Cancer Treatment Reviews 44 (2016) 10–16
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Anti-Tumour Treatment
Chemotherapy in locally advanced head and neck squamous cell carcinoma Bishal Gyawali ⇑, Tomoya Shimokata, Kazunori Honda, Yuichi Ando Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
a r t i c l e
i n f o
Article history: Received 3 August 2015 Received in revised form 28 December 2015 Accepted 15 January 2016
Keywords: Locally advanced head and neck cancer Concomitant Induction Chemotherapy Chemoradiotherapy Cetuximab
a b s t r a c t Chemotherapy, in combination with a local treatment, has a role in nearly all the settings of locally advanced head and neck squamous cell carcinoma (LAHNSCC) treatment: as definitive, adjuvant or induction therapy. However, despite many years of trials, controversies still exist regarding the best approach to using chemotherapy in the multi-modal treatment of LAHNSCC. Opinions are divided on sequential versus concurrent use of chemotherapy and radiotherapy for unresectable LAHNSCC. More debate exists on whether the addition of induction chemotherapy to concomitant chemoradiotherapy is clinically meaningful. After the approval of cetuximab in combination with radiotherapy for this disease, making treatment choices have become further complicated. Although new data from trials are arriving every year, the results have been inconclusive. In this review, we provide the readers with the latest information on various strategies of using chemotherapy and cetuximab that will help to make an evidence-based decision in the treatment of LAHNSCC, including the approach to larynx preservation. We conclude that with the available information, concurrent chemoradiotherapy should be preferred over induction chemotherapy, except in the setting of larynx preservation. Furthermore, given the paucity of positive data and severe financial toxicity associated with cetuximab, concurrent chemoradiotherapy should be the preferred choice over cetuximab–radiotherapy. Future trials in head and neck cancer should be properly planned to address these controversies and provide clear solutions. Ó 2016 Elsevier Ltd. All rights reserved.
Introduction Surgery followed by radiotherapy (RT) was the standard treatment of care for resectable locally advanced head and neck squamous cell carcinomas (LAHNSCC). However, locoregional relapse (LRR) occurs in around 30% and distant metastases (DM) in around 25% of patients even after surgery and radiotherapy, with a poor 5 year survival of less than 40% [1,2]. To overcome this dismal outlook with surgery and RT along with the desire to preserve organ and function, the role of chemotherapy (CT) in LAHNSCC was investigated. Today, it is known that CT plays an undeniably important role in the management of LAHNSCC in all the settings: definitive, adjuvant and neo-adjuvant (also known as induction) treatment. A meta-analysis of chemotherapy in head and neck cancer (MACH-NC) in 2011 showed that the addition of CT was beneficial irrespective of sites of head and neck cancer [3]. Although the role of CT in LAHNSCC management has long been acknowledged, ⇑ Corresponding author at: Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Tel./fax: +81 52 744 1903. E-mail address: [email protected] (B. Gyawali). http://dx.doi.org/10.1016/j.ctrv.2016.01.002 0305-7372/Ó 2016 Elsevier Ltd. All rights reserved.
the schedule and timing of CT is still a matter of debate. In this review, we provide updated evidences in favor of as well as against various approaches to using CT and cetuximab (Cet) in the management of this disease.
Adjuvant treatment in resectable disease Two landmark trials published together in 2004 established the role of CT in the adjuvant setting in the management of LAHNSCC. Resectable LAHNSCC patients were randomized to receive RT alone (standard until then) or concurrent chemoradiotherapy (CCRT) with cisplatin 100 mg/m2 every 3 weeks in the EORTC 22931 [4] and the RTOG 9501 [2] trials in the adjuvant setting. RT was delivered at standard dose at 66 Gy over 6.5 w for EORTC 22931 and 60– 66 Gy over 6–6.6 w for the RTOG 9501 trials. Both these trials showed a significant benefit of progression-free survival (PFS) for the CCRT arm versus RT arm (Table 1). They also unanimously showed the benefit of post-op CCRT over RT alone in controlling the LRR. However, only the EORTC trial showed a significant benefit for the overall survival (OS). In the RTOG 9501, the benefit obtained in PFS didn’t translate into OS benefit.
11
B. Gyawali et al. / Cancer Treatment Reviews 44 (2016) 10–16 Table 1 Comparison of EORTC 22931 and RTOG 9501 trials. Parameters
EORTC 22931
RTOG 9501
Included patients
All stage III/IV; stage 1 or 2 with N2/N3, M0; T1/T2 and N0/N1 with high risk features PFS 55 m vs. 23 m 0.75(0.56–0.99) 0.04 72 m vs. 32 m 0.70 (0.52–0.95) 0.02 18% vs. 31% (at 60 months)
Only high risk
Primary end point Progression free survival (EORTC) or disease free survival (RTOG)
Overall survival
Loco-regional relapse rate
Adverse events (Pgrade 3)
Median HR P Median HR P CI HR P Incidence P
It should be noted here that the primary endpoint for both the trials were not OS, but PFS for the EORTC and LRR for the RTOG. Both these trials were, therefore, positive trials as the primary end point was met. However, as expected, the benefit of adding CT to RT came at a price; the incidence of Pgrade 3 adverse events (AEs) being significantly higher in the CCRT group. The incidence of serious AEs increased significantly with CCRT compared to RT alone by as much as 43% in RTOG 9501 [2] and 20% in EORTC [4] (Table 1). One more caveat in drawing inferences from these two studies is the difference in the inclusion criteria. While the RTOG included only patients at high risk for failure, the EORTC included patients with stage pT3 or pT4 with any N (except T3N0 of larynx) with negative resection margins, or T1 or T2 with N2/N3, M0 or stage T1 or T2 and N0 or N1 with high risk features. The high risk characteristics for the RTOG were defined as any or all of the following: histologic evidence of invasion of two or more regional lymph nodes, extracapsular spread (ECS) of nodal disease, and resection margin positive (MP) while those for EORTC included perineural involvement or vascular tumor embolism in addition to ECS and MP. A pooled analysis of these two trials indicated that tumors with ECS and MP were at higher risk for relapse and would benefit most from CCRT [5], a finding that was later confirmed by the retrospective subset analysis of these trials [6]. These two trials thus established the place of CT firmly in the adjuvant management of LAHNSCC, especially for patients with good performance status (PS) at higher risk of relapse (ECS and MP). Given the high incidence of serious AEs associated with the addition of CT to RT, the benefit of CCRT over RT alone is questionable in patients with no high risk features and those with poor PS [7]. This concern regarding the use of CCRT in patients without high-risk factors has become particularly important with the long term results of RTOG 9501 now published [8]. This updated results after a minimum follow up of 10 years showed that the benefit in terms of LRR and DFS obtained in the first reporting of the trial had lost the statistical significance. However, the benefit was retained in the subgroup of patients with ECS and MP for LRR (21.0% vs. 33.1%, P = 0.02) and for DFS (18.4% vs. 12.3%, p = 0.05), but clear OS advantage was not seen even in this high risk subset (27.1% vs. 19.6%, p = 0.07). Therefore, adjuvant CCRT should be given only to carefully selected patients, given the toxicities of cisplatin. This has also brought the dose of cisplatin used in these landmark studies into question and some oncologists prefer using lower doses of cisplatin similar to that in cervical cancer to avoid the toxicities. Various alternative dose and schedules are being studied including weekly low dose cisplatin at 30 mg/m2 or 50 mg IV weekly [9–11]. Details of the dosing studies are beyond the scope of this review.
0.007 41% vs. 21% 0.001
Local and regional tumor control 0.78 () 0.04 44.9 v 31.9 m 0.84 (0.65–1.09) 0.19 19% v 30% (at 46 months) 0.61 0.01 77% v 34%
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Anti-Tumour Treatment
Chemotherapy in locally advanced head and neck squamous cell carcinoma Bishal Gyawali ⇑, Tomoya Shimokata, Kazunori Honda, Yuichi Ando Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
a r t i c l e
i n f o
Article history: Received 3 August 2015 Received in revised form 28 December 2015 Accepted 15 January 2016
Keywords: Locally advanced head and neck cancer Concomitant Induction Chemotherapy Chemoradiotherapy Cetuximab
a b s t r a c t Chemotherapy, in combination with a local treatment, has a role in nearly all the settings of locally advanced head and neck squamous cell carcinoma (LAHNSCC) treatment: as definitive, adjuvant or induction therapy. However, despite many years of trials, controversies still exist regarding the best approach to using chemotherapy in the multi-modal treatment of LAHNSCC. Opinions are divided on sequential versus concurrent use of chemotherapy and radiotherapy for unresectable LAHNSCC. More debate exists on whether the addition of induction chemotherapy to concomitant chemoradiotherapy is clinically meaningful. After the approval of cetuximab in combination with radiotherapy for this disease, making treatment choices have become further complicated. Although new data from trials are arriving every year, the results have been inconclusive. In this review, we provide the readers with the latest information on various strategies of using chemotherapy and cetuximab that will help to make an evidence-based decision in the treatment of LAHNSCC, including the approach to larynx preservation. We conclude that with the available information, concurrent chemoradiotherapy should be preferred over induction chemotherapy, except in the setting of larynx preservation. Furthermore, given the paucity of positive data and severe financial toxicity associated with cetuximab, concurrent chemoradiotherapy should be the preferred choice over cetuximab–radiotherapy. Future trials in head and neck cancer should be properly planned to address these controversies and provide clear solutions. Ó 2016 Elsevier Ltd. All rights reserved.
Introduction Surgery followed by radiotherapy (RT) was the standard treatment of care for resectable locally advanced head and neck squamous cell carcinomas (LAHNSCC). However, locoregional relapse (LRR) occurs in around 30% and distant metastases (DM) in around 25% of patients even after surgery and radiotherapy, with a poor 5 year survival of less than 40% [1,2]. To overcome this dismal outlook with surgery and RT along with the desire to preserve organ and function, the role of chemotherapy (CT) in LAHNSCC was investigated. Today, it is known that CT plays an undeniably important role in the management of LAHNSCC in all the settings: definitive, adjuvant and neo-adjuvant (also known as induction) treatment. A meta-analysis of chemotherapy in head and neck cancer (MACH-NC) in 2011 showed that the addition of CT was beneficial irrespective of sites of head and neck cancer [3]. Although the role of CT in LAHNSCC management has long been acknowledged, ⇑ Corresponding author at: Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Tel./fax: +81 52 744 1903. E-mail address: [email protected] (B. Gyawali). http://dx.doi.org/10.1016/j.ctrv.2016.01.002 0305-7372/Ó 2016 Elsevier Ltd. All rights reserved.
the schedule and timing of CT is still a matter of debate. In this review, we provide updated evidences in favor of as well as against various approaches to using CT and cetuximab (Cet) in the management of this disease.
Adjuvant treatment in resectable disease Two landmark trials published together in 2004 established the role of CT in the adjuvant setting in the management of LAHNSCC. Resectable LAHNSCC patients were randomized to receive RT alone (standard until then) or concurrent chemoradiotherapy (CCRT) with cisplatin 100 mg/m2 every 3 weeks in the EORTC 22931 [4] and the RTOG 9501 [2] trials in the adjuvant setting. RT was delivered at standard dose at 66 Gy over 6.5 w for EORTC 22931 and 60– 66 Gy over 6–6.6 w for the RTOG 9501 trials. Both these trials showed a significant benefit of progression-free survival (PFS) for the CCRT arm versus RT arm (Table 1). They also unanimously showed the benefit of post-op CCRT over RT alone in controlling the LRR. However, only the EORTC trial showed a significant benefit for the overall survival (OS). In the RTOG 9501, the benefit obtained in PFS didn’t translate into OS benefit.
11
B. Gyawali et al. / Cancer Treatment Reviews 44 (2016) 10–16 Table 1 Comparison of EORTC 22931 and RTOG 9501 trials. Parameters
EORTC 22931
RTOG 9501
Included patients
All stage III/IV; stage 1 or 2 with N2/N3, M0; T1/T2 and N0/N1 with high risk features PFS 55 m vs. 23 m 0.75(0.56–0.99) 0.04 72 m vs. 32 m 0.70 (0.52–0.95) 0.02 18% vs. 31% (at 60 months)
Only high risk
Primary end point Progression free survival (EORTC) or disease free survival (RTOG)
Overall survival
Loco-regional relapse rate
Adverse events (Pgrade 3)
Median HR P Median HR P CI HR P Incidence P
It should be noted here that the primary endpoint for both the trials were not OS, but PFS for the EORTC and LRR for the RTOG. Both these trials were, therefore, positive trials as the primary end point was met. However, as expected, the benefit of adding CT to RT came at a price; the incidence of Pgrade 3 adverse events (AEs) being significantly higher in the CCRT group. The incidence of serious AEs increased significantly with CCRT compared to RT alone by as much as 43% in RTOG 9501 [2] and 20% in EORTC [4] (Table 1). One more caveat in drawing inferences from these two studies is the difference in the inclusion criteria. While the RTOG included only patients at high risk for failure, the EORTC included patients with stage pT3 or pT4 with any N (except T3N0 of larynx) with negative resection margins, or T1 or T2 with N2/N3, M0 or stage T1 or T2 and N0 or N1 with high risk features. The high risk characteristics for the RTOG were defined as any or all of the following: histologic evidence of invasion of two or more regional lymph nodes, extracapsular spread (ECS) of nodal disease, and resection margin positive (MP) while those for EORTC included perineural involvement or vascular tumor embolism in addition to ECS and MP. A pooled analysis of these two trials indicated that tumors with ECS and MP were at higher risk for relapse and would benefit most from CCRT [5], a finding that was later confirmed by the retrospective subset analysis of these trials [6]. These two trials thus established the place of CT firmly in the adjuvant management of LAHNSCC, especially for patients with good performance status (PS) at higher risk of relapse (ECS and MP). Given the high incidence of serious AEs associated with the addition of CT to RT, the benefit of CCRT over RT alone is questionable in patients with no high risk features and those with poor PS [7]. This concern regarding the use of CCRT in patients without high-risk factors has become particularly important with the long term results of RTOG 9501 now published [8]. This updated results after a minimum follow up of 10 years showed that the benefit in terms of LRR and DFS obtained in the first reporting of the trial had lost the statistical significance. However, the benefit was retained in the subgroup of patients with ECS and MP for LRR (21.0% vs. 33.1%, P = 0.02) and for DFS (18.4% vs. 12.3%, p = 0.05), but clear OS advantage was not seen even in this high risk subset (27.1% vs. 19.6%, p = 0.07). Therefore, adjuvant CCRT should be given only to carefully selected patients, given the toxicities of cisplatin. This has also brought the dose of cisplatin used in these landmark studies into question and some oncologists prefer using lower doses of cisplatin similar to that in cervical cancer to avoid the toxicities. Various alternative dose and schedules are being studied including weekly low dose cisplatin at 30 mg/m2 or 50 mg IV weekly [9–11]. Details of the dosing studies are beyond the scope of this review.
0.007 41% vs. 21% 0.001
Local and regional tumor control 0.78 () 0.04 44.9 v 31.9 m 0.84 (0.65–1.09) 0.19 19% v 30% (at 46 months) 0.61 0.01 77% v 34%
