American College of Radiology ACR Appropriateness Criteria POSTOPERATIVE ADJUVANT THERAPY IN NON-SMALL-CELL LUNG CANCER

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1 American College of Radiology ACR Appropriateness Criteria Date of origin: 1996 Last review date: 2010 POSTOPERATIVE ADJUVANT THERAPY IN NON-SMALL-CELL LUNG CANCER Expert Panel on Radiation Oncology Lung: Roy H. Decker, MD 1 ; Corey J. Langer, MD 2 ; Benjamin Movsas, MD 3 ; Kenneth E. Rosenzweig, MD 4 ; Joe Yujiao Chang, MD, PhD 5 ; Richard M. Gewanter, MD 6 ; Mark E. Ginsburg, MD 7 ; Feng-Ming Kong, MD, PhD, MPH 8 ; Brian E. Lally, MD 9 ; Gregory M. Videtic, MD. 10 Summary of Literature Review Introduction Options in the postoperative setting for patients with nonsmall-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 Postoperative Radiotherapy 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 1 Principal Author, Yale University School of Medicine, New Haven, Connecticut. 2 Co-author, Fox Chase Cancer Center, Philadelphia, Pennsylvania, American Society of Clinical Oncology. 3 Panel Chair, Henry Ford Health System, Detroit, Michigan. 4 Panel Vice-chair, Mount Sinai School of Medicine, New York, New York. 5 MD Anderson Cancer Center, Houston, Texas. 6 Memorial Sloan-Kettering Cancer Center, Rockville Centre, New York. 7 Columbia University, New York, New York, Society of Thoracic Surgeons. 8 VA Health Center, Ann Arbor, Michigan. 9 University of Miami, Miami, Florida. 10 Cleveland Clinic Foundation, Cleveland, Ohio. 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 individual or society endorsement of the final document. Reprint requests to: Department of Quality & Safety, American College of Radiology, 1891 Preston White Drive, Reston, VA 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 al [2] evaluated the extent of mediastinal surgical resection in 373 patients accrued to 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 (ACOSOG), the results of which are not yet available. Postoperative Radiotherapy for Mediastinal Lymph Nodes The PORT meta-analysis [3] pooled the outcomes of patients with stage I to III NSCLC, randomized to observation or PORT in seven published [4-10] and two unpublished trials, European Organisation for Research and Treatment of Cancer (EORTC) and Lung Cancer Study Group (LCSG) 841. It was subsequently updated to include an additional published trial [11], for a total of 2,232 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 metaanalysis 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 years) at publication; and the radiation ACR Appropriateness Criteria 1 Postoperative Adjuvant Therapy NSCLC

2 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 al [13] sought to examine PORT in a more modern era using the Surveillance, Epidemiology and End Results (SEER) database. The authors identified 7,465 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 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% versus 20% at 5 years). SEER analyses have several known shortcomings, among them 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 Europe assessing the role of postoperative radiation in patients with N2 disease treated with surgery and chemotherapy. Several authors have investigated the toxicity of PORT, when delivered with modern radiation techniques. The use of CT simulation and three-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 al [16] in a retrospective review of 208 patients treated postoperatively between 1982 and 1998 with modern treatment planning, compared the risk of intercurrent death with age-matched and gender-matched mortality rates. They found a small but nonsignificant increase in intercurrent death rates associated with PORT. Wakelee et al [17] 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 al [18] 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 (HR 1.49), but was not associated with any significant increase in cardiac death in patients treated between 1989 and 1993 (HR 1.08, NS). These studies support the hypothesis that PORT delivered using modern radiation technology is associated with a lower risk of treatment-related death (TRD) than has been noted in older, randomized studies, and therefore TRD is less likely to detract from a potential survival benefit in more modern trials. Postoperative Radiotherapy Dose 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 al [20] comments that most of the recurrences in their retrospective review 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 al [21] prescribed 50 to 56 Gy, Feng et al [22] prescribed 60 Gy, the LCSG 773 trial [4] prescribed 50 Gy, Trodella et al [11] prescribed 50.4 Gy, and the Groupe d Etude et de Traitement des Cancers Bronchiques (GETCB) trial [5] 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 trial [23] prescribed 50.4 Gy in 28 fractions, either alone or with concurrent cisplatin and etoposide. Radiation Therapy Oncology Group (RTOG ) 9705 [24] 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 Center [25] 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 three 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 regarding the adoption of IMRT in the treatment of lung cancer. The most widely used normal tissue dosevolume constraints (ie, V20, mean lung dose) were derived from patients treated with 2D or 3D radiation ACR Appropriateness Criteria 2 Postoperative Adjuvant Therapy NSCLC

3 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 RT 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 3D conformal technique. The use of IMRT resulted in lower dose to the uninvolved lung, and decreased the normal tissue complication probability (NTCP), compared to 3D planning [26]. In a similar study conducted at William Beaumont Hospital in 18 patients, IMRT plans were able to deliver higher radiation dose to patients with mediastinal lymph nodes compared to 3D conformal plans, without increasing the NTCP for 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 MD Anderson Cancer Center, 68 patients with NSCLC were treated with IMRT when 3D 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. Memorial Sloan-Kettering Cancer Center reported on 55 patients who received IMRT, again selected due to unsuitability for 3D planning [28]. Significant pulmonary toxicity was noted in 11% of patients. Neither study included patients treated adjuvantly. Particle Therapy 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 3D conformal RT for stage I and III NSCLC [29]. Proton treatment resulted in the lowest dose to 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; two 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. (See Variant 1, Variant 2 and Variant 3.) Postoperative Radiotherapy for Chest Wall Tumors Invasion of the chest wall (American Joint Committee on Cancer [AJCC] 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 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 following 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, since 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 al [36] reported on 93 patients who underwent definitive surgery for lung cancer involving the chest wall from Sixty-six had completed en bloc resections, and of these, 31 had T3N0 disease. Sixteen 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 al [34] 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 al [37] 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 nine (78%) who received PORT were alive at 5 years compared to only 3 of the 14 (21%) who received no PORT. None of the 13 patients who received PORT experienced local recurrence, while 6 of 22 (27%) who were not irradiated failed locally. Burkhart et al [38] reported on 95 patients who underwent margin-negative, en bloc resection of T3 NSCLC. No PORT was given, and the survival rate after ACR Appropriateness Criteria 3 Postoperative Adjuvant Therapy NSCLC

4 complete resection was similar to that seen for resected T2 tumors. Local failure was not reported. Gould et al [39] 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, and it appears 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 appear to be at increased risk of recurrence locally, and there is no demonstrable benefit to PORT in that group. (See Variant 4.) Postoperative Chemotherapy The potential benefit of postoperative chemotherapy without or with PORT has been evaluated in a number of randomized trials using regimens based on 5-FU, alkylating agents, and platinum combinations. The Nonsmall Cell Lung Cancer Collaborative Group [40] published a meta-analysis in 1995 evaluating the effect of chemotherapy on NSCLC which included 14 trials and 4,357 patients. Five trials used alkylating agents, eight used cisplatin-containing regimen, and three used tegafur or tegafur-uracil (UFT). The authors noted a significantly decreased survival in the studies employing 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 al [41] 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- 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 metaanalysis have examined the efficacy of adjuvant platinumbased chemotherapy compared to observation. Three of the trials showed no significant benefit. In a Japan Clinical Oncology group (JCOG) study, Tada et al [43] 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 (ALPI) trial [44] compared cisplatin, vindesine, and mitomycin C (MVP) for three 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 two groups, although there was a nonsignificant trend towards improved overall survival in the subset of stage II patients. The Big Lung Trial (BLT) [45] included 384 patients treated with one of four platinum-based chemotherapy regimens after surgical resection. There was no difference in overall survival compared to observation. In contrast, a number of more recent trials have demonstrated a significant improvement in recurrencefree or overall survival. The International Adjuvant Lung Cancer Trial (IALT) [46] compared no further treatment to one of four schedules of cisplatin plus either vinorelbine, vindesine, vinblastine, or etoposide in 1,867 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 trial [50] reported the results of 344 patients with stage IB NSCLC, who were randomized following 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 to 0.1. However, in a post-hoc analysis of patients with tumors 4 cm, a significant overall survival advantage was maintained. Mineo et al [51] 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 study [52] 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 appeared to be limited to patients with stage II or III disease. Finally, the Lung Adjuvant Cisplatin Evaluation (LACE) [53] meta-analysis pooled the results of 4,584 patients treated on the five largest platinumbased adjuvant trials (ALPI, ANITA, BLT, 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 following 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 ACR Appropriateness Criteria 4 Postoperative Adjuvant Therapy NSCLC

5 chemotherapy; there appeared 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 two 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. Postoperative Chemoradiotherapy 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 fashion [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. RTOG 9705 [24] 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 to ECOG 3590 (median survival times of 56.3 months vs 33.7 months, respectively). The local failure rates were similar between the studies. In a phase II study conducted at Fox Chase Cancer Center [25] 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 three 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 trial [55] 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 et al [56] 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 al [57] 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 plus vincristine and lomustine for 3 cycles, then the same radiotherapy. There was no difference in disease-free or overall survival rates. Keller et al [23] in a report of an intergroup trial (ECOG 3590), showed that four cycles of cisplatin and VP-16, two given concurrently with PORT and two given after the conclusion of PORT, did not increase survival when compared to PORT alone. PORT appears 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. Conclusions For patients with stage II or III NSCLC, multiple randomized trials and two 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. (See Variant 5.) Supporting Document(s) ACR Appropriateness Criteria Overview Evidence Table ACR Appropriateness Criteria 5 Postoperative Adjuvant Therapy NSCLC

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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(3): 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(10): Koto M, Tsujii H, Yamamoto N, Nishimura H, Yamada S, Miyamoto T. 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(2): McCaughan BC, Martini N, Bains MS, McCormack PM. Chest wall invasion in carcinoma of the lung. Therapeutic and prognostic implications. J Thorac Cardiovasc Surg 1985; 89(6): 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. 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7 wall resection for bronchogenic carcinoma. Ann Thorac Surg 1982; 34(6): Burkhart HM, Allen MS, Nichols FC, 3rd, et al. Results of en bloc resection for bronchogenic carcinoma with chest wall invasion. J Thorac Cardiovasc Surg 2002; 123(4): Gould PM, Bonner JA, Sawyer TE, Deschamps C, Lange CM, Li H. 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(1): Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311(7010): Hamada C, Tanaka F, Ohta M, et al. Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in nonsmall-cell lung cancer. J Clin Oncol 2005; 23(22): Booth C, Shepherd F. Adjuvant Chemotherapy for Resected Nonsmall Cell Lung Cancer. Journal of Thoracic Oncology 2006; 1(2): 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(2): 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(19): 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(1): Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350(4): 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. 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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(9): 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(21): Douillard JY, Rosell R, De Lena M, Riggi M, Hurteloup P, Mahe MA. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-smallcell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 2008; 72(3): The benefit of adjuvant treatment for resected locally advanced non-small-cell lung cancer. The Lung Cancer Study Group. J Clin Oncol 1988; 6(1): Pisters KM, Le Chevalier T. Adjuvant chemotherapy in completely resected non-small-cell lung cancer. J Clin Oncol 2005; 23(14): 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(5): 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(9): The ACR Committee on Appropriateness Criteria and its expert panels have developed criteria for determining appropriate imaging examinations for diagnosis and treatment of specified medical condition(s). These criteria are intended to guide radiologists, radiation oncologists and referring physicians in making decisions regarding radiologic imaging and treatment. Generally, the complexity and severity of a patient s clinical condition should dictate the selection of appropriate imaging procedures or treatments. Only those examinations generally used for evaluation of the patient s condition are ranked. Other imaging studies necessary to evaluate other co-existent diseases or other medical consequences of this condition are not considered in this document. The availability of equipment or personnel may influence the selection of appropriate imaging procedures or treatments. Imaging techniques classified as investigational by the FDA have not been considered in developing these criteria; however, study of new equipment and applications should be encouraged. The ultimate decision regarding the appropriateness of any specific radiologic examination or treatment must be made by the referring physician and radiologist in light of all the circumstances presented in an individual examination. ACR Appropriateness Criteria 7 Postoperative Adjuvant Therapy NSCLC

8 Clinical Condition: Variant 1: Postoperative Adjuvant Therapy in Non-Small-Cell Lung Cancer T2N1 (hilar) with careful mediastinal surgical staging. Negative surgical margins postresection. Treatment Rating Comments Postoperative Adjuvant Therapy Chemo 9 Chemo then RT 2 Concurrent chemo plus RT 1 Chemo then concurrent RT plus chemo 1 RT alone 1 Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate Variant 2: T2N2 with careful mediastinal staging, highest node negative. Negative surgical margins postresection. Postoperative Adjuvant Therapy Treatment Rating Comments Chemo 7 Chemo then RT 8 Concurrent chemo plus RT 4 Chemo then concurrent RT plus chemo 3 RT alone 3 Dose Utilized 30 Gy/2 weeks Gy/2-3 weeks Gy/5-6 weeks Gy /6-7 weeks Gy/7-8 weeks Gy/58 fractions (bid) 1 Treatment Planning Techniques 2D planning (AP/PA and/or off-cord obliques) 3 3D planning 9 IMRT 6 May be appropriate if there is extracapsular extension (ECE). Particle therapy No Consensus Promising strategy requiring more clinical studies. Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate ACR Appropriateness Criteria 8 Postoperative Adjuvant Therapy NSCLC

9 Clinical Condition: Variant 3: Postoperative Adjuvant Therapy in Non-Small-Cell Lung Cancer Clinically staged T2N0, pathologically staged T2N1, no sampling of mediastinal nodes. Negative surgical margins postresection. Clinically staged T2N0 by PET/CT. Treatment Rating Comments Postoperative Adjuvant Therapy Chemo 9 Chemo then RT 5 Concurrent chemo plus RT 1 Chemo then concurrent RT plus chemo 1 RT alone 2 Dose Utilized 30 Gy/2 weeks Gy/2-3 weeks Gy/5-6 weeks Gy /6-7 weeks 5 May be appropriate if there is ECE at hilum Gy/7-8 weeks Gy/58 fractions (bid) 1 Treatment Planning Techniques 2D planning (AP/PA and/or off-cord obliques) 3 3D planning 9 IMRT 6 Particle therapy No Consensus Promising strategy requiring more clinical studies. Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate Variant 4: T3N0 with chest wall invasion, with mediastinal node staging. Negative surgical margins postresection. Treatment Rating Comments Postoperative RT chest wall primary site 2 Postoperative RT mediastinum 1 Postoperative Adjuvant Therapy Chemo alone 8 Chemo then RT 2 Concurrent chemo plus RT 2 Chemo then concurrent RT plus chemo 1 RT alone 1 Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate ACR Appropriateness Criteria 9 Postoperative Adjuvant Therapy NSCLC

10 Clinical Condition: Variant 5: Postoperative Adjuvant Therapy in Non-Small-Cell Lung Cancer T3N2 with mediastinal node staging. Positive margins at the primary site. Treatment Rating Comments Postoperative RT chest wall primary site 9 Postoperative RT mediastinum 9 Postoperative Adjuvant Therapy Chemo then RT 5 RT then Chemo 5 Concurrent chemo plus RT 8 Chemo then concurrent RT plus chemo 5 RT alone 2 Dose Utilized Mediastinum / Hilum 30 Gy/2 weeks Gy/2-3 weeks Gy/5-6 weeks Gy /6-7 weeks 5 May be appropriate if there is ECE Gy/7-8 weeks Gy/58 fractions (bid) 2 Dose Utilized Positive Margin 30 Gy/2 weeks Gy/2-3 weeks Gy/5-6 weeks Gy /6-7 weeks Gy/7-8 weeks Gy/58 fractions (bid) 1 Treatment Planning Techniques 2D planning (AP/PA and/or off-cord obliques) 3 3D planning 9 IMRT 6 Particle therapy No Consensus Promising strategy requiring more clinical studies. Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate ACR Appropriateness Criteria 10 Postoperative Adjuvant Therapy NSCLC