This is the current release of the guideline.

This guideline updates a previous version: Weisenburger TH, Komaki RU, Bradley J, Gewanter RM, Gopal RS, Movas B, Rosenzweig KE, Thoms WW Jr, Wolkov HB, Kaiser LR, Schiller JH, Expert Panel on Radiation Oncology-Lung. Postoperative adjuvant therapy in non-small-cell lung cancer. [online publication]. Reston (VA): American College of Radiology (ACR); 2006. 13 p.

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Non-small-cell lung cancer (NSCLC)

To evaluate the appropriateness of postoperative adjuvant therapy in treatment of patients with non-small-cell lung cancer

Patients with non-small-cell lung cancer

Literature Search Procedure

The Medline literature search is based on keywords provided by the topic author. The two general classes of keywords are those related to the condition (e.g., ankle pain, fever) and those that describe the diagnostic or therapeutic intervention of interest (e.g., mammography, MRI).

The search terms and parameters are manipulated to produce the most relevant, current evidence to address the American College of Radiology Appropriateness Criteria (ACR AC) topic being reviewed or developed. Combining the clinical conditions and diagnostic modalities or therapeutic procedures narrows the search to be relevant to the topic. Exploding the term "diagnostic imaging" captures relevant results for diagnostic topics.

The following criteria/limits are used in the searches.

1. Articles that have abstracts available and are concerned with humans.
2. Restrict the search to the year prior to the last topic update or in some cases the author of the topic may specify which year range to use in the search. For new topics, the year range is restricted to the last 5 years unless the topic author provides other instructions.
3. May restrict the search to Adults only or Pediatrics only.
4. Articles consisting of only summaries or case reports are often excluded from final results.

The search strategy may be revised to improve the output as needed.

The total number of source documents identified as the result of the literature search is not known.

Strength of Evidence Key

Category 1 - The conclusions of the study are valid and strongly supported by study design, analysis and results.

Category 2 - The conclusions of the study are likely valid, but study design does not permit certainty.

Category 3 - The conclusions of the study may be valid but the evidence supporting the conclusions is inconclusive or equivocal.

Category 4 - The conclusions of the study may not be valid because the evidence may not be reliable given the study design or analysis.

The topic author drafts or revises the narrative text summarizing the evidence found in the literature. American College of Radiology (ACR) staff draft an evidence table based on the analysis of the selected literature. These tables rate the strength of the evidence for all articles included in the narrative text.

The expert panel reviews the narrative text, evidence table, and the supporting literature for each of the topic-variant combinations and assigns an appropriateness rating for each procedure listed in the table. Each individual panel member forms his/her own opinion based on his/her interpretation of the available evidence.

More information about the evidence table development process can be found in the American College of Radiology (ACR) Appropriateness Criteria® Evidence Table Development document (see "Availability of Companion Documents" field).

Modified Delphi Technique

The appropriateness ratings for each of the procedures included in the Appropriateness Criteria topics are determined using a modified Delphi methodology. A series of surveys are conducted to elicit each panelist's expert interpretation of the evidence, based on the available data, regarding the appropriateness of an imaging or therapeutic procedure for a specific clinical scenario. American College of Radiology (ACR) staff distributes surveys to the panelists along with the evidence table and narrative. Each panelist interprets the available evidence and rates each procedure. The surveys are completed by panelists without consulting other panelists. The ratings are a scale between 1 and 9, which is further divided into three categories: 1, 2, or 3 is defined as "usually not appropriate"; 4, 5, or 6 is defined as "may be appropriate"; and 7, 8, or 9 is defined as "usually appropriate." Each panel member assigns one rating for each procedure per survey round. The surveys are collected and the results are tabulated, de-identified and redistributed after each round. A maximum of three rounds are conducted. The modified Delphi technique enables each panelist to express individual interpretations of the evidence and his or her expert opinion without excessive bias from fellow panelists in a simple, standardized and economical process.

Consensus among the panel members must be achieved to determine the final rating for each procedure. Consensus is defined as eighty percent (80%) agreement within a rating category. The final rating is determined by the median of all the ratings once consensus has been reached. Up to three rating rounds are conducted to achieve consensus.

If consensus is not reached, the panel is convened by conference call. The strengths and weaknesses of each imaging procedure that has not reached consensus are discussed and a final rating is proposed. If the panelists on the call agree, the rating is accepted as the panel's consensus. The document is circulated to all the panelists to make the final determination. If consensus cannot be reached on the call or when the document is circulated, "No consensus" appears in the rating column and the reasons for this decision are added to the comment sections.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

Criteria developed by the Expert Panels are reviewed by the American College of Radiology (ACR) Committee on Appropriateness Criteria.

ACR Appropriateness Criteria®

Clinical Condition: Postoperative Adjuvant Therapy in Non-Small-Cell Lung Cancer

Variant 1: T2N1 (hilar) with careful mediastinal surgical staging. Negative surgical margins post resection.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 2: T2N2 with careful mediastinal staging, highest node negative. Negative surgical margins post resection.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 3: Clinically staged T2N0, pathologically staged T2N1, no sampling of mediastinal nodes. Negative surgical margins post resection. Clinically staged T2N0 by PET/CT.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 4: T3N0 with chest wall invasion, with mediastinal node staging. Negative surgical margins postresection.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 5: T3N2 with mediastinal node staging. Positive margins at the primary site.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Summary of Literature Review

Introduction

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 Postoperative Radiotherapy

The role of PORT in patient with NSCLC has been examined in retrospective studies, randomized trials, and a meta-analysis. The populations of patient studied have been heterogeneous with respect to histology, tumor (T) and nodule (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. 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. One study 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 pooled the outcomes of patients with stage I to III NSCLC, randomized to observation or PORT in seven published and two unpublished trials, European Organisation for Research and Treatment of Cancer (EORTC) 08861 and Lung Cancer Study Group (LCSG) 841. It was subsequently updated to include an additional published trial, for a total of 2,232 patients enrolled between 1966 and 1997. 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 years) 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 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 patients 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 computed tomography (CT) simulation and three-dimensional planning should result in better target coverage and lower normal tissue irradiation, and this seems to be borne out in more modern treatment series. One group of researchers 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. Another group of researchers 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. A third group 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. One group of researchers 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. Another group of researchers prescribed 50 to 56 Gy, several authors prescribed 60 Gy, the LCSG 773 trial prescribed 50 Gy, and the Groupe d'Etude et de Traitement des Cancers Bronchiques (GETCB) trial prescribed 60 Gy. The Medical Research Council Study found improved local control following 40 Gy in 3 weeks.

Three large prospective trials have examined PORT given concurrently with chemotherapy: The ECOG 3590 trial prescribed 50.4 Gy in 28 fractions, either alone or with concurrent cisplatin and etoposide. Radiation Therapy Oncology Group (RTOG®) 9705 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, 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 dose-volume constraints (i.e., V20, mean lung dose) were derived from patients treated with 2D or 3D 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 RT doses have been suggested for use in IMRT planning (i.e., 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. 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. 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. 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. 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. 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. 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. 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.

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.

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, a known risk factor for local recurrence. 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.

One study reported on 93 patients who underwent definitive surgery for lung cancer involving the chest wall from 1960 to 1980. Sixty-six had complete 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. Another study 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%.

One group of researchers 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. Another group of researchers 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. A third group 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.

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 fluorouracil (5-FU), alkylating agents, and platinum combinations. The Non-small Cell Lung Cancer Collaborative Group 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). One study 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. 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 to observation. Three of the trials showed no significant benefit. In a Japan Clinical Oncology group (JCOG) study, a group of researchers 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 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) 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 recurrence-free or overall survival. The International Adjuvant Lung Cancer Trial (IALT) 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) 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. 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 reported the results of 344 patients with stage IB NSCLC, who were randomized following complete resection to observation or 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. Another study 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 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) meta-analysis pooled the results of 4,584 patients treated on the five largest platinum-based 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 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. 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. 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 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 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 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. Another study 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. A third study 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. 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 (e.g., a positive surgical margin), concurrent therapy may be appropriate, extrapolating from studies demonstrating a benefit to concurrent chemoradiotherapy in patients with gross unresectable disease. 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.

Abbreviations

• 2D, two-dimensional
• 3D, three-dimensional
• AP/PA, anterior-posterior/posterior-anterior
• bid, twice a day
• Chemo, chemotherapy
• CT, computed tomography
• ECE, extracapsular extension
• IMRT, intensity-modulated radiation therapy
• PET, positron emission tomography
• RT, radiation therapy
• TN, primary tumor, regional lymph node

Algorithms were not developed from criteria guidelines.

The recommendations are based on analysis of the current literature and expert panel consensus.

Selection of appropriate postoperative adjuvant therapy for patients with non-small-cell lung cancer (NSCLC)

Subgroups Most Likely to Benefit

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 American College of Radiology (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 U.S. Food and Drug Administration (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.

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

The American College of Radiology (ACR) provided the funding and the resources for these ACR Appropriateness Criteria®.

Committee on Appropriateness Criteria, Expert Panel on Radiation Oncology–Lung

Panel Members: Roy H. Decker, MD; Corey J. Langer, MD; Benjamin Movsas, MD; Kenneth E. Rosenzweig, MD; Joe Yujiao Chang, MD, PhD; Richard M. Gewanter, MD; Mark E. Ginsburg, MD; Feng-Ming Kong, MD, PhD, MPH; Brian E. Lally, MD; Gregory M. Videtic, MD

Not stated

This is the current release of the guideline.

This guideline updates a previous version: Weisenburger TH, Komaki RU, Bradley J, Gewanter RM, Gopal RS, Movas B, Rosenzweig KE, Thoms WW Jr, Wolkov HB, Kaiser LR, Schiller JH, Expert Panel on Radiation Oncology-Lung. Postoperative adjuvant therapy in non-small-cell lung cancer. [online publication]. Reston (VA): American College of Radiology (ACR); 2006. 13 p.

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site.

Print copies: Available from the American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. Telephone: (703) 648-8900.

The following are available:

• ACR Appropriateness Criteria®. Overview. Reston (VA): American College of Radiology; 2 p. Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site.
• ACR Appropriateness Criteria®. Literature search process. Reston (VA): American College of Radiology; 1 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.
• ACR Appropriateness Criteria®. Evidence table development. Reston (VA): American College of Radiology; 4 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.

None available

This NGC summary was completed by ECRI Institute on May 10, 2007. This NGC summary was updated by ECRI Institute on July 7, 2011.

Instructions for downloading, use, and reproduction of the American College of Radiology (ACR) Appropriateness Criteria® may be found on the ACR Web site .