ACR Appropriateness Criteria Nonsurgical Treatment for Non-Small-Cell Lung Cancer: Good Performance Status/Definitive Intent

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1 ACR Appropriateness Criteria Nonsurgical Treatment for Non-Small-Cell Lung Cancer: Good Performance Status/Definitive Intent Richard M. Gewanter, MD, Kenneth E. Rosenzweig, MD, Joe Yujiao Chang, MD, PhD, Roy Decker, MD, Sarita Dubey, MD, Feng-Ming Kong, MD, PhD, MPH, Brian E. Lally, MD, Corey J. Langer, MD, Hoon Ku Lee, MD, and Benjamin Movsas, MD The optimal strategy for the non-surgical definitive treatment of patients with good performance status non-small cell lung cancer (mostly with locally advanced disease) has dramatically evolved over time. This article presents evidence-based data to review this literature. Several decades ago, the standard treatment for most stage III inoperable NSCLC was definitive radiation therapy alone. Randomized trials have since shown superior results with sequential chemotherapy and radiation, and more recently with concurrent chemoradiation, the current standard of care. Studies suggest a limited role for induction or 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. Copyright 2010 American College of Radiology. Reprinted with permission of the American College of Radiology. Curr Probl Cancer 2010;34: /$ doi: /j.currproblcancer Curr Probl Cancer, May/June 2010

2 adjuvant systemic therapy in addition to concurrent chemoradiation. The role of altered radiation fractionation techniques, such as hyperfractionation for locally advanced disease or hypofractionation for early stage disease is also discussed. More recently, the application of more advanced radiation techniques has been explored, including intensity modulated radiation therapy (IMRT) and proton beam radiation. Finally, various case variants are presented as examples of state-of-the-art treatment approaches. Summary of Literature Review I n 1997, the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) adopted changes to the TNM-based staging system. 1 These changes, based mainly on data from small, single-institution databases, were retained in the 6 th edition of the AJCC Cancer Staging Manual (2002). 2 In 2009 the AJCC/UICC will adopt recommendations for a new staging system developed by the International Association for the Study of Lung Cancer (IASLC). 3 The 2009 modifications are based on a much more extensive, validated, multi-institutional database, and better account for the prognostic significance of tumor size. In the new staging system, tumor size 5 cm without positive nodes are stage II, and tumors 7 cm with positive N1 nodes are now relegated to stage IIIA. Same-lobe satellite tumor nodules are now T3 rather than T4, while having ipsilateral nodules in a different lobe now engenders a T4 designation (previously M1). Pleural or pericardial dissemination is to be relegated to stage IV. Patients with T4N0-1 tumors will now be stage IIIA rather than IIIB. As a result of these changes, treatment selections for patients with non-small-cell lung cancer (NSCLC) are likely to change as certain subsets of patients may be considered eligible for different regimens based on their new stage grouping. More early-stage patients may be considered eligible for adjuvant chemotherapy, and more advanced-stage patients may be considered surgical candidates. In addition, some stage-migration phenomena are likely to be seen in future clinical trials. Better results are likely to be seen for trials that enroll only early-stage patients, and these results should allow for better tailoring of treatment for these patients. Many of these favorable-risk patients may be more appropriately selected for emerging nonoperative techniques such as stereotactic hypofractionated radiation therapy (SBRT), while early-stage patients Curr Probl Cancer, May/June

3 with poor risk features can be included in trials of adjuvant systemic therapy. As before, stage I through stage IIIA patients are typically considered operable, with some benefiting from neoadjuvant or adjuvant chemotherapy with or without radiation therapy (RT). 4,5 However, some patients with stage I through stage IIIA (surgically resectable cancer) but having poor lung function or other medically inoperable conditions are candidates for aggressive RT with or without chemotherapy. These patients should be treated with 3-dimensional conformal radiation therapy (3D- CRT) to minimize damage to surrounding normal tissue. In addition, advanced tumor localization and treatment verification techniques such as gated RT or image-guided RT might be helpful in reducing the amount of normal lung tissue that needs to be treated. Stage IIIB will now include patients with more extensive tumor invading the mediastinum (T4) in the presence of ipsilateral mediastinal nodal metastases (N2), or lesser T-stage with metastasis to the contralateral mediastinum, contralateral hila, and ipsilateral or contralateral supraclavicular nodes (N3). They are considered to be surgically unresectable and are usually treated by chemoradiation, RT alone, or chemotherapy alone depending on their performance status and their symptoms. Those patients who have better performance status and 5% weight loss need to be treated with a more aggressive approach, such as concurrent chemotherapy and RT. 6,7 Those patients who have pleural effusion are now stage IVA, which better reflects their prognosis as being more similar to that of patients with distant metastases. These patients are usually treated by chemotherapy followed by palliative RT when indicated to relieve symptoms. Patients with painful or obstructive lesions who are not otherwise candidates for definitive radiation may require prompt palliative RT rather than palliative chemotherapy alone. Radiation Therapy Alone: Standard Fractionation RT alone used to be considered the standard treatment for patients with unresectable and locally advanced NSCLC. The Radiation Therapy Oncology Group (RTOG ) trial 8 tried to optimize time/dose scheduling of RT alone for patients with unresectable and locally advanced NSCLC, including those with poor performance status and 5% weight loss. This trial showed that better local control and 2-year survival were achieved by a total dose of 60 Gy in 6 weeks compared to a lower dose of RT alone. The investigators randomized 375 patients with inoperable or unresectable stage II and stage III cancer to be treated by 4 Gy/day 5 days/week with a 2-week break and repeated 4 Gy/day Curr Probl Cancer, May/June 2010

4 days/week, giving a total dose of 40 Gy in 6 weeks (split course), 40 Gy in 4 weeks, 50 Gy in 5 weeks, or 60 Gy in 6 weeks with continuous RT (2 Gy/day without split). The overall progression-free survival rates were 46% among the patients who received 40 Gy with a split course, 51% for those who received 40 Gy continuous course, 65% for those who received 50 Gy, and 61% for those who received 60 Gy. The difference in the response rates was statistically significant (49% vs 63%, P ) between the groups who received 40 Gy and those who received Gy. Two-year survival rates were 14% among the patients who received 40 Gy in 4 weeks with a continuous course and 18% for those who received Gy, compared to only 10% among those who received a split course, although this difference was not statistically significant. Patients who were treated with Gy with clinical tumor control had a survival rate of 22% in 3 years, compared to 10% if patients failed in the thorax (P 0.005). The initial response rate was significantly better among patients with adenocarcinoma and large-cell carcinoma (69%) compared to those with squamous-cell carcinoma (50%) (P 0.001). Altered Fractionation and Dose-Escalated Radiation Therapy Because of the poor 2-year survival and local control with standard radiation doses and fractionation, a randomized dose escalation study was initiated through RTOG This trial was an attempt to increase local control by using higher total doses, while using a twice-daily fractionation regimen to avoid increasing toxicities of late-responding normal tissue. 9 Eight hundred forty patients were treated with 1.2 Gy twice-daily fractionation separated by 4-6 hours. They were randomized to receive minimum total doses of 60 Gy, 64.8 Gy, and 69.6 Gy. After acceptable acute toxicities, 74.4 Gy and 79.2 Gy arms were added. The best arm received 69.6 Gy in 6.5 weeks and showed a 2-year survival rate of 29% for patients with good performance status and 5% weight loss, which was significantly better than the survival rates among patients who received lower doses (P 0.02). The European Organisation for Research and Treatment of Cancer (EORTC) conducted a randomized study for patients with inoperable or unresectable stage II or III NSCLC who were treated by standard RT (60 Gy in 6 weeks) or continuous, hyperfractionated, accelerated RT (CHART). The majority of the patients had squamous cell carcinoma on histology. CHART was given at 1.5 Gy fractions 3 times a day, 7 days/week with at least a 6-hour interfractional interval. The large volume dose was 37.5 Gy in 25 fractions followed by 16.5 Gy in 11 fractions, Curr Probl Cancer, May/June

5 giving a total dose of 54 Gy. The updated results showed improvement in survival and local control with CHART compared to standard RT (3-year survival rate with the results of CHART was 20% vs 13% with standard RT, and 3-year local control with CHART was 17% vs 12% with standard RT). 10 More moderate or severe acute dysphagia affected 49% of CHART cases, compared with 19% of those treated conventionally. However, there was no significant difference between the two arms in the rate of late complications. Intensity-Modulated Radiation Therapy Attempts to improve tumor control by dose escalation have been limited by the tolerance of normal tissues, especially lung and esophagus. Intensity-modulated radiation therapy (IMRT) has been shown to significantly reduce the doses to normal tissues, and it is therefore a promising technique for facilitating safe dose escalation. Concerns exist regarding the application of IMRT to lung tumors, relating to the accuracy of inhomogeneity calculations, the accurate targeting of a moving lung tumor with a sliding window IMRT technique, and the increase in the percent lung volume receiving low doses. Data on clinical use of IMRT for lung cancer patients are sparse. Investigators at MD Anderson Cancer Center generated IMRT plans for 41 stage III, IV, and recurrent NSCLC patients who had been previously treated with 3D-CRT and found that the IMRT allowed for greater sparing of normal tissues, including heart, lung, and esophagus, with lower probability of lung complications using dosimetric models. 11 A follow-up retrospective report of 151 NSCLC patients treated with IMRT showed an 8% incidence of treatment-related grade 3 pneuomonitis at 12 months, compared with 23% for a similar group of 222 patients treated with 3D-CRT, despite the fact that the IMRT group had a larger mean gross tumor volume. 12 The Memorial Sloan-Kettering Cancer Center experience was reported. 13 Fifty-five patients with stage I-IIIB NSCLC were selected to receive IMRT, mainly due to large tumor size and proximity to critical organs. Doses of cgy were used, and 76% received chemotherapy. The National Tuberculosis Control Program (NTCP) and f dam lung constraints were used, and inhomogeneity correction was applied. Toxicity was not increased in these patients, and 2-year local control and overall survival rates compared favorably with larger prospective series. In summary, IMRT has shown promise in dosimetry modeling studies for reducing normal tissue complication probability to allow for dose escalation in lung cancer patients. Early clinical reports of IMRT indicate 232 Curr Probl Cancer, May/June 2010

6 favorable toxicity profiles and tumor control. Prospective trials are underway to further evaluate this technology in the clinical setting. Proton Beam Radiotherapy Particle beams such as proton, carbon, and neutron beams have potential dosimetric advantages over photon beam therapy. As therapeutic proton beam radiation becomes more widely available, much interest has been generated in examining the potential benefits of this modality for treating lung cancer. The physical characteristics of the proton beam would seem to allow for greater sparing of normal tissues, although there are also unique concerns about its use for lung tumors. The small amount of clinical data on its use consists of small single-institution series. These data as a whole can be challenging to interpret, as various different techniques have been used by these institutions, making comparisons between studies difficult. In one of the larger studies of protons for early-stage disease, clinical stage I patients were treated with two hypofractionation regimens (51 GY RBE or 60 GY RBE in 10 fractions). Local control rates were 87% for T1 lesions and 49% for T2, and side effects were mild to moderate, without pneumonitis. Nihei et al. 15 conducted a dose escalation study using protons at dose levels from CGE (4-4.9 CGE/fraction). Thirty-seven stage I patients were treated, with a local control rate of 80%. They reported three cases of late pulmonary toxicity. Recent report showed that adaptive proton therapy to ablative doses (87.5 Gy RBE with 2.5 Gy/fraction) is well tolerated and produces promising local control rates (89%) for medically inoperable T1N0M0 (central location) or T2-3N0M0 (any location) NSCLC. 16 A study of proton beam therapy for advanced-disease patients was reported by Shioyama et al. 17 They treated 14 patients with stage III, IV, and recurrent disease. For the nine stage III-IV patients, overall survival rates at 2 and 5 years were 62% and 0%, respectively. The first phase II clinical trial using concurrent chemo and proton therapy to 74 Gy (RBE) in 42 patients with stage III NSCLC was presented recently and 87% local control was achieved with no grade 4 and above toxicity and minimal grade 3 esophagitis/pneumonitis. 18 Some technical issues unique to proton beam therapy have been discussed. There is some geometric uncertainty about the range of a given proton beam, and differences in tissue density between tumors and surrounding normal lung tissue can have a profound effect on proton beam planning. To deal with these issues, authors have discussed modifications to the proton therapy concept, and the use of compensatory smearing to ensure target coverage. 19 Hopefully, larger, prospective, Curr Probl Cancer, May/June

7 controlled trials that are underway will clarify the role of proton beam and other particle therapies for lung cancer in the near future. Combined Chemotherapy and Radiation Therapy Given the poor outcome with RT alone and the high rate of metastatic disease, combined chemotherapy and RT approaches were designed in an attempt to improve outcomes. The Cancer and Leukemia Group B (CALGB) 20 randomized 155 patients with stage III NSCLC with good performance status and 5% weight loss who were treated with 2 cycles of vinblastine and cisplatin followed by RT (60 Gy in 6 weeks) or with RT alone (60 Gy in 6 weeks). Patients who were treated by induction chemotherapy followed by RT had a median survival time of 13.8 months (78 patients) compared to 9.7 months for those (77 patients) treated by RT alone. The 2-year survival rate was significantly better among the patients who received combined treatment compared to those who received RT alone, 26% vs 13% (P 0.006). The longer follow-up of this study showed that the 5-year survival rate of patients who received combined treatment was 19%, compared to 7% for those who received RT alone. LeChevalier et al. 21 also reported that a phase III randomized study comparing RT alone to combined chemotherapy and RT showed a significant improvement in 3-year survival rate with combined treatment, 12% vs 4% (P 0.02). Median survival times were 12 months and 10 months, respectively. However, there was no difference in regard to the local control. The RTOG trial 22 randomized 452 patients with stage III NSCLC, good performance status, and 5% weight loss to be treated in three arms. Arm 1 received combined chemotherapy and radiotherapy (CRT). The chemotherapy, using vinblastine and cisplatin, was administered in 2 cycles and was followed by RT with 60 Gy over 6½ weeks. Patients in the other two arms received RT alone, one using 60 Gy of standard fractionation (ST) RT in 6 weeks, the other using 69.6 Gy of hyperfractionated (HFX) RT with a fraction size of 1.2 Gy. The median survival time was 13.2 months in the CRT arm compared to 11.4 months among the patients who received ST RT. The 2-year survival rate was 32% among the patients who received combined treatment vs 19% among the patients who received ST RT alone (P 0.003). The outcome in the HFX RT arm was intermediate between the other two arms (mean survival time of 12 months; 2-year overall survival rate 24%; P 0.08 compared to CRT). Five-year survival rates, however, were 10% in all the study arms. Other phase III trials have been reported since 1988, including an 234 Curr Probl Cancer, May/June 2010

8 EORTC study 23 with a daily cisplatin and simultaneous RT arm, showing a significantly improved 2-year survival rate, 26% compared to 13% among the patients who received RT alone (P 0.009). However, the RT schedule was not considered optimal as a standard of RT in the U.S. The control arm of RT was given 3 Gy in 10 fractions with a 3- to 4-week break followed by 2.5 Gy in 10 fractions as a boost. Wolf et al. 24 also showed an improved median survival time and 2-year survival rate by combined treatment compared to RT alone, 13.7 months vs 9.0 months and 24% vs 12%, respectively. Still other phase III trials have not found any significant improvement by adding chemotherapy to RT Trovo et al. 29 reported that giving cisplatin concurrently with RT of 45 Gy in 3 weeks (3 Gy/day 5 days/week) vs RT alone (45 Gy in 3 weeks) did not show any significant difference in local control and survival. Morton et al. 27 randomized 121 patients to RT alone vs cyclophosphamide, doxorubicin, and cisplatin as induction chemotherapy followed by RT. The latter did not provide any significant improvement in median survival. Mattson et al. 26 randomized 238 patients to RT alone vs chemotherapy [CAP (cyclophosphamide, adriamycin, and cisplatin) regimen] followed by RT and did not find any significant difference in the median survival. Groen et al. 30 randomized 160 patients to RT alone vs continuous infusion carboplatin concurrent with RT. No significant difference in local control or survival was seen at 2 years. Several meta-analyses have now examined the benefit of adding chemotherapy to radiation for stage IIIA and IIIB NSCLC. The Non- Small Cell Lung Cancer Collaborative Group analyzed updated individual patient data from 22 trials, including 3,033 patients. The group excluded all trials in which chemotherapy was given only during RT. Five trials used long-term alkylating agents, mainly cyclophosphamide or nitrosourea in combination with methotrexate. Three used vinca alkaloids or etoposide, and three used other regimens, mostly based on doxorubicin. Eleven trials used chemotherapy regimens containing cisplatin. The group found a significant overall benefit of chemotherapy, which resulted in a 10% reduction in the risk of death, corresponding to absolute benefits of 3% at 2 years and 2% at 5 years. Trials using cisplatin-based chemotherapy gave the strongest evidence in favor of chemotherapy, with absolute benefits of 4% at 2 years and 2% at 5 years. 31 Marino et al. 32 performed a meta-analysis of data extracted from published reports of clinical trials evaluating combined radiation plus chemotherapy vs radiation alone for stage IIIA/B NSCLC. Fourteen trials were analyzed, comprising 1,887 patients. They found a 30% reduction in Curr Probl Cancer, May/June

9 mortality at 2 years for cisplatin-based chemotherapy vs radiotherapy alone, compared with an 18% reduction in mortality at 2 years for the non-cisplatin-based group. No improvement in survival in either chemotherapy group was seen at 3 or 5 years, compared with radiation alone. The MAC3-LC Group 33 analyzed individual data from nine trials (1,764 patients) comparing concurrent CRT with radiotherapy alone. Eligible trials used cisplatin-based or carboplatin-based chemotherapy. The hazard ratio of death for the CRT group was 0.89 compared to RT alone, corresponding to an absolute benefit of chemotherapy of 4% at 2 years. These analyses have provided the evidence that has established combined platinum-based chemotherapy and radiation as the standard of care for the good-performance-status patient with unresectable stage IIIA and IIIB NSCLC and minimal weight loss. Further studies, as described below, have focused on ways of optimizing the sequencing of combination therapy, as well as techniques of radiation delivery and fractionation. Altered Fractionation Radiation Therapy Combined with Chemotherapy The North Central Cancer Treatment Group (NCCTG) conducted a three-arm phase III randomized trial for patients with unresectable (stage III) NSCLC treated with standard fractionated thoracic RT, accelerated HFX thoracic RT, or HFX RT with concurrent etoposide and cisplatin. The standard fractionation was 60 Gy in 30 fractions over 6 weeks. HFX RT was given to 1.5 Gy twice-daily fractionation with a 2-week break after the initial 30 Gy in 2 weeks. This HFX RT was given alone or with concurrent cisplatin (30 mg/m 2, days 1-3 and 28-30) and etoposide (100 mg/m 2, days 1-3 and 28-30). The study group analyzed 99 eligible patients out of the 110 patients entered. There was a suggestion of improvement in the rate of freedom from local recurrence and survival for patients with HFX RT with or without chemotherapy, compared to standard RT (P 0.06 and P 0.1, respectively). There was a significant improvement in survival with accelerated and HFX RT (with or without chemotherapy) in the subgroup of patients with non-squamous-cell carcinoma (P 0.02). There was no difference in freedom from distant metastasis or survival among the patients who received HFX RT with or without concurrent chemotherapy. This study suggested that the patients with stage III NSCLC treated with accelerated HFX RT with or without chemotherapy may have better freedom from local progression and survival compared to those receiving standard RT, especially for patients with non-squamous-cell carcinoma Curr Probl Cancer, May/June 2010

10 The NCCTG next tested concurrent chemotherapy plus once-daily (QD) vs twice-daily (BID) RT. 35 Both arms received cisplatin (30 mg/m 2 ) and etoposide (100 mg/m 2 ) on days 1 and 28 concurrent with RT. Grade 3 nonhematologic toxicity was slightly worse in the twice-daily RT arm. At 2 years there was no difference in local control or overall survival. Subgroup analysis suggested a survival benefit to twice daily in nonsquamous-cell histology, similar to previous findings by the NCCTG. This was in distinction to findings from RTOG (see below) that twice-daily RT improved local control in squamous cancers. RTOG was a randomized trial designed to test the hypothesis that the cytoprotectant amifostine would reduce the incidence of esophageal toxicity during concurrent chemotherapy and HFX RT. Patients received 2 cycles of induction chemotherapy with paclitaxel (225 mg/m 2 ) and carboplatin (area under the curve 6) on days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m 2 ) and carboplatin (AUC 2) with HFX RT (1.2 Gy BID to 69.6 Gy). Patients were randomized to receive or not to receive amifostine (AM) during the radiotherapy. The AM was administered once daily, 4 days a week, before the afternoon treatment. On RT-only days, AM was infused minutes prior to RT administration. On days when chemotherapy was given, RT was administered not later than 180 minutes after AM administration. Acute esophagitis was graded using the NCI Common Toxicity Criteria (CTC), and patients kept a self-assessed swallowing diary. The results showed no significant difference in the incidence of CTC grade 3 esophagitis (30% with AM vs 34% without AM; P 0.9); however, patient-reported swallowing symptoms were significantly less severe with AM, particularly in patients older than 65 years and in women. No differences in median survival or median time to progression were seen between the two arms. The authors concluded that while the trial did not support the hypothesis that AM reduces esophagitis, the findings of the patient-derived self-assessment suggested that further study of AM in lung cancer is warranted. Sequential versus Concurrent Chemotherapy and Radiation Therapy The West Japan Lung Cancer Group conducted a phase III study to investigate whether concurrent or sequential treatment with RT and chemotherapy improves survival for patients with unresectable stage III NSCLC. In the concurrent arm, chemotherapy consisted of cisplatin (80 mg/m 2 on days 1 and 29), vindesine (3 mg/m 2 on days 1, 8, 29, and 36), and mitomycin (8 mg/m 2 on days 1 and 29). RT began on day 2 at a dose of 28 Gy, 2 Gy fractions, 5 fractions/week for a total of 14 fractions. This Curr Probl Cancer, May/June

11 was repeated after a rest period of 10 days; the total tumor dose was therefore 56 Gy in 6 weeks. In the sequential arm, the same chemotherapy was given, with RT initiated after completing 2 cycles of chemotherapy. RT consisted of 56 Gy, 2 Gy/fractions, and 5 fractions/week for a total of 28 fractions. Three hundred twenty patients were entered in this study. The response rate for the concurrent arm was significantly higher (84%) compared to the sequential arm (66%) (P ). Median survival time was significantly improved in patients receiving concurrent chemotherapy and RT (16.5 months) compared with those receiving sequential therapy (13.3 months) (P 0.04). Two- and 5-year survival rates in the concurrent group were 34.6% and 15.8%, respectively, compared to 27.4% and 8.9% in the sequential group. Mild suppression was significantly greater among the patients who received concurrent chemotherapy and RT (P ). There was no significant difference in regard to acute esophagitis between the two groups. 6 Fournel et al. 37 reported results of the French GLOT-GFPC NPC randomized trial. Concurrent chemoradiation patients received etoposide and cisplatin concurrent with 66 Gy of once-daily RT, followed by adjuvant cisplatin/vinorelbine. The sequential arm received induction cisplatin and vinorelbine, followed by the same RT. Survival was better in the concurrent arm, but the difference was not significant. RTOG was a three-arm randomized trial comparing sequential (SEQ) chemotherapy followed by RT (once daily to 63 Gy) with two different concurrent chemoradiotherapy regimens. The latter consisted of either concurrent once-daily RT to 63 Gy (CON-QD), or concurrent twice-daily RT to 69.6 Gy (CON-BID). The SEQ and CON-QD arms each included 2 cycles of cisplatin and vinblastine. The CON-BID used 2 cycles of cisplatin and VP-16 based on the experience in RTOG Acute toxicity was worst in the CON-BID arm. Although time to in-field progression was best in the CON-BID arm, this did not translate into a survival benefit. The best survival times were in the CON-QD arm, significantly better than in the SEQ arm (P 0.046). Median survival times in the three arms were 14.6 months (SEQ), 17 months (CON-QD), and 15.2 months (CON-BID). 38 A meta-analysis of individual patient data from six trials (1,205 patients) comparing concurrent vs sequential CRT in locally advanced NSCLC was recently presented. Improved survival time seen with concurrent therapy compared with sequential, with an absolute benefit of 5.9% at 3 years. The benefit appeared to be due mainly to improvement in loco-regional control, whereas there was no significant difference in distant 238 Curr Probl Cancer, May/June 2010

12 progression. Patients treated with concurrent CRT experienced a significantly increased rate of grade 3-4 acute esophageal toxicity (18% vs 4%). 39 The above data have provided strong support for the use of concurrent, platinum-based chemoradiation as the standard of care for unresectable stage IIIA/B NSCLC patients who have good performance status, with minimal weight loss. Role of Additional Chemotherapy Before or After Concurrent Chemotherapy and Radiation Therapy Several groups have studied the use of additional cycles of adjuvant chemotherapy in an attempt to improve outcomes. The CALGB recently presented initial results of trial 39801, in which patients with unresectable stage III disease were randomized to concurrent weekly carboplatin (AUC 2) and paclitaxel (50 mg/m 2 ) and 66 Gy once-daily RT, vs the same concurrent regimen preceded by 2 cycles of carboplatin (AUC 6) and paclitaxel (200 mg/m 2 ). A nonsignificant increase in median survival time was seen in the induction arm (14 vs 11.4 months, P 0.154), although the survival times in both arms was poor compared with those seen on other recent studies. Significant toxicity was more common on the induction arm. 40 The Southwest Oncology Group (SWOG) reported the results of S9504, a phase II trial in which patients were treated with concurrent CDDP/ VP-16 and standard RT (61 Gy). This was followed by 3 cycles of adjuvant docetaxel as consolidation. Results were promising, with a 3-year survival rate of 37%. 41 However, when the addition of adjuvant docetaxel to concurrent CDDP/VP-16 plus RT was compared to CDDP/ VP-16 plus RT alone in a randomized trial by the Hoosier Oncology Group, toxicity was higher with docetaxel, without an improvement in survival. 42 At the present time, combined treatment consisting of RT and chemotherapy has given better 5-year survival rates than RT alone for patients with medically inoperable and surgically unresectable stage III NSCLC. More recent results showed that concurrent chemotherapy combined with RT improved median survival and local control compared to sequential chemotherapy followed by RT. HFX RT and concurrent chemotherapy appears to give better local control, although survival has not been improved significantly. The risk of acute toxicity, especially esophagitis, is increased when HFX RT is combined with concurrent chemotherapy. The role of additional chemotherapy at the completion of chemoradiation has not been elucidated, and it probably should only be done in the context of a clinical trial or on a case-by-case basis. Curr Probl Cancer, May/June

13 Chemoradiation Alone versus Neoadjuvant Chemoradiation Followed by Surgery for pn2 Patients Patients with stage IIIA disease, with involvement of ipsilateral mediastinal nodes (T1-3, N2), have traditionally been considered inoperable due to poor outcomes following surgical resection. Attempts have been made to improve the results of surgery in these patients with the addition of neoadjuvant chemotherapy with and without RT. Many consider chemoradiation alone to be the standard of care for these patients, particularly those with bulky nodal disease. The North American Intergroup 0139 (RTOG 9309) trial was designed to compare definitive chemoradiotherapy with neoadjuvant chemoradiation followed by surgical resection. 43 Patients in both arms received 2 cycles of cisplatin and etoposide concurrent with 45 Gy of RT. Patients without progression then went on to consolidation. Patients randomized to the surgery arm underwent attempted surgical resection, followed by 2 additional cycles of cisplatin/etoposide. Patients randomized to the chemoradiation arm completed RT to 61 Gy concurrent with 2 additional cycles of cisplatin/ etoposide. The 5-year progressive-free survival rate was significantly improved in the surgery arm (24.4% vs 11.1%), but due to increased postoperative deaths, mainly following pneumonectomies, the overall survival benefit did not reach statistical significance (27.2% vs 20.3% at 5 years, P 0.10). Patients downstaged to pn0 at surgery had a 5-year overall survival rate of 41%, compared to 24% in those with pn1-3. The results of this trial suggest that surgery after chemoradiation can be considered in fit patients, but that this approach may not be optimal in patients requiring a pneumonectomy (Tables 1-3). Neoadjuvant and adjuvant therapy are discussed more completely in the ACR Appropriateness Criteria topic on Induction and Adjuvant Therapy for N2 Non-Small-Cell Lung Cancer. Targeted Therapy Given the overall poor results with standard cytotoxic therapies, and the number of advances that have been made recently in our understanding of the biology of cancer, a strong interest has emerged in targeting pathways unique to neoplastic cells or tumors. One such example is the epidermal growth factor receptor (EGFr), which can be inhibited by either mononclonal antibodies (eg, cetuximab) or small-molecule tyrosine kinase inhibitors (erlotinib or gefitinib). Another example is angiogenesis, which can be inhibited with such drugs as bevacizumab, a monoclonal antibody 240 Curr Probl Cancer, May/June 2010

14 TABLE 1. Variant 1: T2N3M0 (IIIB): 60-year-old male with NSCLC. Chest CT revealed a 5-cm mass in RML APW node enlargement. The patient has hoarseness due to paralyzed left vocal cord. KPS 70, weight loss 5% Treatment Rating* Comments Chemotherapy RT 9 External beam RT alone 2 Chemotherapy alone 2 Endobronchial brachytherapy 1 alone External beam brachytherapy 1 Timing of Chemotherapy with RT if given Concurrent chemo/rt 9 Concurrent chemo/rt followed by chemo 5 Consider if weekly paclitaxel/carboplatin used concurrently with RT Chemofollowed by concurrent 4 chemo/rt RT followed by chemo 3 External Beam Irradiation Gy in 3-5 fractions 1 30 Gy in 10 fractions 1 45 Gy/3 wks 1 54 Gy in 1.5 Gy t.i.d./12 d 2 Not accepted regimen concurrent with chemo Gy in wks or 9 biological equivalent 74 Gy in wks 6 In selected patients with strict dosimetric criteria Treatment Planning Technique 2D radiation (AP/PA and/or 2 off-cord obliques) 3D treatment planning 9 IMRT 8 Tumor motion strategy required in addition to strict dosimetric criteria SBRT (stereotactic body RT) 2 Particle therapy No consensus Promising strategy requiring more clinical studies *Rating scale: 1-3, usually not appropriate; 4-6, may be appropriate; 7-9, usually appropriate. to vascular endothelial growth factor (VEGF). Inhibition of each of these pathways (EGFr and VEGF) has been shown in randomized studies to prolong survival of patients with advanced NSCLC. 44,45 Adjuvant studies are being planned with chemotherapy with or without erlotininb or bevacizumab. A randomized trial conducted by the SWOG (0023) has now been reported to show no benefit to maintenance gefitinib following definitive chemoradiation. In fact, survival was worse in the gefitinib arm. 46 Cetuximab is a drug that targets the EGFr pathway and has radiationsensitizing properties. It has been studied in combination with chemora- Curr Probl Cancer, May/June

15 TABLE 2. Variant 2: T3N3M0 (IIIB): 60-year-old patient NSCLC. Chest CT showed right paratracheal adenopathy with postobstructive pneumonia due to endobronchial lesion at the left mainstem. KPS 70, weight loss 5% Treatment Rating* Comments Chemotherapy RT 9 External beam RT alone 2 Chemotherapy alone 2 Endobronchial brachytherapy alone 1 External beam brachytherapy 7 Consider brachytherapy first to open obstruction Timing of Chemotherapy with RT if given Concurrent chemo/rt 7 Delay chemo if patient febrile or septic Concurrent chemo/rt followed by chemo 5 Delay chemo if patient febrile or septic; consider consolidation chemo if weekly paclitaxel/ carboplatin used concurrently with RT 3 Chemofollowed by concurrent chemo/rt RT followed by chemo 8 External Beam Irradiation Gy in 3-5 fractions 1 30 Gy in 10 fractions 1 45 Gy/3 wks 1 54 Gy in 1.5 Gy t.i.d./12 d 2 Not accepted regimen concurrent with chemo Gy in wks or biological 9 equivalent 74 Gy in wks 6 Treatment Planning Technique 2D radiation (AP/PA and/or off-cord 2 obliques) 3D treatment planning 9 IMRT 8 Tumor motion strategy required in addition to strict dosimetric criteria SBRT (stereotactic body RT) 2 Particle therapy No consensus Promising strategy requiring more clinical studies *Rating scale: 1-3, usually not appropriate; 4-6, may be appropriate; 7-9, usually appropriate. diation on RTOG 0324, a phase II trial that combined cetuximab with conventional (63 Gy) CRT on patients with locally advanced NSCLC. Initial results of this trial have shown this regimen to be feasible. 47 Although the toxicity was equivalent to that reported for conventional CRT, there was an improvement in median survival time to 22.7 months. These results have formed the basis for ongoing RTOG 0617, a Curr Probl Cancer, May/June 2010

16 TABLE 3. Variant 3: T4N3M0: 60-year-old male with a few weeks history of SVCO. Bronchoscopy revealed extrinsic compression of RUL. FNA showed undifferentiated large cell carcinoma. Chest CT showed 6-cm mass in RUL invading directly to mediastinum with compression of SVC, 3 cm left paratracheal node, and right pleural effusion too small to tap. KPS 70, weight loss 5% Treatment Rating* Comments Chemotherapy RT 9 External beam RT alone 2 Chemotherapy alone 1 Endobronchial brachytherapy 1 alone External beam brachytherapy 1 Timing of Chemotherapy with RT if given Concurrent chemo/rt 9 Concurrent chemo/rt followed by chemo 5 Consider if weekly paclitaxel/carboplatin used concurrently with RT Chemofollowed by concurrent 3 chemo/rt RT followed by chemo 3 External Beam Irradiation Gy in 3-5 fractions 1 30 Gy in 10 fractions 1 45 Gy/3 wks 1 54 Gy in 1.5 Gy t.i.d./12 d 3 Not accepted regimen concurrent with chemo Gy in wks or 9 biological equivalent 74 Gy in wks 5 Treatment Planning Technique 2D radiation (AP/PA and/or 2 off-cord obliques) 3D treatment planning 9 IMRT 8 Tumor motion strategy required in addition to strict dosimetric criteria SBRT (stereotactic body RT) 1 Particle therapy No consensus Promising strategy requiring more clinical studies *Rating scale: 1-3, usually not appropriate; 4-6, may be appropriate; 7-9, usually appropriate. randomized study designed to assess the benefit of dose-escalated RT (74 Gy) concurrent with chemotherapy, with or without cetuximab. The CALGB presented preliminary efficacy data of a phase II randomized trial evaluating cetuximab as a component of chemoradiation for stage III NSCLC. Carboplatin and pemetrexed were used, concurrent with 70 Gy thoracic RT, with or without cetuximab. Early results in 99 eligible patients indicate that cetuximab was not associated with improved survival, but further study and follow-up are planned. 48 Curr Probl Cancer, May/June

17 TABLE 4. Variant 4: T1N0M0: 70-year-old male with COPD (PFT: FEV1 800 ml, DLCO 25% predicted), found to have a 2-cm peripheral left lower lobe nodule. FNA showed NSCLC. Medically, inoperable. KPS 70, weight loss 5% Treatment Rating* Comments Chemotherapy RT 1 External beam RT alone 9 Chemotherapy alone 1 Endobronchial brachytherapy alone 1 External beam brachytherapy 1 Radiofrequency ablation 4 Still being evaluated Timing of Chemotherapy with RT if given Concurrent chemo/rt 1 Concurrent chemo/rt followed by chemo 1 Chemofollowed by concurrent chemo/rt 1 RT followed by chemo 1 External Beam Irradiation Gy in 3-5 fractions 1 30 Gy in 10 fractions 2 45 Gy/3 wks 2 54 Gy in 1.5 Gy t.i.d./12 d Gy in wks or biological equivalent 7 If SBRT not available; Use doses 65 Gy 74 Gy in wks 7 If SBRT not available Hypofractionated treatment (eg, 60 Gy in 3 9 fractions or 50 Gy in 4 fractions) Treatment Planning Technique 2D radiation (AP/PA and/or off-cord obliques) 2 3D treatment planning 7 IMRT 8 SBRT (stereotactic body RT) 9 Particle therapy 9 *Rating scale: 1-3, usually not appropriate; 4-6, may be appropriate; 7-9, usually appropriate. Stereotactic Body Radiation Therapy Recently, early-stage tumors have been treated with a hypofractionated approach using advanced treatment delivery techniques such as extracranial stereotactic body radiotherapy (SBRT). A multi-institutional retrospective study in Japan reported the clinical outcomes in 245 patients treated for stage I NSCLC. 49 They observed an extremely favorable local recurrence rate of 14.5% and toxicity in only 2.4% of patients. A phase II trial in the U.S. reported 2-year local control of 95%. 50 However, tumors in the central portion of the lung had excessive toxicity, which led them to recommend not treating lesions in the proximal bronchial tree with doses of 20 Gy per fraction. Emerging institutional data suggest that central early-stage lung lesions can be treated safely with lower doses per 244 Curr Probl Cancer, May/June 2010

18 fraction (eg, Gy per fraction), and this is the subject of RTOG dose escalation study (Table 4). Radiofrequency Ablation Recently, radiofrequency ablation (RFA) has been advocated as potential alternative to conventional RT for early-stage lung tumors. In RFA, a lesion is ablated with an RF electrode that is placed within the tumor through percutaneous techniques, typically CT guidance. A retrospective analysis at a single institution reported a 2-year local control of 64% in tumors smaller than 3 cm and 25% in tumors larger than 3 cm. 51 The authors reported a 28% overall pneumothorax rate, and a 10% rate of chest tube insertions, similar to data reported by Steinke et al. 52 Yoshimatsu et al. 53 have reported higher complication rates when accounting for delayed or recurrent pneumothoraces. Further work needs to be done to determine the role of RFA in early-stage NSCLC as well as in recurrent disease and metastatic disease from other sites to the lung. Disclaimer: 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 exams 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. REFERENCES 1. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111: Curr Probl Cancer, May/June

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