic indicators such as extranodal extension, number of involved lymph node regions, nodal size, presence or absence of subcarinal or subaortic involvement, and histology are often unreported.
The extent of surgical resection and staging is an independent indicator of outcome. In one surgical series of 102 patients with no clinical evidence of mediastinal adenopathy at thoracotomy, 24% had pathologically positive nodes.1 The absence of mediastinal surgical sampling, which is endemic in some parts of the country, may result in understaging. The extent of mediastinal sampling or dissection may affect the amount of subclinical disease present in the mediastinal lymph nodes, which may alter the need for or response to adjuvant therapy. Keller et al2 evaluated the extent of mediastinal surgical resection in 373 patients accrued to the Eastern Cooperative Oncology Group (ECOG) 3590, a randomized trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC, all of whom received PORT. Systematic sampling was performed in 187 patients and mediastinal lymph node dissection in 186 patients. In this unplanned analysis, complete mediastinal lymph node dissection yielded a greater number of positive nodes and was associated with improved survival compared with systematic sampling in patients with right-sided but not left-sided NSCLC. This issue is also the topic of a recent randomized study by the American College of Surgeons Oncology Group, the results of which are not yet available.
PORT FOR MEDIASTINAL LYMPH NODES
The PORT meta-analysis3 pooled the outcomes of patients with stage I to III NSCLC, randomized to observation or PORT in 7 published4–10 and 2 unpublished trials (European Organisation for Research and Treatment of Cancer 08861 and Lung Cancer Study Group (LCSG) 841). It was subsequently updated to include an additional published trial,11 for a total of 2232 patients enrolled between 1966 and 1997.12 The trials included were limited to those with complete surgical resection, and the majority of patients had squamous cell cancer when the histology was known. Collectively, the use of PORT had an adverse effect on survival, with an absolute decrease of 7% in the 2-year survival rate (from 55% to 48%); this proved statistically significant. The greatest survival detriment occurred in patients with early nodal disease (stage N0 and N1). In patients with mediastinal nodes (stage N2), there was neither a detriment nor a benefit to PORT. Notably, all the trials that reported local/regional control end points found that the use of PORT decreased recurrence. Taken together with the observation that the greatest detriment was seen in patients at the lowest risk, these results imply that any potential survival benefit was likely outweighed by an increase in treatment-related toxicity. The meta-analysis has been widely criticized for a number of limitations: the staging evaluation was variable and, for some trials, not specified; early-stage patients, not expected to benefit, were included; the pooled follow-up was short (3.9 y) at publication; and the radiation technique was felt to be inadequate by modern standards, with the inclusion of patients treated with cobalt, patients treated with low radiation dose to large fields, and patients treated excessively late postoperatively.
A large retrospective analysis by Lally et al13 sought to examine PORT in a more modern era using the Surveillance, Epidemiology and End Results (SEER) database. The investigators identified 7465 incidents of stage II or III NSCLC cases managed with surgery between 1988 and 2002, of which 47% received PORT. In a multivariate analysis, there was no difference in the survival between the cohorts treated with PORT and those who received no adjuvant therapy. Similar to the finding of the meta-analysis, there was a survival decrement in the subset of N0 and N1 patients who received PORT. In patient with N2 disease, however, the use of PORT was associated with a significant improvement in overall survival rate (27% vs. 20% at 5 y). SEER analyses have several known shortcomings, among them are the lack of detailed treatment data and the implicit selection bias of retrospective data. Interestingly, in the modern setting of patients with N1 or N2 disease who receive adjuvant chemotherapy, a post hoc subset analysis of the Adjuvant Navelbine International Trialist Association (ANITA) study suggested that patients with N2 disease who received PORT (in addition to chemotherapy) had better overall survival than those who did not receive PORT, whereas no benefit was observed for PORT in patients with resected N1 disease who had received chemotherapy. This important observation has set the stage for a randomized, phase III study in the Europe assessing the role of postoperative radiation in patients with N2 disease treated with surgery and chemotherapy.
Several investigators have investigated the toxicity of PORT, when delivered with modern radiation techniques. The use of computed tomography simulation and 3-dimensional planning should result in better target coverage and lower normal tissue irradiation,14,15 and this seems to be borne out in more modern treatment series. Machtay et al16 in a retrospective study of 208 patients treated postoperatively between 1982 and 1998 with modern treatment planning, compared the risk of intercurrent death with age-matched and sex-matched mortality rates. They found a small but nonsignificant increase in intercurrent death rates associated with PORT. Wakelee et al17 studied the actuarial rate of noncancer deaths in patients treated on ECOG 3590, which compared PORT with concurrent chemotherapy and PORT. They also noted a small but nonsignificant increase in deaths from intercurrent disease when the study groups were compared with matched controls. Lally et al18 in a follow-up SEER analysis examined cardiac mortality in patients with stage II or III NSCLC treated with surgery and PORT. PORT increased the risk of cardiac death in patients treated between 1983 and 1988 (hazard ratio 1.49), but was not associated with any significant increase in cardiac death in patients treated between 1989 and 1993 (hazard ratio 1.08; not significant). These studies support the hypothesis that PORT delivered using modern radiation technology is associated with a lower risk of treatment-related death than has been noted in older, randomized studies, and therefore treatment-related death is less likely to detract from a potential survival benefit in more modern trials.
The appropriate dose in the postoperative setting has not been addressed in a randomized trial. The required dose for sites of potential occult disease may vary depending on the probability of residual disease, the number of sites at risk, the number and radiosensitivity of clonogens present, and the desired control rate.19 Choi et al20 comments that most of the recurrences in their retrospective study occurred at or below a dose of 50 Gy, suggesting that higher doses may be necessary. Several of the randomized trials that examined PORT demonstrated a significantly reduced incidence of local recurrence, suggesting that the mediastinal dose used was adequate for microscopic disease. Mayer et al21 prescribed 50 to 56 Gy, Feng et al22 prescribed 60 Gy, the LCSG 773 trial4 prescribed 50 Gy, Trodella et al11 prescribed 50.4 Gy, and the Groupe d'Etude et de Traitement des Cancers Bronchiques (GETCB) trial5 prescribed 60 Gy. The Medical Research Council Study found improved local control following 40 Gy in 3 weeks.8
Three large prospective trials have examined PORT given concurrently with chemotherapy: The ECOG 3590 trial23 prescribed 50.4 Gy in 28 fractions, either alone or with concurrent cisplatin and etoposide. Radiation Therapy Oncology Group 970524 was a phase II trial of paclitaxel and carboplatin with 50.4 Gy in 28 fractions; a boost of 10.8 Gy was delivered for extranodal extension or T3 tumors. The combination was well tolerated at these radiation doses. In a phase II study conducted at Fox Chase Cancer Center25 42 patients with stage II or III NSCLC were treated with PORT and concurrent carboplatin and paclitaxel after gross total resection. The radiation dose was 50.4 Gy in 28 fractions, with a boost of 10.8 Gy for extranodal extension or 16.2 Gy for involved margins. Five of 42 patients developed grade 3 esophagitis, and 3 developed grade 3 pneumonitis. Together, these studies suggest that PORT doses of 50 Gy or higher are well tolerated when given with concurrent chemotherapy. It should be noted that the older randomized trials using this dose found no survival benefit, presumably due to excess toxicity related to PORT, and that the modern series demonstrating tolerability are retrospective or smaller single-arm phase II studies.
Intensity-modulated Radiation Therapy
Intensity-modulated radiation therapy (IMRT) has been widely adapted in several clinical areas in an effort to improve dose homogeneity and target coverage, and to decrease normal tissue exposure. Yet, there are potential concerns with regard to the adoption of IMRT in the treatment of lung cancer. The most widely used normal tissue dose-volume constraints (ie, V20, mean lung dose) were derived from patients treated with 2-dimensional or 3-dimensional radiation therapy. The use of IMRT may improve these parameters, but may do so at the expense of an increase in the volume of normal tissue exposed to lower radiation doses. This lower dose exposure is not accounted for in most models. The incidence of normal tissue toxicity may therefore be higher than predicted. Dose-volume limits using lower radiation therapy doses have been suggested for use in IMRT planning (ie, V5), but the data regarding the predictive value of these parameters are based on a relatively sparse clinical experience. However, in the definitive management of NSCLC with radiation or chemoradiation, there are dosimetric studies suggesting that IMRT may allow improved sparing of normal tissue structures. In a study from the MD Anderson Cancer Center, IMRT plans were generated for 41 patients with locally advanced disease who had been previously treated with a 3-dimensional conformal technique. The use of IMRT resulted in lower dose to the uninvolved lung, and decreased the normal tissue complication probability, compared with 3-dimensional planning.26 In a similar study conducted at the William Beaumont Hospital in 18 patients, IMRT plans were able to deliver higher radiation dose to patients with mediastinal lymph nodes compared with 3-dimensional conformal plans, without increasing the normal tissue complication probability for the lung or esophagus.27 Both studies were theoretical and conducted in patients treated with definitive, rather than adjuvant, intent. Two large series report on the toxicity of patients treated with IMRT. At the MD Anderson Cancer Center, 68 patients with NSCLC were treated with IMRT when 3-dimensional conformal radiation planning attempts failed to meet normal tissue dose limits.10 The clinically significant pneumonitis rate was 8% at 1 year; lower than expected. The Memorial Sloan-Kettering Cancer Center reported on 55 patients who received IMRT, again selected due to unsuitability for 3-dimensional planning.28 Significant pulmonary toxicity was noted in 11% of patients. Neither study included patients treated adjuvantly.
Charged-particle beams such as protons or carbon ions have theoretical advantages over standard photon therapy. The absorption characteristics of charged particles should allow for normal tissue sparing, but to date the published clinical experience is limited. Dosimetric studies suggest that protons allow for improved target coverage and decreased normal tissue exposure. An MD Anderson Cancer Center study examined dose volume histograms from patients treated with protons, IMRT, and 3-dimensional conformal RT for stages I and III NSCLC.29 Proton treatment resulted in the lowest dose to the lung, spinal cord, and esophagus. Most of the published data regarding protons are based on retrospective, single-institution experiences and are marked by varying techniques and fractionation schemes. Three prospective trials of proton therapy have been published to date; 2 included only stage I patients.30,31 One prospective study from the Loma Linda University Medical Center included 37 patients with stage I to III NSCLC, treated with either protons or a combination of photons and protons depending on the patient's cardiopulmonary reserve. The study included elective mediastinal radiation for selected patients. Two-year local control was 87%, and grade 2 pneumonitis was noted in 5.7% of patients.
Several prospective reports of hypofractionated carbon ion therapy have been reported from the Research Center Hospital for Charged Particle Therapy in Chiba, Japan, based on phase I and II trials in patients with stage I NSCLC.32 Local control was 90%, and grade 2 or greater pneumonitis was noted in 10% of patients. Notably, dosimetric parameters used in photon therapy (V5, V20, V30, and mean lung dose) were not predictive factors for pneumonitis.33
Overall, there are insufficient data to make conclusions regarding the efficacy and toxicity of charged-particle therapy for postoperative adjuvant treatment of NSCLC. Ongoing prospective trials should clarify the role of this promising modality (Tables 1 and 2).
PORT FOR CHEST WALL TUMORS
Invasion of the chest wall (American Joint Committee on Cancer stage T3) is a poor prognostic factor observed in approximately 5% of newly diagnosed NSCLC patients. There are no randomized data specifically examining the role of PORT in patients with the chest wall invasion, but several notable retrospective series have evaluated the risk of local recurrence with and without PORT. Deeper invasion is associated with an increasing risk of positive margins after resection,34 a known risk factor for local recurrence.35 This association confounds the analysis of advanced T stage as a potential indicator for PORT, as many reports do not separately examine the potential benefit of PORT in patients who undergo an en bloc, complete resection as opposed to R1 or R2 resections.
Piehler et al36 reported on 93 patients who underwent definitive surgery for lung cancer involving the chest wall from 1960 to 1980. Sixty-six patients had completed en bloc resections, and of these, 31 had T3N0 disease. Sixteen patients received PORT. The actuarial survival rate at 5 years was the same whether or not PORT was given (53.3% vs. 54.4%), and local recurrence rates were not reported. McCaughan et al34 reported on 125 patients operated on between 1974 and 1983 who had NSCLC invading the chest wall. Invasion beyond the parietal pleura was predictive of incomplete resection and worse overall survival. Patients who had completely resected T3N0 tumors had a reasonably good 5-year overall survival rate of 56%.
Patterson et al37 reported on 35 patients treated between 1969 and 1981, 83% of whom had en bloc resections. Twenty-one patients had T3N0M0 tumors and were completely resected. Seven of the 9 (78%) who received PORT were alive at 5 years compared with only 3 of the 14 (21%) who received no PORT. None of the 13 patients who received PORT experienced local recurrence, whereas 6 of 22 (27%) who were not irradiated failed locally. Burkhart et al38 reported on 95 patients who underwent margin-negative, en bloc resection of T3 NSCLC. No PORT was given, and the survival rate after complete resection was similar to that seen for resected T2 tumors. Local failure was not reported. Gould et al39 reported the patterns of failure in 92 patients with T3N0 NSCLC who underwent resection with negative surgical margins. In this population, the 4-year local control was 94%, and it was not significantly different in those who received PORT.
Collectively, the retrospective series examining PORT in T3 patients suggests that local failure is a significant risk and that adjuvant treatment will reduce this risk. Advanced T stage is associated with a higher risk of positive surgical margins; however it seems that much of the observed risk is driven by patients with significant local residual disease. Patients who undergo en bloc, margin-negative resection of T3 tumors do not seem to be at increased risk of recurrence locally, and there is no demonstrable benefit to PORT in that group (Table 3).
The potential benefit of postoperative chemotherapy with or without PORT has been evaluated in a number of randomized trials using regimens based on 5-FU, alkylating agents, and platinum combinations. The Non-small Cell Lung Cancer Collaborative Group40 published a meta-analysis in 1995 evaluating the effect of chemotherapy on NSCLC, which included 14 trials and 4357 patients. Five trials used alkylating agents, 8 used cisplatin-containing regimen, and 3 used tegafur or tegafur-uracil (UFT). The investigators noted a significantly decreased survival in the studies using alkylating agents (P=0.005) and no change with 5-FU regimens. Platinum-based chemotherapy produced a nonsignificant improvement in survival rate of 5% at 5 years (P=0.08). Hamada et al41 reported a meta-analysis of studies from Japan using UFT regimens given postoperatively. The study population comprised mainly stage I patients. The results showed improved 5-year and 7-year survival rates in a Japanese patient population, but the study's relevance to non-Japanese populations has been questioned.42 Most recent European and North American studies have focused on platinum-based combination regimens.
A number of randomized trials since the 1995 meta-analysis have examined the efficacy of adjuvant platinum-based chemotherapy compared with observation. Three of the trials showed no significant benefit. In a Japan Clinical Oncology group study, Tada et al43 reported on 119 pN2 patients, comparing cisplatin and vindesine to no further treatment after resection. The 5-year overall survival rates were 28.2% in the treated group and 36.1% in the control group (P=0.89). The Adjuvant Lung Project Italy trial44 compared cisplatin, vindesine, and mitomycin C (MVP) for 3 cycles versus no further treatment after resection in stage I, II, and IIIA patients. There was no difference in disease-free or overall survival between the 2 groups, although there was a nonsignificant trend towards improved overall survival in the subset of stage II patients. The Big Lung Trial45 included 384 patients treated with 1 of 4 platinum-based chemotherapy regimens after surgical resection. There was no difference in overall survival compared with observation.
In contrast, a number of more recent trials have demonstrated a significant improvement in recurrence-free or overall survival. The International Adjuvant Lung Cancer Trial (IALT)46 compared no further treatment to 1 of 4 schedules of cisplatin and either vinorelbine, vindesine, vinblastine, or etoposide in 1867 completely resected patients with stage I to III NSCLC. There was a 5.1% (P<0.03) and a 4.1% (P<0.003) increase in disease-free and overall 5-year survival rates, respectively, and the greatest survival benefit was noted in stage III patients. The North American Intergroup trial (JBR-10)47,48 included 482 patients with stage IB and II NSCLC randomized to observation or to adjuvant chemotherapy with vinorelbine and cisplatin after complete resection. The 5-year survival rate improved from 54% to 69% (P=0.03) with adjuvant chemotherapy. In a more recent update, the survival advantage held up at 7 years.49 A planned subgroup analysis indicated that the therapeutic advantage was almost exclusively confined to the patients with stage II disease and that the benefit for stage IB patients was present only in those whose primary tumors measured >4 cm, but was not statistically significant.
The Cancer and Leukemia Group B (CALGB) 9633 trial50 reported the results of 344 patients with stage IB NSCLC, who were randomized after complete resection to observation or to adjuvant treatment with 4 cycles of paclitaxel and carboplatin. The 5-year overall survival rates were 59% in the observation arm and 71% in the treatment arm, which in the initial analysis proved significantly different, but over time, the advantage eroded with a rise in P value from 0.028 to 0.1. However, in a post hoc analysis of patients with tumors ≥4 cm, a significant overall survival advantage was maintained. Mineo et al51 randomized 66 patients with pT2N0 NSCLC to cisplatin and etoposide for 6 cycles or to observation. The 5-year survival rate was 59% in the treated group and 30% in the control group (P=0.02). The ANITA study52 compared adjuvant cisplatin/vinorelbine to observation in 840 patients with stages IB to IIIA disease. An absolute improvement in survival rate of 8.4% at 7 years was observed in the patients who received adjuvant therapy. The survival benefit seemed to be limited to patients with stage II or III disease. Finally, the Lung Adjuvant Cisplatin Evaluation53 meta-analysis pooled the results of 4584 patients treated on the 5 largest platinum-based adjuvant trials (Adjuvant Lung Project Italy, ANITA, Big Lung Trial, IALT, and JBR-10) and demonstrated an absolute 5-year overall survival benefit of 5.4%. Patients with stage IA disease had a trend towards worse survival after adjuvant therapy, and patients with stage IB disease had a trend towards improved survival that did not prove statistically significant. However, patients with stage II and III disease experienced a significant survival benefit. All patients included in the meta-analysis received cisplatin-based chemotherapy; there seemed to be no difference between vinorelbine, etoposide, vinca alkaloids, or other agents when combined with cisplatin.
For patients with stage II or III NSCLC who undergo complete resection, multiple randomized trials and 2 meta-analyses have demonstrated a significant improvement in overall survival with the addition of adjuvant cisplatin-based chemotherapy. For patients without nodal disease but with tumors >4 cm, a survival benefit was evident in a subset analysis of the CALGB 9633 trial, and consideration should be given to treating selected stage IB patients based on these criteria.
The value of combining PORT sequentially or concurrently with postoperative chemotherapy is less well defined. Two of the positive postoperative chemotherapy trials, IALT and ANITA, allowed PORT in a nonrandomized manner.46,52 The radiotherapy in these studies was given after the chemotherapy. The interaction between PORT and adjuvant chemotherapy in the ANITA trial has been examined in a separate publication.54 In the trial, PORT was recommended, but not mandatory, for node-positive patients, and was administered after systemic therapy. In a post hoc subset analysis, patients with N2 disease who received PORT (in addition to chemotherapy) had better overall survival than those who did not receive PORT, whereas no benefit was observed for PORT in patients with resected N1 disease who had received chemotherapy.
Several prospective studies have examined PORT with concurrent chemotherapy. The Radiation Therapy Oncology Group 970524 was a single-arm phase II trial of 88 resected stage II and IIIA patients treated with concurrent radiotherapy and carboplatin and paclitaxel. The toxicities were considered acceptable, and the survival was favorable when compared with the ECOG 3590 (median survival times of 56.3 mo vs. 33.7 mo, respectively). The local failure rates were similar between the studies. In a phase II study conducted at the Fox Chase Cancer Center25 42 patients with stage II or III NSCLC were treated with PORT and concurrent carboplatin and paclitaxel after gross total resection. The radiation dose was 50.4 Gy in 28 fractions, with a boost of 10.8 Gy for extranodal extension or 16.2 Gy for involved margins. Five of 42 patients developed grade 3 esophagitis, and 3 developed grade 3 pneumonitis. Locoregional control was 88% at 5 years.
Several randomized studies have evaluated PORT with or without chemotherapy, although all of these were older efforts. The LCSG 791 trial55 compared radiotherapy (split course) to the same radiotherapy concurrently with cyclophosphamide, doxorubicin, and cisplatin (CAP) in patients with NSCLC who had incomplete resections (positive margins or involvement of the most proximal lymph node in the mediastinum). There was an improvement in recurrence-free survival in the chemotherapy arm, but overall survival was not increased. Pisters and Le Chevalier56 compared postoperative vindesine, platinum, and mediastinal radiotherapy to mediastinal radiotherapy alone in 72 patients with stage III disease (28 of whom were incompletely resected). There was no difference in recurrence-free or overall survival rates. Dautzenberg et al57 reported on 267 patients (259 with stage II or III disease) who in a randomized trial received either radiotherapy of 60 Gy to the mediastinum or CAP and vincristine and lomustine for 3 cycles, then the same radiotherapy. There was no difference in disease-free or overall survival rates. Keller et al23 in a report of an intergroup trial (ECOG 3590), showed that 4 cycles of cisplatin and VP-16, 2 given concurrently with PORT and 2 given after the conclusion of PORT, did not increase survival when compared with PORT alone.
PORT seems to increase local control in patients who have also received chemotherapy, and is reasonable to consider in patients who have mediastinal nodal involvement and who are felt to be at high risk of local recurrence. Studies that included PORT sequentially with chemotherapy typically sequenced the systemic therapy first, due to the survival benefit associated with adjuvant chemotherapy in patients with nodal disease found at surgery. Sequential therapy is better supported by the data for routine adjuvant therapy. For patients at the highest risk of local/regional recurrence (eg, a positive surgical margin), concurrent therapy may be appropriate, extrapolating from studies demonstrating a benefit to concurrent chemoradiotherapy in patients with gross unresectable disease.58 To date, however, there has been no formal phase III trial evaluating the role of PORT in the modern therapeutic era, nor has any trial compared concurrent chemotherapy and PORT to sequential chemotherapy and PORT.
For patients with stage II or III NSCLC, multiple randomized trials and 2 meta-analyses have demonstrated a significant improvement in overall survival with the addition of adjuvant cisplatin-based chemotherapy after resection. For patients without nodal disease, but with tumors >4 cm, a survival benefit was evident in a subset analysis of the CALGB 9633 trial, and consideration should be given to treating selected stage IB patients with adjuvant chemotherapy based on these criteria.
The role of postoperative radiation remains controversial. For patients with completely resected T1-2, N0-N1 NSCLC, there is little evidence to suggest a benefit to PORT. For patients with N2 disease, it is reasonable to discuss the potential risks and benefits of PORT after completion of adjuvant chemotherapy. Patients with positive surgical margins and selected patients with T3 tumors may also benefit from PORT. To date, however, no prospective phase III trial has yet demonstrated a survival advantage for the use of PORT in resected stage IIIa patients (Table 4).
1. Fernando HC, Goldstraw P. The accuracy of clinical evaluative intrathoracic staging in lung cancer as assessed by postsurgical pathologic staging. Cancer. 1990;65:2503–2506
2. Keller SM, Adak S, Wagner H, et al. Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer. Eastern Cooperative Oncology Group. Ann Thorac Surg. 2000;70:358–365 discussion 365–356.
3. PORT Meta-analysis Trialists Group. . Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet. 1998;352:257–263
4. The Lung Cancer Study Group. . Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Engl J Med. 1986;315:1377–1381
5. Dautzenberg B, Arriagada R, Chammard AB, et al. A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Groupe d'Etude et de Traitement des Cancers Bronchiques. Cancer. 1999;86:265–273
6. Debevec M, Bitenc M, Vidmar S, et al. Postoperative radiotherapy for radically resected N2 non-small-cell lung cancer (NSCLC): randomised clinical study 1988-1992. Lung Cancer. 1996;14:99–107
7. Lafitte JJ, Ribet ME, Prevost BM, et al. Postresection irradiation for T2 N0 M0 non-small cell carcinoma: a prospective, randomized study. Ann Thorac Surg. 1996;62:830–834
8. Stephens RJ, Girling DJ, Bleehen NM, et al. The role of post-operative radiotherapy in non-small-cell lung cancer: a multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease. Medical Research Council Lung Cancer Working Party. Br J Cancer. 1996;74:632–639
9. Van Houtte P, Rocmans P, Smets P, et al. Postoperative radiation therapy in lung caner: a controlled trial after resection of curative design. Int J Radiat Oncol Biol Phys. 1980;6:983–986
10. Yom SS, Liao Z, Liu HH, et al. Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2007;68:94–102
11. Trodella L, Granone P, Valente S, et al. Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial. Radiother Oncol. 2002;62:11–19
12. Burdett S, Stewart L. Postoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysis. Lung Cancer. 2005;47:81–83
13. Lally BE, Zelterman D, Colasanto JM, et al. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol. 2006;24:2998–3006
14. von Lieven H, Burkhardt E. Postoperative radiotherapy of NSCLC: outcome after 3-D treatment planning. Strahlenther Onkol. 2001;177:302–306
15. Wilson EM, Joy Williams F, Lyn BE, et al. Comparison of two dimensional and three dimensional radiotherapy treatment planning in locally advanced non-small cell lung cancer treated with continuous hyperfractionated accelerated radiotherapy weekend less. Radiother Oncol. 2005;74:307–314
16. Machtay M, Lee JH, Shrager JB, et al. Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma. J Clin Oncol. 2001;19:3912–3917
17. Wakelee HA, Stephenson P, Keller SM, et al. Post-operative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA non-small cell lung cancer (NSCLC) does not increase the expected risk of death from intercurrent disease (DID) in Eastern Cooperative Oncology Group (ECOG) trial E3590. Lung Cancer. 2005;48:389–397
18. Lally BE, Detterbeck FC, Geiger AM, et al. The risk of death from heart disease in patients with nonsmall cell lung cancer who receive postoperative radiotherapy: analysis of the Surveillance, Epidemiology, and End Results database. Cancer. 2007;110:911–917
19. Marks LB. A standard dose of radiation for “microscopic disease” is not appropriate. Cancer. 1990;66:2498–2502
20. Choi NC, Grillo HC, Gardiello M, et al. Basis for new strategies in postoperative radiotherapy of bronchogenic carcinoma. Int J Radiat Oncol Biol Phys. 1980;6:31–35
21. Mayer R, Smolle-Juettner FM, Szolar D, et al. Postoperative radiotherapy in radically resected non-small cell lung cancer. Chest. 1997;112:954–959
22. Feng QF, Wang M, Wang LJ, et al. A study of postoperative radiotherapy in patients with non-small-cell lung cancer: a randomized trial. Int J Radiat Oncol Biol Phys. 2000;47:925–929
23. Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med. 2000;343:1217–1222
24. Bradley JD, Paulus R, Graham MV, et al. Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA non-small-cell lung cancer: promising long-term results of the Radiation Therapy Oncology Group—RTOG 9705. J Clin Oncol. 2005;23:3480–3487
25. Feigenberg SJ, Hanlon AL, Langer C, et al. A phase II study of concurrent carboplatin and paclitaxel and thoracic radiotherapy for completely resected stage II and IIIA non-small cell lung cancer. J Thorac Oncol. 2007;2:287–292
26. Murshed H, Liu HH, Liao Z, et al. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;58:1258–1267
27. Grills IS, Yan D, Martinez AA, et al. Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation. Int J Radiat Oncol Biol Phys. 2003;57:875–890
28. Sura S, Gupta V, Yorke E, et al. Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol. 2008;87:17–23
29. Chang JY, Zhang X, Wang X, et al. Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in Stage I or Stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2006;65:1087–1096
30. Bush DA, Slater JD, Shin BB, et al. Hypofractionated proton beam radiotherapy for stage I lung cancer. Chest. 2004;126:1198–1203
31. Hata M, Tokuuye K, Kagei K, et al. Hypofractionated high-dose proton beam therapy for stage I non-small-cell lung cancer: preliminary results of a phase I/II clinical study. Int J Radiat Oncol Biol Phys. 2007;68:786–793
32. Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week. J Thorac Oncol. 2007;2:916–926
33. Koto M, Tsujii H, Yamamoto N, et al. Dosimetric factors used for thoracic X-ray radiotherapy are not predictive of the occurrence of radiation pneumonitis after carbon-ion radiotherapy. Tohoku J Exp Med. 2007;213:149–156
34. McCaughan BC, Martini N, Bains MS, et al. Chest wall invasion in carcinoma of the lung. Therapeutic and prognostic implications. J Thorac Cardiovasc Surg. 1985;89:836–841
35. Sawyer TE, Bonner JA, Gould PM, et al. Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks. Ann Thorac Surg. 1997;64:1402–1407 discussion 1407–1408.
36. Piehler JM, Pairolero PC, Weiland LH, et al. Bronchogenic carcinoma with chest wall invasion: factors affecting survival following en bloc resection. Ann Thorac Surg. 1982;34:684–691
37. Patterson GA, Ilves R, Ginsberg RJ, et al. The value of adjuvant radiotherapy in pulmonary and chest wall resection for bronchogenic carcinoma. Ann Thorac Surg. 1982;34:692–697
38. Burkhart HM, Allen MS, Nichols FC III, et al. Results of en bloc resection for bronchogenic carcinoma with chest wall invasion. J Thorac Cardiovasc Surg. 2002;123:670–675
39. Gould PM, Bonner JA, Sawyer TE, et al. Patterns of failure and overall survival in patients with completely resected T3 N0 M0 non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 1999;45:91–95
40. Non-small Cell Lung Cancer Collaborative Group. . Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995;311:899–909
41. Hamada C, Tanaka F, Ohta M, et al. Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer. J Clin Oncol. 2005;23:4999–5006
42. Booth C, Shepherd F. Adjuvant chemotherapy for resected non-small cell lung cancer. J Thorac Oncol. 2006;1:180–187
43. Tada H, Tsuchiya R, Ichinose Y, et al. A randomized trial comparing adjuvant chemotherapy versus surgery alone for completely resected pN2 non-small cell lung cancer (JCOG9304). Lung Cancer. 2004;43:167–173
44. Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst. 2003;95:1453–1461
45. Waller D, Peake MD, Stephens RJ, et al. Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial. Eur J Cardiothorac Surg. 2004;26:173–182
46. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351–360
47. Butts CA, Ding K, Seymour L, et al. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol. 2010;28:29–34
48. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin versus observation in resected non-small-cell lung cancer. N Engl J Med. 2005;352:2589–2597
49. Vincent MD, Butts C, Seymour L, et al. Updated survival analysis of JBR.10: a randomized phase III trial of vinorelbine/cisplatin versus observation in completely resected stage IB and II non-small cell lung cancer (NSCLC). J Clin Oncol (Meeting Abstracts). 2009;27:7501
50. Strauss GM, Herndon JE II, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008;26:5043–5051
51. Mineo TC, Ambrogi V, Corsaro V, et al. Postoperative adjuvant therapy for stage IB non-small-cell lung cancer. Eur J Cardiothorac Surg. 2001;20:378–384
52. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer [Adjuvant Navelbine International Trialist Association (ANITA)]: a randomised controlled trial. Lancet Oncol. 2006;7:719–727
53. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552–3559
54. Douillard JY, Rosell R, De Lena M, et al. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys. 2008;72:695–701
55. The Lung Cancer Study Group. . The benefit of adjuvant treatment for resected locally advanced non-small-cell lung cancer. J Clin Oncol. 1988;6:9–17
56. Pisters KM, Le Chevalier T. Adjuvant chemotherapy in completely resected non-small-cell lung cancer. J Clin Oncol. 2005;23:3270–3278
57. Dautzenberg B, Chastang C, Arriagada R, et al. Adjuvant radiotherapy versus combined sequential chemotherapy followed by radiotherapy in the treatment of resected nonsmall cell lung carcinoma. A randomized trial of 267 patients. GETCB (Groupe d'Etude et de Traitement des Cancers Bronchiques). Cancer. 1995;76:779–786
58. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 1999;17:2692–2699
non-small cell lung cancer; radiotherapy; chemotherapy; Appropriateness Criteria
© 2011 by Lippincott Williams & Wilkins, Inc
Highlight selected keywords in the article text.