Combined modality therapy for thoracic and head and neck cancers: a review of updated literature based on a consensus meeting



Combined modality therapy is a mainstay option for thoracic malignancies and head and neck cancers. The integration of different strategies is based on the multidisciplinary approach of modern clinical oncology. Radiation oncologists have to be educated, trained, and updated to provide state-of-the-art care to cancer patients and thus educational meetings are crucial.


The Italian Association of Radiation Oncology Young Members Working Group (AIRO Giovani) organized its 8th national meeting, focused on combination therapy in lung, esophageal, and head and neck cancer (with a specific focus on larynx-preservation strategies for larynx/hypopharynx tumors), involving young professionals working in Italy. The meeting was addressed to young radiation oncologists, presenting state-of-the-art knowledge, based on the latest evidence in this field. We performed a review of the current literature based on the highlights of the Congress.


The multimodality approach of head and neck and thoracic malignancies includes surgery, chemotherapy, and radiotherapy, but also has to take into account new information and data coming from basic and translational research and including molecular biology, genetics, and immunology. All these aspects are crucial for the treatment of non-small-cell lung cancer and esophageal, esophagogastric junction, and larynx/hypopharynx malignancies. The integration of different treatments in the clinical decision-making process to combine therapies is crucial.


Combination therapy has proved to be a consolidated approach in these specific oncologic settings, highlighting the importance of multimodality management in modern clinical oncology. Dedicated meetings on specific topics are helpful to improve knowledge and skills of young professionals in radiation oncology.

Tumori 2016; 102(5): 459 - 471

Article Type: REVIEW



Pierfrancesco Franco, Alba Fiorentino, Francesco Dionisi, Michele Fiore, Silvia Chiesa, Stefano Vagge, Francesco Cellini, Luciana Caravatta, Mario Tombolini, Fiorenza De Rose, Icro Meattini, Gianluca Mortellaro, Giuseppina Apicella, Lorenza Marino, Daniela Greto

Article History


Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission.

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The Italian Association of Radiation Oncology (AIRO) Giovani (AIRO Young Members Working Group) is the young section of AIRO. It was founded in 2007 and has constantly grown during the years with a strong commitment towards the development and coordination of educational programs and specific projects tailored to young radiation oncology professionals, both trainees and young medical officers, in order to investigate issues pertinent to their professional life (1-2-3-4-5-6). Moreover, AIRO Giovani organizes annual meetings specifically focused on the multidisciplinary approach of cancer and on the role of radiotherapy in different oncologic settings (7-8-9-10). The 8th AIRO Giovani meeting was held in Montecatini Terme, Italy, in June 2015 and was dedicated to the combined modality therapy of thoracic malignancies and head and neck cancers with a specific focus on larynx-preservation strategies in larynx/hypopharynx cancers. Invited talks and interactive workshops took place during the Congress. A review of the current literature has been performed following the highlights of the meeting. The latest evidence in terms of clinical results and treatment approaches is summarized in the present report.


A complete literature review was performed by the Young Members Working Group of AIRO, with the external contribution of the speakers involved in the 8th AIRO Giovani meeting. The electronic databases employed for data collection were PubMed, Scopus, Embase, and Cochrane Library. The search was limited to a specific timeframe, specifically from 1990 to 2015, using the following keywords: combined modality treatment, head and neck cancer, lung cancer, esophageal cancer, gastro-esophageal junction cancer, surgery, radiotherapy, chemotherapy, multidisciplinary. The electronic browse was supplemented by manual analysis and selection of reference lists derived from selected articles and consensus meeting reports. Manuscripts were categorized according to disease site. The members of the working group discussed the results according to the Oxford CRBM suggestions.

Locally advanced non-small-cell lung cancer

Combination therapy including surgery, radiotherapy (RT), and chemotherapy (CT) is standard of care in the treatment of locally advanced non-small-cell lung cancer (NSCLC). We summarize state-of-the-art knowledge regarding multimodality therapy, RT approach, and new drugs potentially employed in this setting.

The role of multimodality treatment

Stage III NSCLC includes heterogeneous presentations in terms of tumor location and extension, including different nodal involvement, from occult mediastinal nodal spread to unresectable bulky nodal disease. Clinical stage IIIA-IIIB disease represents nearly 40% of newly diagnosed NSCLC patients, with generally a dismal prognosis (5-year overall survival [OS]: 16% and 7%, respectively). The optimal treatment for these patients is widely debated. Different factors related to both patient and tumor characteristics should be taken into account in order to choose the most appropriate treatment strategy (11). Multimodality therapy appropriately integrating surgery, CT, and RT is preferable in most cases. A multidisciplinary team including pulmonologist, radiation and medical oncologist, dedicated radiologist, and thoracic surgeon would preferably discuss all medical cases (12). Accurate preoperative mediastinal lymph node staging in patients having potentially resectable NSCLC is crucial. Recent European Society of Thoracic Surgeons guidelines point out the importance of an algorithm integrating morphologic and functional imaging with endoscopic and surgical techniques to provide the most appropriate diagnostic workup for mediastinal staging (13). The proper identification of specific subsets of patients within the stage III disease classification allows us to properly tailor the therapeutic approach to each patient. The first setting includes patients with an incidental intraoperative finding of involved omolateral mediastinal lymph nodes (occult pN2 diagnosis) after primary surgery. The optimal adjuvant therapy is a crucial topic in this scenario. At present, the use of adjuvant platinum-based CT is recommended (level 1 evidence) with an absolute 4% increase in OS at 5 years, irrespective of prior treatments (surgery ± RT) (14). On the other hand, the role of postoperative radiation therapy (PORT) remains controversial. The PORT meta-analysis concluded that adjuvant RT is detrimental to patients with completely resected early-stage NSCLC, and has a controversial role in pN2 tumors (15). Recently, Robinson et al (16) analyzed pathologic N2 NSCLC patients after complete resection and adjuvant CT, stratifying them according to the use of modernly delivered PORT, which confers an additional OS advantage (45.2 v 40.9 months, respectively) beyond the one achieved with adjuvant CT alone. These results are under confirmation with ongoing prospective trials such as the LungART Trial ( The management of incompletely resected NSCLC is debated. Hancock et al (17) analyzed 3,102 patients with NSCLC (5.7% of resections) with a positive surgical margin after surgical resection, concluding that the administration of both CT and RT is associated with an improved survival in patients with microscopically positive surgical margins, irrespective of stage. Since patients with positive margins are an infrequent finding, performing prospective trials on this group of patients is difficult (18, 19). Few retrospective data are available at present and therefore adjuvant treatments are recommended with a low level (III) of evidence (12).

The second subset of patients with stage III NSCLC includes those with minimal omolateral mediastinal nodal involvement (single-station N2) after surgery and with potentially operable T4 with high risk of incomplete resection. Possible strategies include several options: induction CT followed by surgery, induction radiochemotherapy (RT-CT) followed by surgery, or concurrent definitive RT-CT. The INT 0139 phase III trial compared concurrent RT-CT followed by surgical resection to standard concurrent definitive RT-CT (20). Progression-free survival (PFS) was higher for the first approach, with a median time of 12.8 months vs 10.5 months, but with no statistical significance. However, a trimodality approach had a better OS if lobectomy was performed. The authors concluded that CT plus RT with or without resection (preferably lobectomy) are valid options for patients with stage IIIA (N2) NSCLC. A very large retrospective analysis was conducted to assess the role of neoadjuvant RT-CT in patients with N2-positive stage IIIA NSCLC, pointing out improved OS for patients undergoing neoadjuvant chemoradiation followed by lobectomy (21). The identification of the optimal neoadjuvant treatment, either CT alone or RT-CT, is an open issue. Different studies investigated this setting, with no differences found between the 2 options (Tab. I) (22-23-24-25).

Selected clinical trials investigating the role of combined radiotherapy and chemotherapy in locally advanced non-small-cell lung cancer

Authors Year Design Patients Stage Induction CT Resectability rate, % Pathologic response, % Median survival, mo
CBDCA = carboplatin; CDDP = cisplatin; CT = chemotherapy; RT = radiotherapy; Tax = Taxol; VNR = vinorelbine.
Thomas et al (22) 2008 Phase III 524 IIIA-IIIB (initially unresectable) CT (260) vs RT-CT (264) 59 vs 54 20 vs 60 (p<0.0001) 33 vs 32.4 (p = 0.54)
Girard et al (23) 2010 Phase II 46 IIIA-N2 (initially resectable) CT (14) vs RT-CT (CDDP-VNR) (17) vs RT-CT (CBDCA-Tax) (15) 93 vs 88 vs 87 57 vs 82 vs 86 24 vs 13 vs NA
Katakami et al (24) 2012 Phase III 60 IIIA-N2 (initially resectable) CT (29) vs RT-CT (31) 86 vs 90 21 vs 40 (p = 0.21) 30 vs 40 (p = 0.4)
Sher et al (25) 2015 Observational 1,076 IIIA CT (376) vs RT-CT (700) 100 (both) 49 vs 58 (p = 0.004) 41 vs 35 (p = 0.56)

The third subset includes patients with bulky and/or multilevel N2 nodal involvement or unresectable T4. Concurrent RT-CT is the treatment of choice in this subgroup (level 1 evidence) and results in terms of OS are superior to those of sequential CT and RT protocols (26). Nevertheless, patients unfit for the concomitant approach may be treated with induction CT and sequential RT with curative intent (27).

In conclusion, the optimal management of resectable stage III NSCLC is an open debate. This setting is the most controversial (28). The best candidates for preoperative RT-CT should have the following requirements: preoperatively planned lobectomy, no weight loss, female sex, and only one involved nodal station (28). Multidisciplinary assessment is crucial for this group of patients in order to select the proper candidate for multimodality treatment and account for comorbidities, age, location, and tumor extension.

Combined chemoradiation: considerations on radiotherapy

Concurrent RT-CT is the treatment of choice in nonsurgical stage IIIA and stage IIIB NSCLC. A recent meta-analysis analyzed data from 22 trials on 3,033 patients treated with RT plus CT. A significant overall benefit was observed with the addition of CT, in which the risk of death can be reduced by 10%, resulting in an absolute benefit of 3% at 2 years and 2% at 5 years. Trials employing cisplatin (CDDP)-based CT provided the strongest evidence favoring CT, with absolute benefits of 4% at 2 years and 2% at 5 years (29). Regarding the most suitable timing to deliver RT-CT, sequential administration has the advantage of better tolerance for patients, but several drawbacks such as higher accelerated tumor repopulation, eventual emerging radioresistance, and delayed delivery of RT. Conversely, concomitant RT-CT has higher acute toxicity but may favor radiosensitization, decrease tumor repopulation, and have timely delivery. Therefore, sequential chemoradiotherapy should be considered in case of relevant comorbidities (26). No benefit was found in clinical studies employing strategies other than the concurrent approach (30). The reference prescription dose for NSCLC RT comes from the RTOG 7301 study (60-66 Gy 2 Gy daily) (31). Recently, the phase III RTOG 0617 study investigated toxicity profile and local control of a dose escalation strategy up to 74 Gy delivered with standard fractionation (32). Patients with stage IIIA-IIIB NSCLC were treated to a total dose of 60 Gy vs 74 Gy delivered with 3D conformal radiotherapy or intensity-modulated radiotherapy, administering concurrent weekly paclitaxel and carboplatin ± cetuximab. Surprisingly, the experimental arm (74 Gy) resulted in higher toxicity and worse prognosis. Several hypotheses were formulated to explain this finding: probably the longer overall treatment time may enhance tumor repopulation. Moreover, the observed higher lung toxicity may be due to a higher cardiac dose in the experimental arm. Hence the dose of 60 Gy remains the standard reference in definitive radiation for NSCLC. Altered fractionation schedules have been explored in lung cancer RT, with or without CT. The NCCTG compared, within the frame of a 3-arm phase III randomized trial, conventionally fractionated vs accelerated hyperfractionated (HFX) vs HFX thoracic RT with concomitant etoposide and CDDP (33) for stage III unresectable NSCLC. Conventional fractionation was delivered up to 60 Gy in 30 fractions over 6 weeks. The HFX RT was given with 1.5 Gy twice daily with a 2-week interruption after the first 30 Gy in 2 weeks. The HFX RT was given exclusively or with concomitant CDDP (at a dose of 30 mg/m2 on days 1-3 and 28-30) and etoposide (100 mg/m2 on days 1-3 and 28-30). Higher local control and survival were seen for HFX RT (with or without CT) compared to standard RT. This benefit was higher in patients with nonsquamous cell carcinoma. This study suggested that patients with stage III NSCLC treated with accelerated HFX RT with or without CT may have better freedom from local progression and survival compared to those receiving standard RT, especially for nonsquamous histology. Furthermore, 3 studies evaluated the benefit of accelerated schedules: 1.2 Gy t2/daily, 1.5 Gy /2/daily, and 1.5 Gy 3/daily /13 fractions vs 66 Gy 2/daily (RTOG 8311, EORTC CHART, and CHARTWEL, respectively) in NSCLC (34-35-36). Despite some limitations of the CHART and CHARTWEL studies, a higher local control was found for hyperfractionated accelerated RT schedules, providing a basis for further trials exploring treatment intensification for locally advanced NSCLC with eventual combination with CT. Only a few studies tested dose escalation and/or acceleration through hypofractionation in NSCLC. The only randomized trial investigating hypofractionation compared 60 Gy/30 fractions vs 60 Gy in 12 fractions once a week. The hypofractionation arm revealed higher local control and survival rates. Complete tumor response rate was similar in both arms, but 2-year survival rate was 29% for hypofractionation compared to 23% for conventional RT. A lower acute esophagitis rate was also observed in the hypofractionation arm (37). More recently, phase I/II trials explored the role of hypofractionation in NSCLC. A phase I study of dose escalation up to 94.5 Gy in 42 fractions within 6 weeks concluded that this approach for small-volume lung tumors is safe if mean lung dose is below 11.3 Gy (38). Intensity-modulated radiotherapy is actually considered a useful approach to deliver NSCLC RT, since it provides more conformal dose distribution and better critical structure sparing (39). Interplay effects can be minimized with the use of motion management techniques and fractionated regimens. Target missing and/or organs at risk overdosage can be minimized by using image-guided radiotherapy and adaptive replanning. Intensity-modulated radiotherapy seems to improve quality of life for patients with NSCLC by minimizing treatment-related toxicities such as acute pneumonitis and esophagitis. Intensity-modulated radiotherapy can allow further dose escalation within the planning target volume based on anatomical, biological, and molecular information without prolonging treatment time when techniques employing a simultaneous integrated boost are used (39). Proton therapy represents a form of RT that can exploit the physical properties of protons to achieve potential clinical benefit compared to photon-based RT. The use of proton-based RT-CT compared to photon-based RT-CT for NSCLC is currently being tested in the RTOG 1308 phase III trial (

Integrating radiotherapy with target therapies or immunotherapy

Progress in understanding tumor molecular biology and targeted drug development may have a strong influence in the treatment of NSCLC. Molecular target agents such as the EFGR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, the anti-EGFR antibody cetuximab, anti-vascular endothelial growth factor (VEGF) antibody bevacizumab, and several VEGF receptor TKIs have already been tested in the metastatic setting. The same drugs and others are under investigation also in the context of locally advanced disease. The EGFR pathway acts in several pro-oncogenic processes, such as cell growth, invasion, resistance, and neoangiogenesis. Recent studies tried to integrate these drugs into combined modality therapy for stage III lung cancer. The CALGB 30407, a randomized study testing RT-CT either with or without concomitant cetuximab, failed to show any additional survival benefit with cetuximab (18-month OS: 54% and 58%, respectively). Adding cetuximab to RT-CT had no detrimental effect on toxicity (40). No difference in objective response was reported by another randomized phase II study at 29 months with cetuximab plus RT-CT compared to concurrent cisplatin and 66 Gy RT alone. The 1-year OS was 71% vs 82%, respectively (41). More recently, RTOG 0617 reported no benefit in terms of OS for patients treated with the addition of cetuximab to concurrent RT-CT (32). All patients received concurrent CT with paclitaxel/carboplatin and 2 weeks after radiation (60 Gy vs 74 Gy), 2 other cycles of consolidation CT with paclitaxel/carboplatin. Median OS was 28.7 months for patients who received 60 Gy and 20.3 months for those who received 74 Gy. No differences in OS were reported between the arm with and without cetuximab (25 months vs 24 months). Cetuximab was associated with a higher rate of major toxicities (32). Tyrosine kinase inhibitors increase the radiosensitivity of NSCLC cell lines, suppressing DNA repair mechanisms. In a prospective study, daily concurrent RT (70 Gy) was associated with either gefitinib or erlotinib (250 mg and 150 mg, respectively) in stage III NSCLC. The median PFS and OS were 10.2 and 21.8 months, respectively, with limited reported toxicity (42). Conversely, another study of concurrent gefitinib and RT was terminated for acute pulmonary toxicity (43). Clinical studies have also investigated the combination of gefitinib with RT-CT. Unresectable stage III patients were treated with 2 cycles of induction CT (carboplatin/irinotecan/paclitaxel) followed by concurrent treatment with gefitinib plus CT (carboplatin and paclitaxel) and RT (74 Gy). Results reported a median OS and PFS of 16 and 9 months, respectively (n = 23). Grade 3 toxicity were relevant for esophagitis and cardiac arrhythmia (19.5% and 9.5%) (44). The phase II CALGB 30106 trial tested different combined modality treatment strategies stratifying patients according to the level of risk. High-risk patients, such as those having weight loss >5% or low performance status, underwent induction CT and subsequent concurrent gefitinib and RT (66 Gy), while low-risk patients also received concomitant paclitaxel and carboplatin. Surprising median OS was found to be superior in high-risk patients (19 months vs 13 months) (45). The phase III SWOG S0023 investigated the role of concurrent RT (61 Gy) and CT followed by 3 cycles of docetaxel given as consolidation therapy. Patients with no progressive disease were randomly assigned to receive either maintenance gefitinib or placebo. Survival was lower within gefitinib than within placebo arm (median OS: 23 months vs 35 months, respectively) (46). Erlotinib may enhance radiosensitivity, with the induction of cell cycle arrest and apoptosis. A phase II trial reported results from patients treated with erlotinib concurrently with RT (63 Gy) and CT (carboplatin/paclitaxel). Results are promising, with median OS of 25.8 months and PFS of 13.6 months. Limited grade 3 toxicity was reported (47). The aforementioned findings did not show any advantage in targeting EGFR within a multimodality treatment including RT in NSCLC. The therapeutic improvement is to be found in a sensitive population that can benefit from this combination (48-49-50). On the contrary, patients with wild-type EGFR treated with combination therapy have the highest rate of progressive disease (49). Probably, as supported by preclinical evidence, EGFR TKIs cause a G1 cell cycle arrest in wild-type EGFR cell lines, with a consequent lower effectiveness of combined CT and RT. Ionizing radiation enhances the expression of several proangiogenic factors, including VEGF. Radiation-induced upregulation VEGF receptor pathway signaling may reduce the tumoricidal effect by enhancing the rate of vascular repair (50). Antiangiogenic agents are potential therapies for NSCLC, including both monoclonal antibodies such as bevacizumab and multitarget TKIs such as sunitinib, sorafenib, and vandetanib (50). Bevacizumab was tested together with CT for stage III NSCLC, with poor results. A study combining bevacizumab and RT-CT (pemetrexed/carboplatin), followed by bevacizumab maintenance, was stopped early due to 2 cases of trachea-esophageal fistula, due to the combination of radiation and anti-VEGF antibody (51). The use of immunotherapy is under investigation in NSCLC to increase response rate with a safe toxicity profile. The aim is to support the hosts’ anticancer immune response. Once thought of as a type of cancer that was poorly immunogenic, lung cancer has several tumor-specific or tumor-selective T cells, which can be mobilized for therapeutic purposes. Novel treatment strategies include vaccine therapy and immune checkpoint modulation. Vaccine immunotherapy may induce antitumor response by exploiting the immune system. The vaccine contains an allogeneic tumor antigen from a different source (like the whole tumor cell, the DNA bearing viral vectors, proteins, or peptides) to stimulate the humoral immune response against a specific target. Clinical data are limited, especially in the treatment of locally advanced NSCLC together with RT and CT. Experience with vaccine therapy in lung cancer is not yet promising. Recently, a phase III trial (START) of the liposomal-BLP MUC-1 peptide vaccine (tecemotide), given after definitive RT-CT in stage III NSCLC, as a maintenance therapy, reported no significant differences in OS (median OS: 25.6 vs 22.3 months, respectively). Better results were shown for patients receiving concurrent RT-CT (median OS: 30.8 vs 20.6 months) (52). A major turning point in cancer immunotherapy is the clinical application of antibodies that block immune checkpoints. To date, the pathways of PD-1 and CTLA-4 are considered the main checkpoint molecules for effective immunotherapies in solid tumors. Several antibodies have been developed to block the PD-1 receptor (nivolumab or pembrolizumab) or its ligand PDL-1 (lambrolizumab) or CTLA-4 (ipilimumab). Encouraging results come from phase I/II and 2 separate phase III trials of nivolumab, ipilimumab, or pembrolizumab were designed but no clinical data were reported for concurrent treatment of stage III NSCLC with RT or RT-CT and immunotherapy. A phase II study assessed the activity of ipilimumab plus paclitaxel and carboplatin in stage III/IV NSCLC. Ipilimumab was administered as concurrent or phased. The study confirmed an improvement in immune-related PFS and PFS only for the phased ipilimumab. These data support debate and further investigation for anti CTLA-4 in NSCLC (53). Garon et al (54) assessed the efficacy and safety of PD-1 inhibition with pembrolizumab in patients with advanced NSCLC enrolled within a phase I study. Pembrolizumab had an acceptable toxicity profile and showed antitumor activity in patients with advanced NSCLC. PD-L1 expression in at least 50% of tumor cells was correlated with the improved efficacy of pembrolizumab. Recent results from a phase III study, enrolling patients with nonsquamous NSCLC after progression during or after platinum-based doublet CT randomized to receive nivolumab or docetaxel, showed a longer OS with nivolumab. In addition, toxicity was very mild with the anti PD-1 (55). Similar advantages have been reported also for squamous cell lung tumors (56). Similar important clinical advantages, from the same research group, are merged for the treatment of squamous NSCLC (57). Several advances in the clinical research of locally advanced NSCLC have been reached. However, the biological basis of the integration among target therapy, immunotherapy, CT, and RT have yet to be fully explained and capitalized in their potential synergistic effect. A summary of the aforementioned data can be found in Table II.

Combination of target therapies with RT or RT-CT for locally advanced NSCLC and reports from multimodality immunotherapy

Study type No. Multimodality (RT-CT or RT) Median PFS, mo Median OS, mo Toxicity
C = cetuximab; CI = concurrent ipilimumab; CT = chemotherapy; D = docetaxel; G = gefitinib; GR = good risk patients; N = nivolumab; NSCLC = non-small-cell lung cancer; OS = overall survival; P = placebo; PFS = progression-free survival; PI = phased ipilimumab; PR = poor risk patients; RT = radiotherapy; T = tecemotide.
EGFR inhibitors
 Cetuximab CALGB 30407 (40) Phase II (randomized) 101 RT-CT 13.5 (P) vs 11.8 (C) 54% (C) vs 58% (P) at 18 Low
Van den Heuvel et al (41) Phase II (randomized) 102 RT-CT 69% (P) vs 73% (C) at 12 82% (P) vs 71% (C) at 12 Increased
RTOG 0617 (32) Phase II (randomized) 166 RT-CT 25 (P) vs 24 (C) Increased
 Gefitinib Stinchcombe et al (44) Phase II 23 RT-CT 9 16 Not increased
CALGB 30106 (45) Phase II 63 RT or RT-CT 13.4 (PR) vs 9.2 (GR) 19 (PR) vs 13 (GR) Not increased
SWOG S0023 (46) Phase III 243 RT-CT 23 (G) vs 35 (P) Not increased
 Erlotinib Komaki et al (47) Phase II 36 RT-CT 36.5% Low
VEGFR inhibitor
 Bevacizumab Spigel et al (51) Phase II 5 RT-CT High
Vaccine therapy
 Liposomal BLp MUC-1 START (52) Phase III 1513 RT-CT 25.6 (T) vs 22.3 (P) Low
Immune checkpoint modulation
 Anti PD-1
  Nivolumab Borghaei et al (55) Phase III 582 CT 2.3 (N) vs 4.2 (D) 12.2 (N) vs 9.4 (D) Low
Brahmer et al (56) Phase III 272 CT 3.5 (N) vs 2.8 (D) 9.2 (N) vs 6 (D) Low
  Pembrolizumab Garon et al (54) Phase I 495 3.7 12 Very low
 Anti CTL-4
  Ipilimumab Lynch et al (53) Phase II 204 CT 5.1 (PI) vs 5.5 (CI) vs 4.2 (P) 12.2 (PI) vs 9.7 (CI) vs 8.3 (P) Low

Esophageal and esophagogastric junction (GEJ) tumors

Evidence supporting the role of trimodal (RT-CT followed by surgery) and bimodal approaches (definitive RT-CT) are presented together with the comparison between neoadjuvant RT-CT and exclusive preoperative CT and future development of scientific research in this field. See Table III for a summary of literature data.

Trimodality therapy (TMT) in esophageal and gastroesophageal tumors

Authors Year Trials included Period Patients Survival benefit for TMT Notes
CT = chemotherapy; OS = overall survival; RT = radiotherapy.
Urschel et al (72) 2003 9 1992-2002 1116 Yes at 1, 2, and 3 years Higher 3-year OS benefit for concomitant vs sequential RT-CT
Fiorica et al (73) 2004 6 1992-2001 764 Yes at 3 years Postoperative mortality increased
Arnott et al (70) 1998 5 1981-1992 1147 Nonsignificant trend at 2 and 5 years
Greer et al (71) 2005 6 1992-2001 738 Small nonsignificant trend Same trials selected as in Fiorica et al
Gebski et al (107) 2007 10 trials: RT-CT 1982-2006 1,209 (2,933 total) Yes at 2 years Smaller significant benefit also for CT only
8 trials: CT alone
Jin et al (74) 2009 11 1992-2008 1308 Yes at 1, 3, and 5 years
Sjoquist et al (75) 2011 12 trials: RT-CT 1983-2004 2,048 (4,188 total) Yes at 2 years CROSS trial reported as abstract
9 trials: CT alone
2 trials: RT-CT vs CT alone
Wang et al (76) 2012 12 1992-2009 1529 Yes at 1, 3, and 5 years Survival benefit only for RT-CT and squamous histology
Deng et al (77) 2014 13 2001-2013 1930 Significant reduction: local and distant relapses CROSS trial fully included

Trimodal approach

The interest in esophageal and GEJ lesions considered as a unique entity amenable for multimodal treatments has grown since the diffusion of the last TNM edition, defining GEJ as a subsite of esophageal cancers. That was done on the basis of similarities in terms of epidemiology, pattern of localization and spread, and survival, even if some authors still have interpretational issues (58-59-60-61-62). Multimodal integrated approaches, with the availability of concomitant radiosensitizer drugs and the possibility to overcome radioresistance of specific histologies (adenocarcinoma), led to the progressive adoption of RT-CT beyond the treatment of unresectable lesions or as a palliative option (63). Five of the most relevant randomized trials testing the trimodal approach against surgery alone were published between 1996 and 2012 (64-65-66-67-68). Three of these trials found a statistically significant survival benefit from the integration of neoadjuvant RT-CT over surgery alone, while 2 did not, but showing a trend favoring the combined modality (64-65-66-67-68). Walsh et al (64) randomized 100 patients with esophageal adenocarcinoma (lesions of the cardia: 20%). The schedule adopted was 40 Gy (2.7 Gy daily) plus concomitant 5-fluoruracil (5FU) and CDDP. Although the trial reported a significant survival benefit for the experimental arm, increasing the 3-year OS from 6% (surgery alone) to 36% (RT-CT + surgery), it led to some criticism about the poor results of the surgery-alone arm and about the lack of standardized baseline patient evaluation, not routinely including CT scan. Conversely, Burmeister et al (66) accrued 256 patients (adenocarcinoma: 60) mostly (75%) with lower third lesions. They did not find a significant benefit by the adoption of the trimodal approach. The prescribed dose was slightly lower than in other reports (35 Gy; 2.4 Gy daily) and it is not completely clear if only conformal RT-CT was applied. Moreover, a nonsignificant trend favored preoperative RT-CT (3-year OS: trimodality 42% vs surgery 36%) and a subgroup analysis revealed a significant survival benefit for squamous lesions, suggesting that the global result could have suffered by the high rate of adenocarcinomas (66). Recently, the CROSS trial enrolled 366 patients (adenocarcinoma: 75%), with around 25% of lesions located in the GEJ (69). In the experimental arm, patients received RT-CT (41.2 Gy; 1.8 Gy daily) plus paclitaxel and carboplatin. The trimodal approach gained a significant benefit in 5-year OS (RT-CT + surgery 58% vs surgery 47%) (69). Results favored significantly both squamous cell tumor and adenocarcinomas in subgroup analyses. To further investigate the value of the trimodal approach vs surgery alone, several meta-analyses were performed. With differences in the endpoint analyzed and background of the evaluated studies, few of them revealed only a nonsignificant trend in favor of RT-CT, while most of them showed a significant benefit (70-71-72-73-74-75-76-77). If the role of preoperative RT-CT over surgery alone seems well-established, its benefit over preoperative CT alone seems more controversial. Two randomized trials recently explored this setting. Burmeister et al (78) randomized 75 patients in a phase II trial (RT-CT given as 35 Gy; 2.4 Gy daily + 5FU/CDDP). They found a nonsignificant trend in favor of RT-CT in terms of median OS (29 vs 32 months) and PFS (14 vs 26 months). No difference in terms of toxicity and a significant advantage for RT-CT in the rate of pathologic complete response (pCR) (8 vs 31%) was found. Stahl et al (79) accrued GEJ lesions only, for a total of 126 patients, administering 12 weeks of induction CT followed by RT-CT (30 Gy; 2 Gy daily + CDDP/etoposide) for 3 weeks. Also in this trial a nonsignificant trend favoring RT-CT for 3-year OS (47.4 vs 27.7%) was found. As previously seen, RT-CT showed a significant improvement in terms of pCR rates (2% vs 15.6%). To properly consider these 2 trials, we should highlight that both were statistically underpowered due to low accrual. The meta-analysis performed by Sjoquist et al (75) collected 24 randomized trials employing preoperative treatments (14 RT-CT, the rest CT alone). A significant benefit by the use of preoperative treatments vs surgery alone was found in terms of 2-year OS. The magnitude of benefit was stronger for RT-CT (8.7%) than for CT alone (5.1%). The authors also directly compared RT-CT to CT alone: results were not significantly in favor of RT-CT even if this subgroup analysis was only based on 2 trials (78, 79). Further studies will more clearly state if the interesting results of trimodal approach are or are not superior compared to surgery alone and also to preoperative CT alone followed by surgery. In this frame, the issue of optimal treatment for GEJ lesions is even more complex. Although the union of GEJ to esophageal lesions was suggested by the TNM classification on the basis of similarities, it remains unquestioned if the higher rate of adenocarcinomas (around 90% of GEJ) would play a role in clinical outcome. Moreover, GEJ lesions were in the past grouped with either esophageal or gastric tumors, thus a clear interpretation of the result from trials is difficult. A recent meta-analysis from Ronellenfitsch et al (80) found a significant benefit by the administration of preoperative CT (either associated with RT or not) for esophageal, gastric, and GEJ adenocarcinomas, globally analyzed, with an absolute OS increase of 9% at 5 years. Moreover, GEJ adenocarcinomas were the only subgroup maintaining significance in separated analysis, suggesting a potential specific role of trimodal approach in this subset. Several aspects need further investigation. The identification of the optimum regimen of neoadjuvant therapy would require optimization of concomitant chemosensitization (paclitaxel gained interesting results, 5FU and CDDP represent a consolidated alternative). The integration with new targeted therapies, such as the human epidermal growth factor (HER) type 2 targeting agents, is under investigation. Reduction of trimodal treatment toxicity by improvement in definition of target volumes and amelioration in treatment techniques will be of major importance. Finally, the identification and selection of patients to tailor the trimodal integrated approach on the basis of predictive modeling including molecular and genetic features informative about outcome and potential toxicities would be extremely useful.

Definitive chemoradiation as bimodality approach

For locally advanced esophageal cancers, a multimodal treatment based on chemoradiotherapy with planned surgery should be recommended (75). Definitive CT-RT is a suitable option for selected locally advanced patients unable or unwilling to undergo surgery and for patients with carcinoma of the cervical esophagus (75). The benefit of definitive CT-RT in the treatment of nonmetastatic squamous cell or adenocarcinoma of the esophagus was evaluated in the Radiation Therapy Oncology Group (RTOG) 85-01 study, a randomized phase 3 trial comparing the effect of RT alone (64 Gy) to concurrent CT-RT (CDDP, 5FU, and RT up to 50 Gy) (81). At 5 years of follow-up, concomitant CT-RT resulted in better OS (26% vs 0%) and decreased local failure rate (26% vs 37%) than RT alone. In addition, a strong sensitivity of squamous cell histology to concomitant CT-RT was seen (81). Definitive CT-RT was also compared to neoadjuvant RT-CT in 2 large randomized trials. The German study, which included only squamous cell carcinomas, showed at 10-year follow-up an improved 2-year PFS for the surgery arm (64% vs 41%), without a benefit in OS at 5 and 10 years in the trimodality arm (28% and 19.8% vs 17% and 12.9% in the RT-CT arm) (79). These results were confirmed in the large study conducted by Federation Francophone de Cancerologies Digestive (FFCD 9102), which performed a randomization of patients having operable T3N0-1 epidermoid tumor (90%) or adenocarcinoma (10%) of the thoracic esophagus with a response after 46 Gy of RT-CT plus CDDP/5FU to further RT-CT up to 66 Gy vs surgery. Trimodal therapy again resulted in higher local control (65% vs 57%), but not in improved OS, because of the increased early mortality associated with neoadjuvant therapy (82). In the context of the definitive RT-CT, the benefit of dose escalation has been investigated in the Intergroup 0123 randomized trial, where 236 patients with T1-4, N0-1, M0 received CDDP and 5FU with concurrent RT up to 50.4 Gy, with or without a boost of 14.4 Gy (3). There was no significant difference in OS and locoregional failure between the 2 arms, but an unexpected high number of severe toxicities in the boost arm was shown, although 7 of 11 deaths occurred before 50.4 Gy for unclear reasons (83). Brachytherapy (BRT) boost has also been evaluated within a phase II trial, where 49 eligible patients received external beam radiotherapy up to 50 Gy followed, after 2 weeks, by BRT (either 3 weekly fractions of 5 Gy delivered with high dose rate BRT or low dose rate BRT up to 20 Gy). Concurrent CDDP and 5FU were administered. Toxicity occurred in up to 24% of patients, who experienced life-threatening toxic events such as 6 tracheoesophageal fistulas. A total of 10% died. Based on the results of both studies, although many European and Asian groups still favor higher doses, the standard of care in the United States remains 50-50.4 Gy in 1.8-2 Gy fractions using external beam radiation (84). Concerning the best cytotoxic agents to use concurrently with RT, carboplatin and paclitaxel were compared to the more frequently and widespread used CDDP and 5FU in a multicenter comparative study of 102 patients, showing comparable outcomes in terms of DFS and OS (85). In addition, a better toxicity profile in terms of hematologic and nonhematologic toxicity (≥G3) was observed in the carboplatin/paclitaxel group (4% and 18%) compared to CDDP/5FU (19% and 38%) with a higher rate of patients having completed the planned regimen (82% vs 57%) (85).

The efficacy and safety of oxaliplatin plus 5FU and leucovorin (FOLFOX treatment regimen) instead of CDDP/5FU was assessed in the PRODIGE5/ACCORD17 study, a randomized phase II/III trial. No difference in PFS and OS was noted. However, in view of a different toxicity profile with a higher incidence of neuropathy and transaminases rise in the FOLFOX arm, compared to a higher rate of mucositis, alopecia, and creatinine rise in the 5FU/CDDP arm, FOLFOX was found to be safely used as an alternative treatment in CDDP-intolerant patients (86). Finally, concerning the role of induction CT, the RTOG 0113 trial tested the eventual difference between 2 regimens (CDDP and paclitaxel ± 5FU) in achieving a 1-year survival rate higher than 77.5%, with better results compared to the 66% rate derived from the RTOG 9405 study. The 1-year survival rate was 75.7% in one arm, close to but not over the planned endpoint. However, high-grade morbidity was frequent in both arms (87).

Head and neck cancer

In the framework of combined modality therapy, strategies involving both surgical and radiochemotherapy approaches for larynx preservation in cancer of the larynx and hypopharynx have been discussed during the meeting and are summarized. See Table IV for a summary of literature evidence.

Combined radiotherapy and chemotherapy as larynx preservation strategy in cancers of the larynx and hypopharynx

Trial Year Patients Site Stage Treatment Larynx preservation rate OS
AltPF = alternating cisplatin, 5-fluorouracil; Cet = cetuximab; CT = chemotherapy; OS = overall survival; PF = cisplatin, 5-fluorouracil; RT = radiotherapy; TPF = docetaxel, cisplatin, 5-fluorouracil.
VALCSG (97) 1991 332 Larynx III-IV PF + RT vs surgery + RT 64% 68% at 2 years
EORTC 24891 (98) 2009 202 Hypopharynx II-IV PF + RT 22% at 5 years 38% at 5 years; 13.1% at 10 years
Surgery + RT 33% at 5 years; 13.8% at 10 years
RTOG 9111 (99) 2003 547 Larynx III-IV PF + RT 67.5% at 10 years 39% at 10 years
RT-CT 82% at 10 years 27.5% at 10 years
RT 64% at 10 years 31.5% at 10 years
GORTEC 2000-01 (101) 2009 213 Larynx-hypopharynx III-IV PF + RT 57% at 3 years 60% at 3 years
TPF + RT 70% at 3 years 60% at 3 years
EORTC 24954-22950 (100) 1996 450 Larynx-hypopharynx III-IV PF + RT 48% at 5 years 53% at 5 years
AltPF + RT (6 wk) 52% at 5 years 60% at 5 years
Tremplin (103) 2013 153 Larynx-hypopharynx III-IV TPF + RT 95% at 3 months 92% at 18 months
TPF + RT/Cet 93% at 3 months 89% at 18 months

Surgical approaches in larynx preservation strategies

The global tumor burden for laryngeal cancer has consistently decreased over the last 20 years, while 5-year survival rates remain stable (88). The most appropriate treatment strategy strongly depends on a detailed baseline evaluation of the patients including fiber optic examination (evaluation of tumor subsite and vocal cord motility) and radiologic imaging with CT scan and magnetic resonance imaging (assessment of thyroid/cricoid cartilage invasion and adjacent structure involvement) (88). Other clinical factors were shown to be crucial. For example, in supraglottic larynx tumors, nodal involvement is important to drive treatment choice. Open or laser surgical excision is a standard option for T1-T2 and selected T3 node negative tumors, while, for T1-T3N1 presentation, RT ± CT should be regarded as preferable. Supraglottic laryngectomy combined with bilateral neck dissection may also be considered in this context (88, 89). For locally advanced disease (T3-T4, N2-N3), chemoradiation is the standard of care. For glottic cancer, the clinical decision-making process is easier since early-stage disease (T1-T2 and selected T3) can either undergo surgery or RT, while locally advanced disease can be submitted to total laryngectomy + adjuvant treatments or combined RT-CT (88). Surgical larynx preservation strategies include laser surgery and partial laryngectomies, which are classified as supraglottic, supracricoid, and supratracheal according to the anatomical level of resection (90). The most frequently performed procedures are supraglottic laryngectomy (open or laser), supracricoid laryngectomies (with cricohyoidopexy according to Labayle [CHP] or cricohyoidoepiglottopexy according to Meyer Piquet [CHEP]), and supratracheal laryngectomies (with tracheohyoidopexy [THP] or tracheohyoidoepiglottopexy [THEP]). Since supraglottic tumors have a consistent nodal spread diffusion, elective neck dissection is focal. Dissection should be bilateral in case of midline, locally advanced, or node-positive tumors (90). Laser surgery for glottic cancer is classified in 6 types of cordectomies according to the European Laryngological Society (91). For invasive cancer, the most frequent surgical approach is Type III laser cordectomy. Local control, larynx preservation, and survival rates are comparable among transoral laser surgery, open surgery, and RT, while voice quality depends on the extent of resection (92, 93). In general, laser surgery has several advantages, such as the short hospitalization required, the possibility to perform an intraoperative biopsy, the good swallowing outcome, and the wide range of salvage therapies available. Open surgery is useful whenever larynx exposition is not optimal or lesion control under microlaryngoscopy is not complete. Supracricoid laryngectomies have favorable outcomes in terms of swallowing and breathing after appropriate rehabilitation training even if the glottic plane is excised (94). Notably, the cricoarytenoid is preserved and consequently may act as a sphincter with phonatory and deglutitory functions. In general, supracricoid laryngectomy with CHP is used in T2 glottic and supraglottic cancer not amenable to supraglottic laryngectomy because of false cord or Morgagni ventricle floor invasion or glottic involvement. It can also be employed in selected T3 glottic and supraglottic tumors with fixed vocal cord but preserved arytenoid motility or with pre-epiglottic space invasion (95). Conversely, supracricoid laryngectomy with CHEP can be employed in case of vocal cord infiltration by tumor with consequent hypomobility or in case of glottic cancer with anterior commissure or Morgagni ventricle floor involvement (93). Robot-assisted transoral surgery is an emerging technique, which can be used in different disease contexts (local excisions, partial or total laryngectomies) and is presently gaining increasing clinical evidence. Larynx preservation is an extremely heterogeneous field that requires prospective trials designed with adequate clinical endpoints accounting for both oncologic and functional outcomes.

Combined chemoradiation in larynx preservation strategies

Several randomized trials have shown the feasibility of organ preservation approaches in patients with advanced laryngeal and hypopharyngeal cancer. The best option remains a challenging question. Multidisciplinary evaluation is of importance to select the most suitable treatment strategy for each specific patient. Combined CT and RT is the standard of care and includes different possibilities: induction chemotherapy (ICT) followed by definitive RT (±CT), concurrent RT-CT, and alternating chemoradiation (altCT-RT) (96). The historical VALCSG trial compared ICT (2 cycles of CDDP and 5FU) followed by definitive RT in good responders to total laryngectomy and postoperative RT (97). Larynx preservation was achieved in 64% of patients in the ICT arm. Estimated 2-year survival was 68% in both arms. No significant differences in OS were observed according to tumor stage or site. Patients in the ICT arm had higher local failure but lower distant metastasis rate (97). The EORTC 24851 trial had similar design, testing ICT followed by definitive RT vs total laryngectomy and adjuvant radiation in pyriform sinus and aryepiglottic fold cancers (98). The 3- and 5-year rates of preserving a functional larynx in the ICT arm were 64% and 58%, respectively. Survival rates at 5 years were observed to be similar between treatment arms. Results also showed a lower distant spread rate in the ICT arm and a higher response rate for T2 tumors compared to T3-T4 (98). The authors concluded that ICT + definitive RT is a safe and acceptable option in this context. The RTOG 91-11 trial compared 3 different treatment strategies in the management of stage III-IV laryngeal cancer: CDDP/5FU-based ICT followed by definitive radiation vs concurrent RT-CT (3-weekly CDDP) and exclusive radiation (99). The rate of larynx preservation at 10 years was higher in the RT-CT group (81.7%) compared to ICT (67.5%) and RT alone (63.8%). Ten-year disease-free survival did not differ in the 3 groups. Toxicity profile was higher for patients submitted to chemotherapy-containing strategies (99). A trend towards worse OS rate was observed at 10 years for the RT-CT arm compared to ICT. For instance, the number of deaths not attributed to larynx cancer was higher in the RT-CT arm. Taking into account composite endpoints, which includes also speech and swallowing evaluation, RT-CT and ICT seemed equal (99). The EORTC 24954 trial compared altCT-RT vs ICT (4 cycles of PF) + definitive RT in locally advanced laryngeal and hypopharyngeal cancers (100). AltCT-RT consisted of 4 cycles of CDDP/5FU-based CT alternating with RT given in 3 courses of 20 Gy lasting 2 weeks between CT cycles. After a median observation time of 6.5 months, no differences were found in terms of survival with a functional larynx between the 2 approaches. Acute toxicity was higher for ICT. Late toxicity was similar. With respect to the best ICT regimen, the GORTEC 2000-01 phase III trial tested whether the addition of docetaxel to CDDP and 5FU could increase functional larynx preservation rate in larynx-hypopharynx cancer. At 5-year follow-up, TPF showed higher laryngoesophageal dysfunction-free survival (101). Similar data have also been observed in a retrospective subset analysis of the TAX 327 trial (102). Biotherapies have been evaluated in the TREMPLIN phase II trial (103). Stage III-IV larynx and hypopharynx cancer were treated with 3 cycles of ICT (TPF). Those having an objective response <50% underwent surgery. The others were randomized to receive either concurrent CDDP or cetuximab. Larynx preservation at 3 months was similar between arms. Tolerance to and compliance with cetuximab were higher. Local failures were lower with CDDP, but salvage surgery was more effective after cetuximab, resulting in comparable OS rates. Data on RT-CT, ICT, and altCT-RT showed that all these approaches are feasible as larynx preservation strategies. The optimal approach has yet to be determined (104). Future prospective trials with better patient selection and more reliable clinical outcomes will help to clarify this topic (105).


In locally advanced NSCLC, concurrent chemoradiation is the standard of care in locally advanced disease (stage IIIA not amenable to surgery and stage IIIB). For borderline resectable disease, preoperative combination therapy may be an option. Postoperative radiation combined with chemotherapy is an effective treatment for disease presentation with omolateral mediastinal involvement after surgical excision. New molecules are under investigation in the context of locally advanced disease in combination with conventional chemotherapy and radiation. Among them, EGFR and VEGFR inhibitors and immune-modulating agents are being tested. In the context of esophageal and gastroesophageal cancers, radiotherapy is gaining credibility as an integration part of trimodality treatment also in adenocarcinoma histology. Definitive chemoradiation remains a valid option for locally advanced disease, particularly for squamous tumors. With respect to larynx and hypopharynx cancers, combination therapy remains a mainstay possibility as larynx preservation strategy. Concerns have been raised recently regarding long-term mortality of concurrent chemoradiation, while treatment regimens employing induction chemotherapy and cetuximab are presently under investigation. Finally, radiotherapy has a crucial role in the combined modality treatment of thoracic malignancies and head and neck cancers (106). Thus, young radiation oncologists will need to acquire a multidisciplinary profile in terms of knowledge, skills, and attitude to be able to properly fit into the multimodality bent of modern clinical oncology. Meetings such as the one organized by the Young Members Working Group of AIRO (AIRO Giovani) represent an extremely helpful chance to fulfill this task.


Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission.
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  •  Department of Oncology, Radiation Oncology, University of Turin, Turin - Italy
  •  Radiation Oncology, Ospedale Sacro Cuore-Don Calabria, Negrar (Verona) - Italy
  •  Department of Oncology, Proton Therapy Unit, Azienda Provinciale per i Servizi Sanitari (APSS), Trento - Italy
  •  Radiotherapy Unit, Campus Bio-Medico University, Rome - Italy
  •  Radiation Oncology Department-Gemelli ART, Sacred Heart Catholic University, Rome - Italy
  •  Department of Radio-Oncology, IRCCS AOU San Martino IST, National Institute for Cancer Research, Genoa - Italy
  •  Department of Radiation Oncology, Regional Oncological Hospital, Cagliari - Italy
  •  Department of Sensory Organs, Institute of Otorhinolaryngology, Audiology and Phoniatrics, Sapienza University, Rome - Italy
  •  Radiotherapy and Radiosurgery Department, Humanitas Clinical and Research Center, Rozzano (Milan) - Italy
  •  Department of Sperimental and Clinical Biomedical Sciences, Radiation Oncology, AOU Careggi, Florence - Italy
  •  Radiation Oncology Department, ARNAS Civico Hospital, Palermo - Italy
  •  Radiotherapy Department, University Hospital ‘Maggiore della Carità,’ Novara - Italy
  •  Radiotherapy Department, Centro REM, Catania - Italy

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