Henning Willers, MD

Concurrent chemotherapy/radiotherapy has been considered the standard treatment for patients with a good performance status and inoperable stage III non–small-cell lung cancer (NSCLC). Three-dimensional chemoradiation therapy and intensity-modulated radiation therapy have been reported to reduce toxicity and allow a dose escalation to 70 Gy and beyond. However, the Radiation Therapy Oncology Group 0617 trial recently showed that dose escalation from 60 Gy to 74 Gy with concurrent chemotherapy in stage III NSCLC was associated with higher toxicity and worse survival. A “one size fits all” treatment approach may need to be changed and adapted to each patient’s particular disease and unique biologic/anatomic features, as well as the most appropriate radiotherapy modalities for that patient. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application, by the panel, of a well-established consensus methodology (modified Delphi technique) to rate the appropriateness of imaging and treatment procedures. In instances in which evidence is lacking or not definitive, expert opinion may be used as the basis for recommending imaging or treatment.

The treatment of inoperable stage III non–small-cell lung cancer (NSCLC) remains a challenge due to high rates of distant metastasis, local recurrence, and toxicity associated with definitive therapy. Radiotherapy (RT) plays a crucial role in the management of lung cancer. However, conventional RT to a dose of 60 Gy is associated with less than 50%–60% local control, and the median survival time is only 15–17 months, with 5-year survival rates of 13%–16% even when patients receive concurrent chemotherapy and RT.[1] Radiation dose escalation/acceleration has been shown to improve local control and potentially survival in lung cancer in nonrandomized studies. However, the optimal chemoradiation regimen remains unknown. To improve clinical outcome of stage III NSCLC, the Radiation Therapy Oncology Group (RTOG) conducted a phase III study (RTOG 0617)[2] in which the radiation dose was escalated from 60 Gy to 74 Gy with concurrent carboplatin/paclitaxel ± cetuximab. The preliminary data from RTOG 0617 showed that the 74-Gy dose is associated with poorer survival compared with a dose of 60 Gy, although the survival appears improved in both arms based on short-term follow-up compared with the historical RTOG 9410 data. This study raises many questions about the controversial issues of safety and efficacy of dose escalation in stage III NSCLC. The difficulty with dose escalation is toxicity due to tumor proximity to surrounding critical structures. Advanced radiation techniques, such as image-guided radiotherapy (IGRT); optimized intensity-modulated radiation therapy (IMRT); stereotactic ablative radiotherapy (SABR, also known as stereotactic body RT); proton therapy[3]; and better integration of systemic therapy, particularly molecular marker–guided targeted therapy,[4] are required to further improve the therapeutic ratio.

Tissue heterogeneity in the vicinity of the lung has implications for the accuracy of the radiation dose distributions. Dose that normally would have been deposited in the tumor is carried away into the surrounding lung tissue, resulting in potential underdosage of the tumor. The literature is replete with articles demonstrating the need for accurate, “heterogeneity-corrected” dose algorithms in lung cancer planning.[5,6] Consequently, the RTOG has adopted the requirement that algorithms employing heterogeneity corrections be used for treatment planning for both early-stage and locally advanced lung cancer.[7-9] To mitigate inaccuracies in dose calculations, it is strongly recommended that algorithms employing accurate heterogeneity correction techniques be utilized for lung cancer treatment planning. Pencil beam–type algorithms should be avoided.[10]

Radiation Therapy Alone: Standard Fractionation

RT alone used to be considered the standard treatment for patients with unresectable and locally advanced NSCLC. The RTOG 7301 trial[11] 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 with a lower dose of RT alone. Two-year survival rates were 14% in the patients who received 40 Gy in 4 weeks with a continuous course of therapy and 18% in those who received 50–60 Gy, compared with only 10% in those who received a split course, although this difference was not statistically significant. By 5 years, all dose regimens yielded a similarly poor survival outcome of < 10%. Patients treated with 50–60 Gy who achieved clinical tumor control had a survival rate of 22% at 3 years, compared with 10% if treatment failed in the thorax (

 = .005). This historical randomized study established the standard radiation dose of 60 Gy in 30 fractions in NSCLC. However, the local control rate with this regimen is less than 50%, and survival rates are dismal.

For many years, the standard RT for NSCLC in the United States was to first deliver 40–50 Gy to the regional lymph nodes (ipsilateral, contralateral, hilar, mediastinal, and occasionally supraclavicular) that showed no evidence of tumor involvement and then deliver an additional 20 Gy to the primary tumor through reduced fields. The rationale against the use of elective nodal irradiation is the high rate of local disease recurrence within the previously irradiated tumor and the high risk of distant metastasis and toxicity associated with a large radiation volume.

Furthermore, if the gross disease cannot be controlled, there is no point in enlarging the irradiated volumes to include areas that may harbor microscopic disease.

Three major factors have changed since the RTOG 7301 trial established the standard RT for NSCLC: the use of chemotherapy, the advent of three-dimensional conformal radiation therapy (3D-CRT) and IMRT, and better staging and target delineation with positron emission tomography (PET) and endobronchial ultrasound (EBUS). Emerging clinical data show that omitting prophylactic lymph node irradiation does not reduce the local control rate in patients receiving definitive RT. In these patients, the local recurrence rates in the isolated outside-field (field of RT) have been < 8%, particularly in patients with stage I disease and in those who have undergone PET scanning for staging.[12-14] A recent randomized study appeared to support the involved-field irradiation approach.[15]

Thus, in patients with NSCLC, it is important to deliver adequate doses of radiation to primary tumor and involved nodal or mediastinal areas. Irradiation of other electively treated lymph nodes may not be necessary, particularly in patients whose tumors are staged with computed tomography (CT), PET, and EBUS. Clinical judgments regarding pattern of failure, anatomy, and toxicity need to be considered in order to decide on clinical treatment volume. In addition, if local control and survival continue to improve along with radiation dose escalation techniques, the issue of elective nodal irradiation may need to be revisited in the future.

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 8311. This trial was an attempt to increase local control by administering higher total doses while using a twice-daily fractionation regimen to avoid increasing the toxicities to late-responding normal tissue.[16] A total of 840 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 (

The European Organisation for Research and Treatment of Cancer (EORTC) conducted a randomized study of 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 histologic examination. CHART was given in 1.5-Gy fractions 3 times a day, 7 days per week, with an interfractional interval of at least 6 hours. The large-volume dose was 37.5 Gy in 25 fractions, followed by 16.5 Gy in 11 fractions, for 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 for CHART treatment was 20% vs 13% with standard RT, and 3-year local control with CHART was 17% vs 12% with standard RT).[17] More moderate or severe acute dysphagia affected 49% of CHART cases, compared with 19% of patients treated conventionally. However, there was no significant difference between the two study arms in the rate of late complications. Follow-up studies of accelerated fractionation regimens include the CHARTWEL trial, published in 2011, which did not show a survival improvement for 60 Gy given over 2.5 weeks vs 66 Gy standard fractionation given in 6.5 weeks.[18] The exact reason for this lack of benefit remains unclear but may relate to the lower fraction of squamous cell cancers, which would benefit most from accelerated RT, compared with the original CHART trial.

Several studies, including a recent analysis of RTOG trial data from 1,390 patients, showed that an increased biologically effective dose (BED) is associated with improved local control and survival.[19,20] In recent years, image-guided SABR has been shown to achieve higher than 90% local control with promising survival in stage I NSCLC when a BED > 100 Gy is delivered to target within 3 to 5 fractions.[21,22] With implementation of cutting-edge technologies such as IGRT, 3D-CRT, IMRT, and proton therapy, a few pilot studies are evaluating image-guided proton/photon hypofractionated dose escalation/acceleration with dose up to 60 Gy in 15 fractions in locally advanced disease, while respecting normal tissue tolerance, and without concurrent chemotherapy.[23] The preliminary data appear promising, and an ongoing phase III randomized study is comparing IGRT at 60 Gy in 15 fractions with 60 Gy in 30 fractions in poor performance status patients with stage III NSCLC.

Attempts to improve tumor control by dose escalation have been limited by the tolerance of normal tissues, especially lung and esophagus. IMRT has been shown to significantly reduce doses to normal tissues, and it is therefore a promising technique for facilitating safe dose escalation. Concerns regarding the application of IMRT to lung tumors are related to the accurate targeting of a moving lung tumor with IMRT due to the interplay effect, and the potential increase in the percent lung volume receiving low doses. Data on clinical use of IMRT for lung cancer patients are sparse.

Investigators at The University of Texas MD Anderson Cancer Center generated IMRT plans for 41 patients with stage III NSCLC who had been treated previously with 3D-CRT. They found that IMRT allowed for greater sparing of normal tissues, including heart, lung, and esophagus, with a lower probability of lung complications using dosimetric models.[24] A follow-up retrospective report of 151 patients with NSCLC treated with IMRT showed an 8% incidence of treatment-related grade 3 or higher pneumonitis 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.[25] Recent studies also indicate that IMRT reduced esophageal toxicity compared with 3D-CRT. In addition, clinical implementation of IMRT, 4D-CT simulation, and PET images is associated with improved local control and survival in stage III NSCLC.[26] The Memorial Sloan-Kettering Cancer Center experience was reported[27] as follows: 55 patients with stage I-IIIB NSCLC were selected to receive IMRT, mainly due to large tumor size and proximity of tumor to critical organs. Doses of 6,000–9,000 cGy were used, and 76% received chemotherapy. Normal tissue complication probability and fdam (fraction of damaged functional subunits) 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 those from larger prospective series.

In summary, IMRT has shown promise in dosimetric modeling studies for reducing normal tissue complication probability to allow for dose escalation in lung cancer patients. Early clinical reports of IMRT indicate favorable toxicity profiles and tumor control. IMRT allows integrated dose painting to high-risk regions with minimal increased dose to normal tissues, which could translate into improvements in local control and quality of life.[3] However, motion control and IGRT are required in IMRT, and prospective trials are underway to further evaluate this technology in the clinical setting.

Proton therapy has potential dosimetric advantages over photon beam therapy.[28] 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 due to respiratory motion and the low density of the lung parenchyma.

Prospective and retrospective studies indicated the utility of using protons in locally advanced NSCLC to increase the radiation dose while avoiding normal tissue. Chang et al[29] recently completed a phase II study of 44 patients with stage III NSCLC who received 74 Gy via conventional fractionation (2 Gy per fraction) with weekly concurrent carboplatin and paclitaxel. Despite the very high intensity of this treatment course, no grade 4 or 5 toxicities occurred, and grade 3 toxicities were minimal. Because of the tolerability of this regimen, patients were more likely to complete treatment. The median overall survival duration was 29.4 months, and the overall survival and progression-free survival rates at 2 years were both above 55%. An ongoing phase II randomized study is comparing proton therapy vs IMRT using 74 Gy with concurrent chemotherapy in stage III NSCLC.[30]

Some technical issues unique to proton beam therapy have been discussed. First, proton therapy is more sensitive to motion and anatomy change than photon therapy. 4D-CT–based planning and adaptive RT are required when using this technique.[31] 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. In addition, it is challenging to use current passive-scattering proton therapy techniques to treat lung tumors that have a complicated anatomy. Intensity-modulated proton therapy (IMPT) will further improve conformity of therapy, but motion uncertainty in that setting is even more profound.[32] A prospective study using IMPT is ongoing.

In summary, due to their physical characteristics, protons can spare normal tissues to a greater extent and may allow further dose escalation/acceleration. However, there are more uncertainties about proton therapy in lung cancer, and much improvement and optimization are still needed. Proton therapy may not be suitable for all lung cancer patients. In addition, proper case selection and proper proton techniques based on motion and anatomy are crucial to improve the therapeutic ratio. It is hoped that in the near future larger prospective controlled trials now underway will clarify the role of proton beam therapy for lung cancer.

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) trial randomized 155 patients with stage III NSCLC with good performance status and < 5% weight loss to treatment with 2 cycles of vinblastine and cisplatin followed by RT (60 Gy in 6 weeks) or to RT alone (60 Gy in 6 weeks).[33] Patients who were treated by induction chemotherapy followed by RT (n = 78) had a median survival time of 13.8 months compared with 9.7 months for those (n = 77) treated by RT alone. The 2-year survival rate was significantly better in the patients who received combined treatment compared with those who received RT alone, 26% vs 13% (

= .006). The longer follow-up to this study showed that the 5-year survival rate of patients who received combined treatment was 19%, compared with 7% for those who received RT alone.

LeChevalier et al also reported that a phase III randomized study comparing RT alone to combined chemotherapy and RT showed a significant improvement in the 3-year survival rate with combined treatment, 12% vs 4% (

 = .02).[34] Median survival times were 12 months and 10 months, respectively. However, there was no difference with regard to local control.

The RTOG 8808 trial[35] randomized 452 patients with stage III NSCLC, good performance status, and < 5% weight loss to be treated in three arms. Patients in arm 1 received combined chemotherapy and RT. The chemotherapy, using vinblastine and cisplatin, was administered in 2 cycles and was followed by RT at a total dose of 60 Gy over 6.5 weeks. Patients in the other two arms received RT alone, one using 60 Gy of standard fractionation 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 chemotherapy and RT arm compared with a median survival time of 11.4 months in patients who received standard fractionation RT. The 2-year survival rate was 32% in patients who received combined treatment vs 19% in patients who received standard fractionation RT alone (

 = .003). The outcome in the HFX RT arm was intermediate between outcomes reported in the other two study arms (mean survival time of 12 months; 2-year overall survival rate of 24%; 

 = .08 compared with chemotherapy and RT). Five-year survival rates, however, were < 10% in all study arms.

The EORTC study showed that daily cisplatin and simultaneous RT significantly improved 2-year survival rates (26% vs 13%) as compared with the patients who received RT alone (

 = .009).[36] However, the RT schedule was not considered optimal as a standard of RT in the United States. The control arm of RT was given 3 Gy in 10 fractions with a 3-week to 4-week break, followed by 2.5 Gy in 10 fractions as a boost.

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 that included 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 to 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 provided the strongest evidence in favor of chemotherapy, with absolute benefits of 4% at 2 years and 2% at 5 years.[37]

Marino et al 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.[38] Fourteen trials comprising 1,887 patients were analyzed. They found a 30% reduction in mortality at 2 years for cisplatin-based chemotherapy vs RT 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 (Meta-Analysis of Cisplatin/carboplatin based Concomitant Chemotherapy in non–small-cell Lung Cancer) Group analyzed individual data from nine trials (with a total of 1,764 patients) comparing concurrent chemotherapy and RT with RT alone.[39] Eligible trials used cisplatin-based or carboplatin-based chemotherapy. The hazard ratio of death for the chemotherapy and RT 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 to optimize 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 hyperfractionated (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 in a 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 (at a dose of 30 mg/m

 on days 1–3 and 28–30) and etoposide (100 mg/m

 on 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 in survival for patients with HFX RT with or without chemotherapy compared with standard RT (

 = .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 (

 = .02). There was no difference in freedom from distant metastasis or overall survival among patients who received HFX RT with or without concurrent chemotherapy. This study suggested that patients with stage III NSCLC treated with accelerated HFX RT with or without chemotherapy may have better freedom from local progression and survival compared with those receiving standard RT, especially for those with non–squamous-cell carcinoma.[40]

The NCCTG next tested concurrent chemotherapy plus once-daily (qd) vs twice-daily (bid) RT.[41] Both arms received cisplatin (30 mg/m

) 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 for chemotherapy plus twice daily RT in patients with non–squamous-cell histology, similar to previous findings by the NCCTG. This was in contrast to findings from RTOG 9410 (discussed later in this article) that adding twice-daily RT improved local control in patients with squamous cell cancers.

RTOG 9801[42] 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 using 3D-CRT (1.2 Gy bid to 69.6 Gy). The results showed no significant difference in the incidence of NCI Common Toxicity Criteria grade ≥ 3 esophagitis (30% with amifostine vs 34% without it), although patient-reported swallowing symptoms were significantly less severe with amifostine. No differences in median survival (17.3 months with amifostine vs 17.9 months with no amifostine) were reported.

Sequential vs 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

 on days 1, 8, 29, and 36), and mitomycin (8 mg/m

 on days 1 and 29). RT was begun on day 2 at a dose of 28 Gy, in 2-Gy fractions, at 5 fractions per week for a total of 14 fractions. This regimen 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 patients had completed 2 cycles of chemotherapy. RT consisted of 56 Gy, in 2 Gy/fractions, at 5 fractions per week for a total of 28 fractions. A total of 320 patients were entered into this study. The response rate for patients in the concurrent arm was significantly higher (84%) compared with those in the sequential arm (66%; 

= .0002). 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; 

 = .04). The 2-year and 5-year survival rates in the concurrent-therapy group were 34.6% and 15.8%, respectively, compared with rates of 27.4% and 8.9%, respectively, in the sequential-therapy group. Mild suppression was significantly greater among the patients who received concurrent chemotherapy and RT (

 = .0001). There was no significant difference in regard to acute esophagitis between the two groups.[43]

Fournel et al[44] reported results of the French Groupe Lyon-Saint-Ãtienne d’Oncologie Thoracique (GLOT)-Groupe FranÃ§ais de Pneumo-Cancerologie (GFPC) NPC 95-01 randomized trial. Patients in the concurrent chemoradiation group received etoposide and cisplatin concurrent with 66 Gy of once-daily RT, followed by adjuvant cisplatin/vinorelbine. Those in the sequential arm received induction cisplatin and vinorelbine, followed by the same RT dose. Survival was better in the concurrent arm, but the difference was not significant.

RTOG 9410 was a three-arm randomized trial comparing sequential (SEQ) chemotherapy followed by RT (once daily at 63 Gy) with two different concurrent chemoradiotherapy regimens. The latter consisted of either concurrent once-daily RT at 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 arm used 2 cycles of cisplatin and etoposide, based on the experience in RTOG 9204. Acute toxicity was worst in the CON-bid arm. Although time to in-field progression was longest in the CON-bid arm, this did not translate into a survival benefit. The best survival times were in the CON-qd arm, and these were significantly better than in the SEQ arm (

 = .046). Median survival times in the three arms were 14.6 months (SEQ), 17 months (CON-qd), and 15.2 months (CON-bid).[1]

Two meta-analyses further support the survival advantage of concurrent chemoradiation. A Cochrane meta-analysis demonstrated a significant 14% reduction in the risk of death with concurrent chemoradiation as compared with sequential treatment.[45] The NSCLC Collaborative Group discovered a significant survival advantage with concurrent chemoradiation compared with sequential treatment (hazard ratio = 0.84) with an absolute benefit of 5.7% at 3 years.[46] The above data have provided strong support for use of concurrent, platinum-based chemoradiation as the standard of care for patients with unresectable stage IIIA/B NSCLC who have good performance status and minimal weight loss (see Variant 1, Variant 2, Variant 3, Variant 4 in this article, and the 

, available in the online posting of this article at www.cancernetwork.com).

Radiation Dose Escalation With Concurrent Chemotherapy

In RTOG 9410, the locoregional failure rate after concurrent chemotherapy and RT at a standard radiation dose of approximately 60 Gy was about 34%–43%. To improve the local control rate, three groups (RTOG, NCCTG, and the University of North Carolina) separately performed radiation dose-escalation trials in patients with stage III NSCLC; their results supported the safety and efficacy of using 74 Gy concurrently with chemotherapy in this population.[47-49] On the basis of promising local control and survival rates and an acceptable toxicity level obtained using 3D-CRT to a dose of 74 Gy with concurrent chemotherapy, RTOG conducted the following phase III study in stage IIIA or IIIB NSCLC: patients were treated with an RT dose of 60 Gy vs a dose of 74 Gy delivered by 3D-CRT or IMRT, with both study groups receiving concurrent therapy with weekly paclitaxel and carboplatin ± antibody against the epidermal growth factor receptor (EGFR) inhibitor cetuximab. Surprisingly the preliminary analysis showed that there was no overall survival improvement in the group randomized to the higher radiation dose.[2] In fact, survival in the high-dose arm was worse. One interpretation of this outcome is that dose escalation is not oncologically beneficial, but this runs counter to basic biology and a large body of evidence, including prospective phase II and III trials. A competing explanation is that 74 Gy is too toxic when delivered by the photon-based radiation technologies used in the current setting of RTOG 0617. It is also possible that 74 Gy is still an inadequate dose-the early-stage NSCLC data suggest the need for a BED of 100 Gy in the absence of radiosensitizers, but this dose threshold has not been clearly assessed in the presence of concurrent chemotherapy-and a higher biological dose using image-guided hypofractionated RT to reduce total treatment days should be considered. In addition, IGRT and strict quality assurance are crucial to achieve an optimal outcome. This puzzling trial result has resulted in much debate, and we hope that these issues are further clarified when the final outcomes are published.

Role of Additional Chemotherapy Before or After Concurrent Chemotherapy and Radiation Therapy

Induction chemotherapy followed by concurrent chemoradiotherapy was proposed as an alternative to concurrent chemoradiotherapy as a way to potentially improve systemic control and survival in patients with unresectable stage III NSCLC. The CALGB recently presented the initial results of trial 39801, in which patients with unresectable stage III disease were randomized to concurrent weekly carboplatin (at an area under the concentration-time curve [AUC] of 2) and paclitaxel (50 mg/m

) and RT at 66 Gy once daily, vs the same concurrent regimen preceded by 2 cycles of carboplatin (AUC 6) and paclitaxel (200 mg/m

). A nonsignificant increase in median survival time was seen in the induction arm (14 months vs 11.4 months, 

 = .154), although survival times in both arms were poor compared with those seen in other recent studies. Significant hematologic toxicity was more common in the induction arm, but radiation-related toxicities were similar.[50]

A three-arm study compared sequential chemotherapy/RT, induction chemotherapy followed by concurrent chemoradiotherapy, and concurrent chemoradiotherapy followed by consolidation chemotherapy in stage III NSCLC.[51] The median survival time was 16.3 months, 12.7 months, and 13 months in the consolidation arm, induction arm, and sequential arm, respectively. The induction and consolidation arms were associated with greater toxicity, and the incidences of grade 3/4 esophagitis and pulmonary toxicity were highest in the consolidation arm. Although the study was not powered for direct comparison of survival in the three treatment arms, the prolonged median survival observed with concurrent treatment followed by consolidation chemotherapy supports the concept that providing the definitive concurrent chemoradiotherapy up front is the preferred therapeutic approach in stage III NSCLC.

The Southwest Oncology Group (SWOG) reported the results of S9504, a phase II trial in which patients were treated with concurrent cisplatin/etoposide 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%.[52] However, when the addition of adjuvant docetaxel to concurrent cisplatin/etoposide plus RT was compared with cisplatin/etoposide plus RT alone in a randomized trial by the Hoosier Oncology Group, toxicity was higher in the group that also received docetaxel, without an improvement in survival.[53]

In summary, 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 with sequential chemotherapy followed by RT. Use of 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 either as induction chemotherapy or consolidative chemotherapy at the completion of chemoradiation has not been well elucidated. Sometimes induction chemotherapy is used when there is a high risk of distant metastasis or the disease is too bulky to comply with RT dose-volume constraints. Adjuvant full-dose carboplatin/paclitaxel after concurrent RT and weekly low-dose carboplatin/paclitaxel is standard of care, whereas adjuvant chemotherapy with cisplatin/etoposide after concurrent RT should not be used outside of clinical trials.[54]

Therapeutic decisions in NSCLC are currently based on histology, disease stage, and performance status. However, NSCLC is a heterogeneous disease, and different treatment outcomes have been observed even in patients with similar clinical and histologic features. Given the poor overall results seen 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. The availability of such targeted biologics requires that their use be matched to tumors of corresponding molecular vulnerability, to achieve maximum efficacy. One such example is the epidermal growth factor receptor (EGFR), which can be inhibited by either monoclonal antibodies (eg, cetuximab, panitumumab) or small-molecule tyrosine kinase inhibitors (TKIs; erlotinib, gefitinib, or afatinib).

Concurrent chemotherapy and radiation therapy (RT) remains the standard of care for nonsurgical treatment of stage III non–smallcell lung cancer (NSCLC) patients with good performance status.

Although we should continue to explore radiation dose escalation/ acceleration in locally advanced NSCLC, administration of RT at doses of 60 Gy to 66 Gy with concurrent chemotherapy remains the standard regimen in the community setting.

Both 3D conformal RT and intensity- modulated RT (IMRT) are acceptable for treatment of locally advanced NSCLC. Proton therapy may have the potential to further spare critical normal tissues, although more prospective studies are needed.

Molecular marker–based targeted therapy might have the potential to improve the therapeutic ratio in locally advanced NSCLC, but more prospective studies are needed. At this time, there is no level 1 evidence to support adding targeted therapy with concurrent chemotherapy/RT.

These agents have been tested in conjunction with radiation and chemotherapy in stage III NSCLC, but results have been mixed at best.[55-58] A preliminary report from RTOG 0617 did not find an early survival benefit for cetuximab.[59] These data highlight the need for predictive biomarkers to identify subsets of patients with wild-type 

 tumors who would benefit from the combination of EGFR-targeted agents with standard chemotherapy/radiation, if those exist. NSCLCs harboring activating mutations in the

 gene, occurring in approximately 10% of patients in the United States, are typically highly responsive to EGFR TKIs, at least in the stage IV setting. However, there are few data regarding incorporation of these inhibitors in patients with stage III 

 mutation–positive NSCLC. The use of EGFR TKIs as an induction regimen prior to standard chemotherapy/radiation in patients with 

-mutant NSCLC is under investigation by the RTOG (1306) and other groups.[60,61] Similarly, use of crizotinib as induction for patients with NSCLC driven by fusions of the anaplastic lymphoma kinase (

) gene with the echinoderm microtubule-associated protein-like 4 (

) gene is being tested in the RTOG 1306 trial.

The most commonly mutated oncogene in NSCLC is 

, but compared with treatments targeting the 

 genes, development of effective therapies against 

 mutation renders the affected tumors more resistant to chemotherapy and radiation therapy remains to be established.[62,63] The presence of somatic

 mutations is associated with a lack of sensitivity to EGFR inhibitors.[64]

Another example of targeted therapy involves angiogenesis, which can be inhibited with such drugs as bevacizumab, a monoclonal antibody against 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.[65,66] Adjuvant studies are being planned with chemotherapy with or without erlotinib or bevacizumab. However, incorporation of bevacizumab into radiation treatment is potentially toxic.[67]

Directions for Future Research: Knowledge-Based Personalized Radiotherapy and Systemic Therapy

Current NSCLC treatment approaches are largely empiric, and result in minimal improvement in outcome. As we know, not all cancers are created equal. Some cancer cells may be resistant to RT and require a higher BED of RT, but certain patients may not be able to tolerate high doses of RT due to unique genetic and clinical profiles. Conventional RT doses of 60 Gy to 66 Gy are associated with poor local control and dismal survival. The challenge is to escalate/accelerate dose safely and effectively. Optimizing systemic therapy with RT also plays a crucial role in clinical outcome, including local control, survival, and toxicities. There is no magic drug or magic RT modality/technique/regimen that is effective for all lung cancer patients. Personalized approaches based on tumor genetic makeup that guide systemic therapy as well as knowledge-guided RT dose escalation/acceleration using cutting-edge technologies (such as IGRT, SABR, IMRT, and proton therapy) will likely result in significantly improved survival in these patients. Prospective clinical studies using biomarker-driven therapy in selected patients and personalized RT to maximize local control with dose escalation/acceleration while minimizing toxicities are crucial to improving the therapeutic ratio in NSCLC.

These studies, such as molecular marker-based targeted therapy with concurrent chemoradiotherapy and biologic PET image-guided dose escalation (RTOG studies), are ongoing.

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.

Benjamin Movsas, MD, FACR, reports research support to Henry Ford Health System Radiation Oncology Department from Varian, Inc, Philips, Inc, and Resonant, Inc. R. Bryan Barriger, MD, reports receiving a stipend from D3 Oncology Solutions for his work as Co-Chair of both the Lung Cancer Pathways and Esophageal Pathways committees of Via Oncology

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