Oral Oncology 51 (2015) 795–799

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Late toxicity after radical treatment for locally advanced head and neck cancer Miren Taberna a,b,c,⇑, Antonio José Rullan a,c, Cinta Hierro d, Valentín Navarro e, Silvia Vázquez a,b, Alicia Lozano f,b, Esther Vilajosana a, Manel Maños g,b,c, Antonio Marí h,b,c, Joan Viñals i,b,c, Ricard Mesía a,b,c a

Medical Oncology Department, Hospital Duran I Reynalds, Catalan Institute of Oncology, Spain Head and Neck Unit, Bellvitge University Hospital, Catalan Institute of Oncology, Spain Universitat de Barcelona, Spain d Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Spain e Statistics Unit, Hospital Duran I Reynalds, Catalan Institute of Oncology, Spain f Radiotherapy Department, Hospital Duran I Reynalds, Catalan Institute of Oncology, Spain g ENT Department, Bellvitge University Hospital, Barcelona, Spain h Maxillofacial Surgery Department, Bellvitge University Hospital, Spain i Plastic and Reconstructive Surgery Department, Head and Neck Unit, Spain b c

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Article history: Received 25 February 2015 Received in revised form 7 May 2015 Accepted 11 May 2015 Available online 4 June 2015 Keywords: Head and neck cancer Locally advanced head and neck carcinomas Long survivors Late toxicity Quality of life Cisplatin Cetuximab Radiotherapy Quality of life (QoL)

s u m m a r y Background: Multimodal treatment for locally advanced head and neck carcinomas (LAHNC) has been reported to improve survival. However, it is less clear to what extent this survival gain is given at the expense of an impact on the quality of life of our patients. Our aim is to analyze the ongoing late toxic effects among long survivors, to determine how much these impairments affect their QoL, and if there is any factor that clearly impacts on this toxicity. Methods: 152 Patients diagnosed with LAHNC were treated radically in our clinical practice, either with concomitant chemoradiotherapy or bioradiotherapy, with or without induction chemotherapy. We prospectively assessed these patients’ treatment-related late toxicities according to the Radiation Therapy Oncology Group scoring system, and patients answered a QoL question to subjectively evaluate the degree of impact caused by these sequelae in their daily life. Multivariate logistic regressions were performed to detect factors that could influence in toxicity. Results: 21.9% Patients experienced grade 3–4 toxicity. Concomitant chemoradiation with cisplatin was found to be a risk factor of moderate and severe late toxicity compared to concomitant cetuximab in the adjusted analysis by RT fractionation. OR for moderate toxicity 0.292 (CI: 0.125–0.680, p = 0.004); OR for severe toxicity: 0.299 (CI: 0.0909–0.999, p = 0.05). Induction chemotherapy was found to be a protective factor for moderate late toxicity compared to concomitant treatment alone. Conclusion: Patients treated with concomitant chemoradiation with cisplatin have significantly more late toxicity compared to bioradiotherapy, whereas induction chemotherapy prevents from developing moderate late toxicity. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Abbreviations: LAHNC, locally advanced head and neck carcinomas; CRT, chemoradiotherapy; BRT, bioradiotherapy; RT, radiotherapy; RTOG, radiation therapy oncology group; QoL, quality of life question; HPV, Human Papiloma Virus; IMRT, Intensity-Modulated Radiation Therapy; EORTC, European Organization for Research and Treatment of Cancer; CCRT, concomitant chemoradiotherapy treatment; PF, Cisplatin–5Fluorouracil; TPF, Docetaxel–Cisplatin–5Fluo rouracil; PPF, Paclitaxel–Cisplatin–5Fluorouracil. ⇑ Corresponding author at: Department of Medical Oncology, Hospital Duran I Reynalds, Catalan Institute of Oncology, L’Hospitalet de LLobregat, Barcelona, Spain. Tel.: +34 93 260 77 44; fax: +34 93 260 77 41. E-mail address: [email protected] (M. Taberna). http://dx.doi.org/10.1016/j.oraloncology.2015.05.002 1368-8375/Ó 2015 Elsevier Ltd. All rights reserved.

Head and neck cancers are a heterogeneous group of cancers that arise from the squamous epithelium in the cavities of the head and neck area. Statistics of patients with squamous cell carcinoma of the head and neck indicate a gradual trend to increased survival of these patients. A recent review about changes in survival in the late 20th and early 21st century demonstrated a major statistically significant improvement in survival among head and neck cancer patients. The overall 5-year relative survival rate went from 54.7%

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in 1992–1996 to 65.9% in 2002–2006. Notably, improvements in cancer of the oral cavity, tongue, tonsils and nasopharynx were observed in the subgroup analysis, with the greatest improvements observed in tonsillar carcinoma and carcinoma of the tongue [1]. Therapy for head and neck cancer has evolved over the past decade. Significant efforts have been made to improve multimodal treatments, adding new therapeutic options for these patients, which have translated into better survival results. Several studies have hypothesized that certain factors might have been responsible for these positive results: the Human Papiloma Virus (HPV) appearance in certain oropharynx sublocalizations [2], improvements of surgical techniques with the emergence of robotic surgery and microvascular flaps, the emergence of new radiotherapy techniques such as the implementation of the Intensity-Modulated Radiation Therapy (IMRT) [3] the use of combined chemotherapy (cisplatin) [4] or biotherapy (cetuximab) [5] regimens alongside with radiotherapy or more intensive induction chemotherapy schedules (Do cetaxel–Cisplatin–5Fluorouracil) [6]. However, these encouraging results are accompanied by a not unworthy toxicity. We cannot assure whether the mortality is closely associated with patient’s comorbidity: either the mortality is increasing by using a more aggressive approach, or it is declining due to learning curve completion of these new therapies and the accurate implementation of supportive care measures. Taking into consideration that our long survivors may develop chronic toxicities related to our treatments, we need to assume that these limitations will certainly have an impact on their daily activities for the rest of their lives. Hence, it is time to better characterize and quantify this chronic toxicity and to start developing effective rehabilitation programs, in order to restore the functionality of our patients as much as we can. It is well known that patients heal physically after treatment, but as clinicians we must be able to improve its undesired consequences and to reduce the impact that an impaired capacity may have in our patients’ social relationships. Remarkably, there are important variations in the toxicity reporting methods, which has lead to a certain confusion in the past, and this is even more pronounced when it refers to evaluating long-term toxicity [7–9]. Unfortunately, there is a lack of information, since the vast majority of clinical trials published to date do not report long-term outcomes regarding late toxicity. The aim of this study is to analyze the late toxic effects present among our LAHNC long survivors and to determine how much these chronic toxicities may affect their lives. We will also pursue to explore whether any clinical or epidemiological factors could be related with the severity of the toxicity. The knowledge of these factors could translate into better tailored treatment strategies, towards a more personalized medicine for our LAHNC patients. Material and methods To develop this study at our institution, we prospectively assessed 152 LAHNC long survivors treated radically between March 1994 and July 2010. All of them had received either concomitant treatment with CRT or BRT, or fractionated RT with or without induction chemotherapy. The late toxicity assessment coincided with planned follow-up appointments in the Head and Neck Oncology Unit, so no additional appointments were needed. If the eligible patients were keen to participate into the study, they completed the proposed assessments that same day. Patients graded their treatment-related late toxicities according to the RTOG scoring system, and answered a QoL question to subjectively evaluate the degree of impact caused by these sequelae in their daily life. A prospective analysis was conducted among all long-term survivors, treated for a stage III/IVa-b LAHNC at the Head and Neck Oncology Unit at our Institution. We considered as a long-term

survivor that patient who lived more than two years since the diagnosis with no diagnosis of recurrence disease. The median time between treatment completion and evaluation was 60 months (24–214). Patients and treatment We selected 152 consecutive patients followed as an outpatients, that underwent radical treatment between January 1994 and January 2010. All cases were initially discussed by our multidisciplinary head-and-neck oncology team for tumor staging and treatment recommendations. Routine pre-treatment evaluation consisted of a complete medical history, physical examination, endoscopic evaluation, blood test, computed tomography (CT) or magnetic resonance imaging (MRI) and chest X-ray or chest CT. State of mind of patients and their social situation were also explored. All patients had a LAHNC from the oral cavity, larynx, hipopharynx, oropharynx, nasopharynx or unknown primary from the head and neck area. We excluded patients previously treated with surgery, those who were treated with palliative intent or if they had less than 24 months of follow-up. All patients had received treatment with radical intention. During the treatment, patients were seen almost once a week by a radiation oncologist, a medical oncologist, a specialist nurse, an oral surgeon, an ENT surgeon and a dietician and even more frequently when necessary. Acute adverse effects, oral intake, weight, vital signs and concomitant treatments were thoroughly documented. After completion of treatment, patients started their follow-up visits performed by the treating physicians. Each visit consisted of a history of medical symptoms, physical examination, endoscopic evaluation when needed, and toxicity assessment. Radiologic evaluation was done once a year for the first three years or when a relapse was suspected. Follow-up data were reviewed from January 2012 to January 2013 in the follow-up visits with each patient. All relevant examinations were performed, and patients also answered about changes in their QoL. Late morbidity assessments We prospectively reviewed consecutive long-term survivors in an outpatient clinic, answering a subjective assessment of late toxicity based on the RTOG/European Organization for Research and Treatment of Cancer (EORTC) scoring system on skin, subcutaneous tissue, mucous membrane, salivary glands, larynx and bone (jaw). A prospective database was created containing one item for each kind of toxicity. We analyzed late toxicities in patients alive with more than 2 years of follow-up, and later on, these toxicities’ correlation with the oxic habits of the patients, their tumor characteristics and previous therapies received. Toxic habits such as tobacco and alcohol abuse were recorded in different time points: before the diagnosis of the tumor, during the treatment and after completing the treatment. A self-reported QoL question was completed by each patient; assessing how the side effects related to previous treatments affected their lifestyle. The answer was graded in several categories ‘‘normal live without limitations, partial restricted normal life, limited normal life and extremely limited normal life’’, to allow us to quantify the degree of limitation that the impairment caused them. Statistical analysis Frequency tables for each toxicity were performed. The presence/absence of moderate and severe toxicity was calculated adding the information of each toxicity item. Univariate and

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multivariate odds ratio were obtained throughout logistic regressions (link logit) for moderate and severe toxicity (95% CI).

Results Patients and treatment characteristics There were 136 men (89.5%), median age at evaluation 73 years old (range 29–78). All of them had locally advanced carcinomas, 124 (82%) squamous cell carcinoma and 28 (18%) undifferentiated carcinoma. Locations were: 25.0% oropharynx , 9.9% oral cavity, 23.7% larynx, 17.1% hipopharynx , 19.0% nasopharynx and 5.3% unknown primary of the head and neck (Table 1). Toxic habits of patients before diagnosis, during, and after treatment are (Table 2). Concomitant radical treatment was conducted in 78.9% patients, 51% based on CDDP and 28% based on Cetuximab. 21% patients had received only RT without CT, always after induction chemotherapy. 55.9% had received Induction CT prior to

Table 1 Patient characteristics.

Table 2 Toxic habits. Toxic habits before diagnosis n (%) Former smoker 43 (28.3) Active smoker 95 (62.5) Non-smoker 14 (9.2)

Former alcohol use Regular alcohol use Non-alcohol use

29 (19.1) 98 (64.5) 25(16.4)

Toxic habits during treatment n (%) Former smoker 115 (75.7) Active smoker 23 15.1) Non-smoker 14 (9.2)

Former alcohol use Regular alcohol use Non-alcohol use

105 (69.1) 22 (14.5) 25 (16.4)

Toxic habits after completing treatment n (%) Former smoker 107 (70.4) Former alcohol use Active smoker 31 (20.4) Regular alcohol use Non-smoker 14 (9.2) Non-alcohol use

74 (48.7) 53 (34.9) 25 (16.4)

Toxic habits of patients before diagnosis, during, and after treatment.

concomitant treatment: 43.5% with PF-like, 21.2% with TPF, and 35.3% with PPF, followed by concomitant treatment. All 152 patients completed RT: 81.0% normofractionated, 19% hyperfractionated, with a median dose of 70 Gy. 31 patients were treated with 2 D technique, 103 with 3D and 18 with IMRT.

Characteristics

All 152 patients n (%)

Late toxicity

Sex Male Female Mean age (range), y

136 (89) 16 (11) 73 (29–78)

Primary tumor site Oral cavity Oropharynx (10% HPV-related) Larynx Hipopharynx Nasopharynx Unknown primary

15 (9.9) 38 (25.0) 36 (23.7) 26 (17.1) 29 (19.0) 8 (5.3)

Histology Squamous cell carcinoma Undifferentiated carcinoma

124 (82) 28 (18)

T stage T1 T2 T3 T4 Tx

14 (9.2) 37 (24.3) 47 (30.9) 46 (30.3) 8 (5.3)

N stage N0 N1 N2 (a,b,c) N3

32 24 81 15

All patients had at least one RTOG/EORTC G1-2 late toxicity. Furthermore, 34 (21.9%) patients experienced grade 3–4 toxicity. G4 RTOG/EORTC toxicity is listed here: 13 patients (8.6%) had a permanent tracheostomy (G4 larynx affection), 7 patients (4.6%) experienced speech pathology, 6 patients (3.9%) a permanent gastrostomy (G4 dysphagia), 3 patients (2%) have severe ototoxicity , 2 patients (1.3%) were diagnosed of jaw’s osteonecrosis and 1 patient (0.7%) suffered from subcutaneous toxicity.1–2 and G3 RTOG/EORTC toxicities were listed on Table 3. Age gender, tobacco or alcohol consumption were not indepents predictors of moderate to severe (G2–4) late toxicity using logistic regression as a multivariate analysis. However T4b stage was an independent predictor of moderate (G2) late toxicity: OR 7.2 (CI: 1.69–3.09, p = 0.008), despite no significant differences were found for severe toxicity. Oral cavity was found to be the location with significant more toxicity (OR 5.6 [CI: 1.01–30.9, p = 0.048]). On the other hand, concomitant chemoradiation with cisplatin was found to be a risk factor of moderate (G2) and severe (G3–4) late toxicity compared to concomitant Cetuximab in the adjusted analysis by RT fractionation (hyperfractionated-normofractionated).

Stage III IVa IVb

36 (23.7) 101 (66.5) 15 (9.9)

Induction chemotherapy PF like TPF PPF

N 85 (55.9) 37 (43.5) 30 (35.3) 18 (21.2)

Concomitant chemotherapy Cisplatin Cetuximab Radiotherapy alone

N 152 (100) 77 (50.6) 43 (28.3) 32 (21.1)

Radiotherapy fractionation Normofractionated Hyperfractionated

N 152 (100) 123 (81.0) 29 (19)

Radiotherapy technique 2D 3D IMRT

31 (20) 103 (68) 18 ((12)

Neck dissection

14 (9.2)

Patients characteristics.

(21.0) (15.8) (53.3) (9.9)

Table 3 Toxicity. Toxicity

G1–2 n (%)

G3–4 n (%)

Fatigue Anorexia Sticky saliva Dry mouth Tongue twitching Speech pathology Trismus LhermitteSd. Dysphagia Cutaneous toxicity Subcutaneous toxicity Larynx affection Jaw’s osteonecrosis Ototoxicity Neurotoxicity Nephrotoxicity

46 (30.3) 12 (7.9) 123 (80.9) 68 (44.7) 17 (11.2) 58 (38.2) 41 (26.9) 20 (13.2) 57 (37.5) 22 (14.5) 100 (65.8) 29 (19.1) 4 (2.6) 64 (42.1) 50 (32.9) 3 (1.9)

0 0 2 (1.3) 1 (0.7) 1 (0.7) 7 (4.6) 2 (3) 0 9 (5.9)a 1 (0.7) 3 (1.9) 14 (9.2)a 4 (2.6) 5 (3.3) 0 0

RTOG/EORTC toxicities. a Dysphagia G4 (Gastrostomy) 6 (4%) and Larynx affection G4 (Tracheostomy) 13 (8.5%).

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OR for moderate toxicity Cetuximab vs Cisplatin 0.292 (CI: 0.125– 0.680, p = 0.004). OR for severe toxicity Cetuximab vs Cisplatin: 0.299 (CI: 0.0909–0.999, p = 0.05). Moreover, concomitant chemoradiation with cisplatin was found to be a risk factor of moderate (G2) late toxicity compared to concomitant Cetuximab in the adjusted analysis by RDT technique (2D, 3D and IMRT. All patients treated with 2D technique were concomitated with cisplatin). OR for moderate toxicity Cetuximab vs. Cisplatin 0.402 (CI: 0.176–0.92, p = 0.03). Induction chemotherapy was found to be a protective factor for moderate late toxicity compared to concomitant treatment without previous induction in the analysis adjusted by RT fractionation and in the independent analysis. Non-adjusted analysis OR: 3.013 (CI: 1.46–6.21, p = 0.003; adjusted analysis by RT fractionation OR: 3.79 (CI: 1.76–8.2; p = 0.001). Interaction was also analyzed for CRT and BRT but not estimation was possible due to low number of patients. Quality of life More than half of the patients (88/152, 57.8%) considered that their QoL was affected by the treatment. Inside this group, 41% of patients considered that their everyday life was only partially altered. However 17% of patients reported that they were very disabled to carry on with their usual activities. Neither age, T stage or tumor localization were found to be statistically significant as a risk factor.

showed that treatment with CRT is an independent risk factor for the development of moderate to severe late toxicity adjusted by RT fractionation (OR for moderate toxicity 0.292 [CI: 0.125– 0.680, p = 0.004]); OR for severe toxicity Cetuximab vs. Cisplatin: 0.299 (CI: 0.0909–0.999, p = 0.05). There is no Phase III clinical trial currently comparing concomitant treatment with cisplatin vs cetuximab for LAHNC. Despite this there is data, either from comparison with historical series [5] or from phase II studies [14] suggests that there is are no significant differences in terms of disease control between concomitant CRT versus BRT . Furthermore, in contrast with other targeted directed therapies, there is no validated predictive biomarker to decide which patients should receive cetuximab instead of chemotherapy concomitant to RT. Further study results will expand the clinical evidence regarding the efficacy and safety of CRT with cisplatin versus cetuximab among LAHNC patients. Until then, treatment for LAHNC should be highly individualized based on the tumor burden and symptoms, and the best therapeutic approach for every patient will rely on whether the aim is to slow tumor growth, to improve symptoms or to treat with radical intention. Moreover, induction chemotherapy has always been related to additional toxicity to our patients. Interestingly, our study suggests that in our patient sample, induction chemotherapy may prevent for the development of moderate toxicity. These results could be explained by the volume replanning due to tumor reduction during induction chemotherapy treatment, mostly in T4 and N2b–N3 stages.

Discussion Although there is much data available on risk factors for acute toxicity due to concomitant chemoradiotherapy treatment, the factors that influence late toxicity have not been so widely studied among LAHNC. An RTOG analysis that added up data from three clinical trials using CCRT for LAHNC concluded that older age, advanced T-stage, larynx/hypopharynx localization and neck dissection where significantly related to higher severe late toxicity [10]. Another study analyzed which factors where associated with long-term dysphagia after definitive radiotherapy; concluding that the addition of CT, radiotherapy schedule, increasing age and tumor primary site were risk factors for the development of long-term dysphagia [11]. In our analysis we found that neither age, gender, tobacco nor alcohol intake were significantly associated to a more frequent late severe toxicity. On the other hand, we found that the oral cavity location, stage IVb, concomitant treatment with cisplatin or treatments without previous induction chemotherapy are risk factors to develop late toxicity. Concomitant BRT has been widely implemented in the treatment of patients with LAHNC since its approval. Cetuximab has a completely different mechanism of action compared to classical chemotherapies [12], in parallel with a different toxicity profile which can even influence responses to the treatment [13]. Within this context, late toxicity after concurrent BRT has not yet been fully studied. Recently The Phase II study TREMPLIN has been published, comparing the efficacy and safety of induction chemotherapy followed by CRT or BRT. The primary end point was larynx preservation at 3 month. They found no evidence that the experimental arm was superior to the standard one, but the results highlighted that salvage surgery was feasible only in BRT arm. However we will probably need to wait for more robust data regarding late toxicity in each arm of treatment, to extrapolate these observations in a generalized way [14]. Given this facts, we compared the apparition of late toxicity in patients treated with CRT vs patients treated with BRT. The results

Conclusion Current treatments against LAHNC tend to cause toxicity among patients. The vast majority of our surviving patients will suffer from long-standing toxicity in some degree. Although most of them will be able to adapt, it is known that nearly 20% of them will experience severe chronic adverse effects. Our challenge as an Head and Neck Cancer specialist will be to maintain overall survival rates, while trying to reduce these lasting sequelae. The combination of BRT appears to contribute to the reduction of chronic toxicity in long-surviving patients, alongside with the use of induction chemotherapy that is emerging as a protective factor against moderate chronic toxicity. Conflict of interest RM has taken part in advisory boards and educational meetings as faculty and speaker for Merck Serono, Bayer and AstraZeneca, he has also received occasional travel fund to conferences/symposia/ meetings by Merck Serono. MT has taken part in advisory broads as a speaker for Merck Serono Group. The rest of the authors declare that they have no conflict of interests. Acknowledgements The authors thank the patients who consented to participate in this study and their families and carers. We also thank all the colleagues who have collaborated in this study and are not included in the list of authors. All authors reviewed the data and commented on the report. References [1] Rodriguez CP, Adelstein DJ. Survival trends in head and neck cancer: opportunities for improving outcomes. The Oncologist 2010;15(9):921–3. http://dx.doi.org/10.1634/theoncologist.2010-0237.

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