Abstract
Aim: To examine the role of a non-surgical multimodality approach in patients with locally advanced pharyngeal cancer who refuse surgery or are inoperable. Patients and Methods: Between 2006 and 2011, 19 patients with T3-4 hypopharyngeal cancer received multimodality non-surgical treatment. Out of these patients, nine refused surgery, and nine were inoperable. Their age range was 52-86 years (median, 68 years). Ten patients had T3, and 9 had T4 (two with stage III and 17 with stage IV). Neoadjuvant induction chemotherapy was administered in 11 patients. Hyperthermia was performed in patients with advanced lymph node metastasis. Radiotherapy was administered at a median of 61 Gy (60-61.2 Gy) in conventional fractionation. Concurrent chemotherapy was administered to all patients: through intra-arterial infusion in seven, systemic infusion in 10, or both in two. Median follow-up time was 27 months (range: 6-50 months). Results: At the primary site, 16 patients (84%) achieved a complete response and three (16%) with partial response, resulting in a 100% response rate. Locoregional failure appeared in the form of six local and two regional lesions, and in one case in both types of lesions. Three-year local control, disease-free and overall survival rates, and laryngeal preservation rates were 65%, 48%, 50%, and 83%, respectively. Anemia was the only strong predisposing factor, not only for reduced local control but also for reduced progression-free and overall survival rates. Acute toxicities of grade 3 or more included hematological toxicity in four patients, gastrointestinal toxicity in two, and pneumonia in 6. Late adverse reaction of dysphagia grade 3 was found in one patient, whereas dysphagia grade 4 was not observed. Conclusion: Multimodality non-surgical treatment could be a useful option for patients who refuse surgery and have inoperable disease with substantial curative potential without severe adverse reactions.
- Hypopharyngeal cancer
- chemoradiotherapy
- larynx preservation
- hyperthermia
- intra-arterial infusion chemotherapy
Hypopharyngeal cancer (HPC) is an ominous disease of the head and neck. Historically, the standard choice of treatment for advanced HPC was surgical resection followed by adjuvant radiotherapy (RT). However, the substantial impairment of quality of life after surgical resection has enhanced the development of organ-conservative techniques. Induction chemotherapy (ICT) followed by RT has been shown to produce equivalent survival to that after laryngectomy following RT (1). According to randomized trials and meta-analysis (2-4) of patients with laryngeal or hypopharyngeal squamous cell carcinoma, comparing total laryngectomy with ICT followed by RT in good responders or total laryngectomy alone in poor responders, ICT with cisplatin-fluorouracil (PF) did not jeopardize the overall survival rate. In a more recent study, a docetaxel-PF regimen led to show significantly high laryngeal preservation rates than did PF-alone, with no difference in the overall survival rates (5).
Patients often can not undergo surgery for various reasons (e.g. inoperative condition with comorbidities, fear of surgical intervention). Therefore, we attempted to improve the outcome of non-surgical treatments by combining multimodality treatments. For advanced local disease, the curative group was identified by a good ICT response. However, we used intra-arterial infusion chemotherapy to maximize the efficacy of chemoradiotherapy without hampering organ function. In addition, we used hyperthermia in patients with advanced lymph node involvement of N2 or more. Here we present the outcomes of these multimodality treatments.
Patients and Methods
Nineteen patients with nonmetastatic squamous cell HPC who refused surgery or had nonresectable disease received definitive multimodality treatment at Kurume University Hospital between 2005 and 2011. The patients' characteristics are summarized in Table I. Tumors were staged according to the sixth version of Union for International Cancer Control (UICC) (6). External-beam RT (1.8-2.0 Gy/day) was administered five times a week in once-daily fractions using a 4-6 MV photon beam produced by a Linac MHCL 15DP (Mitsubishi Co., Tokyo, Japan). A radiation planning system for 3D conformal RT was used to schedule treatments. RT (up to 40-46 Gy) was initially administered with opposed lateral fields to the primary and upper neck areas matched to the anterior fields for the lower neck and supraclavicular regions. The primary lesion and involved neck nodes were further boosted to 60.8 (60-67) Gy with oblique parallel opposed fields to spare the spinal cord. The gross tumor volume (GTV) was defined as the total volume of the primary lesion and the involved lymph nodes and was determined using laryngoscopy, computed tomography (CT), magnetic resonance imaging (MRI), and 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) positron emission tomography (PET) scans. A positive lymph node was defined as >10 mm in the short axis on CT/MRI or positive by 18F-FDG PET findings. The clinical target volume (CTV) was defined as the GTV plus a 10-mm margin to cover microscopic disease. The planning target volume (PTV) was defined as the CTV plus 5-mm margins in every direction. CTV prophylactic was designed to include the lymph nodes at levels II-V, the retropharyngeal, and subclavicular lymph nodes. PTV prophylactic was defined as the CTV prophylactic plus 5-mm margins. The initial field included the PTV prophylactic area.
Out of the 19 patients, 11 (58%) underwent multi-agent ICT consisting of 6 cisplatin and 5-FU (FP) and four cisplatin and 5-FU and docetaxel (TPF) and one FP followed TPF. Non-ICT was used in 8 patients (37%). All patients received concurrent chemoradiotherapy, which consisted of nine systemic chemotherapies (two FP and seven cisplatin), and nine intra-arterial infusion chemotherapies. Hyperthermia was induced in nine patients with advanced lymph node metastasis of N2 or more using an Aloka microwave hyperthermia machine MMS-015 (Hitachi-Aloka Medical Ltd, Tokyo, Japan), and was provided for 30-40 min after RT. Hyperthermia was induced every week on the same day during RT. All patients were enrolled in this study after obtaining written informed consent prior to treatment in accordance with the guidelines of the Institutional Review Board. Patients were followed-up every month during the first six months and every 3–6 months thereafter. The median follow-up time was 27 months (range, 6-50 months). Acute and late toxicities were scored according to the Common Terminology Criteria of Adverse Events, version 3.0 (7).
Statistical analysis. All statistical analyses were performed using the Stat-view 5.0 statistical software (SAS Institute, Inc., Cary, NC, USA). Frequencies were analyzed using the χ2 test. Means were compared using the Student's t-test for normally distributed data and Mann-Whitney U-test for skewed data. Survival data and cumulative incidences were estimated by the Kaplan–Meier method and examined for significance using the log-rank test. Cox's proportional hazard model was used for the multivariate analysis. Cut-off values were set as the average or median value of each variable unless otherwise stated. All analyses used the conventional p<0.05 level of significance.
Patients' characteristics.
Results
All patients completed their treatment without interruption of more than four days. At the primary site, 16 patients (84%) achieved a complete response, and three (16%) had a partial response, resulting in a 100% response rate. At the last follow-up, 10 (53%) patients were still alive; and seven (37%) had died from HPC. Nine patients (47%) were alive without any evidence of disease, and one patient (5%) was alive with recurrent disease. The 3-year overall survival rate, progression-free survival, local control, and laryngeal preservation rates for all patients were 50%, 48%, 65%, and 70.3%, respectively. Six patients including those with partial responses showed recurrence at primary sites (three each of T3 and T4), and these patients died of their disease. Three patients had lymph node recurrence (cN2b), and only one patient was able to undergo salvage surgery and remained free from disease. The 3-year lymph node control rate was 80%.
A low pre-treatment serum hemoglobin was identified as the only factor predisposing not only for poorer local control (p=0.04) but also for poorer overall survival rate (p=0.02; Table II, Figure 1). Multivariate analysis revealed this value to be a significant prognostic factor for worse progression-free survival (p=0.03, hazard ratio 11.17, 95% confidence interval=1.23-96.8; Table II). Progression-free survival at 3 years for patients with a pre-treatment hemoglobin value of ≥11.5 g/dl was 62%, whereas those with lower hemoglobin levels had 33% progression-free survival (p=0.05; Figure 1). In addition, anemia was found to be a strong predicator of poorer local control (p=0.04) and overall survival (p=0.02).
Influence of pre-treatment serum hemoglobin values on survival and tumor control using a cut-off of 11.5 g/dl. a: Progression-free survival rates. Patients with pre-treatment hemoglobin of 11.5 g/dl or more had 62% progression-free survival at 3 years, whereas that the lower counterpart was 33% (p=0.05). b: Local control rate. Patients with a pre-treatment hemoglobin of 11.5 g/dl or more had 90% local control rate at 3 years, whereas of the lower counterpart was 34% (p=0.04). c. Overall survival rates. Patients with pre-treatment hemoglobin of 11.5 g/dl or more had 70% overall survival rate at 3 years, whereas that of the lower counterpart was 33% (p=0.02).
Eight acute grade 3 toxicities were observed in six patients (32%; four with hematological toxicity; three with gastrointestinal toxicity, of which two required stomach tube feeding; and one with pneumonia; Table III). No acute toxicity of grade 4 or more was found. For late toxicity, one patient required gastrostomy for grade 3 dysphagia, and two had grade 2 reactions, including one with thyroid dysfunction and mild dysphagia with choke-over (Table III). Synchronous and metachronous malignancies were found in five patients (26%; one with hepatocellular carcinoma, one stomach cancer, one rectal cancer, one patient had both stomach and lung cancer, one patient had both stomach and hepatocellular cancer).
Discussion
As a rare incidence of HPC, almost all series include other sites (oral, nasopharynx, oropharynx, larynx, etc.) of head and neck cancer (2, 6), including postoperative RT and RT alone (1). Few reports regarding definitive chemoradiotherapy for HPC have been published (9-11). Lefebvre et al. reported the results of a randomized Phase III study comparing an ICT arm with immediate surgery, with or without a postoperative radiotherapy arm, in patients with stage II-IV HPC (1). The trial included 194 patients, and the 3/5-year OS rates were 57/30% for the ICT arm group and 43/35% for the postoperative RT arm. Disease-free survival rates were 43% (3-year) and 25% (5-year) for the ICT group and 32% (3-year) and 27% (5-year) for the postoperative RT arm group. Tai et al. published the treatment outcomes of ICT followed by concurrent chemoradiotherapy in 42 patients with stage III-IV HPC at a single institution (10). The 3-year overall survival, disease-free survival, and local control rates were 35.3%, 33.1%, and 54.8%, respectively, with a median follow-up time of 42.9 months (10). Recently, Nakahara et al. reported good outcome, with 5-year overall survival rate of 50.4%, a progression-free survival rate of 47.1%, and a local control rate of 63.1% for T3-4 HPC (11). In a surgical series conducted at the Kurume University Hospital, Chijiwa et al. reported the 5-year overall survival rates of 45% for T3 and 36% for T4 HPC (12), which the outcomes presented in our study concurred with. Therefore, although we included patients with inoperative as well as poor condition, our data confirm the potential of non-surgical multimodality treatment.
Analysis of prognostic factors in therapy of hypopharyngeal cancer.
Intra-arterial infusion chemotherapy revealed a curative potential even for advanced tumors if the chemotherapeutic agent was adequately distributed throughout the entire tumor. Furusaka et al. reported a favorable outcome after intra-arterial chemotherapy (docetaxel and cisplatin) followed by chemoradiotherapy in a study of 57 patients with HPC (13). The 5-year survival rates for the T classes were 96.0% (10-year rate, 88.6%) for T3, 48.1% for T4a, and 16.7% for T4b. The 5-year laryngeal preservation rates were 92.4% (10-year rate, 87.6%) for T3, 36.2% for T4a, and 16.7% for T4b. No irreversible side-effects, complications, or sequelae were reported.
In addition, hyperthermia is considered a good treatment option for effective tumor control. Huigol et al. employed a randomized trial to compare RT with and without hyperthermia and RT alone in patients with head and neck cancer (14). A complete response was observed in the RT-alone group of 42.4% compared with that in the hyperthermia group of 78.8% (p<0.05), and an improved survival was noted in the hyperthermia-RT group. Moreover, we considered inducing hyperthermia as a favorable treatment option because of the complete response in a patient with N3 disease who survived without the recurrence of disease for 50 months after treatment. In addition, several retrospective trials have revealed its efficacy; however, in this advanced chemotherapeutic era, sufficient evidence to show an increase of tumor control rate is not available. Therefore, it is not our aim and it is beyond the scope of this study to relate the role of hyperthermia in tumor control, which remains to be further evaluated.
Adverse reaction.
A negative impact of the pre-treatment hemoglobin level on treatment outcomes has been suggested by several studies (15-18). Becker et al. found that a pre-treatment hemoglobin level of ≥12 g/dl was significantly associated with improved overall survival rate and locoregional control in a multivariate analysis of 153 patients with non-metastatic stage IV squamous cell carcinoma of the head and neck (17). Denis et al. reported that a pre-treatment hemoglobin level of <12.5 g/dl was a significant negative prognostic factor in a study of 226 patients with non-metastatic stage III or IV oropharyngeal cancer (18). The prognostic value of hemoglobin may be explained by radiobiological data that associate hypoxia with increased resistance of tumor cells to RT. Tumor oxygenation is affected by the oxygen-carrying capacity of the blood represented by the hemoglobin level.
In conclusion, multimodality non-surgical treatment could be a useful option for patients who refuse surgery and have inoperable disease, with substantial curative potential without severe adverse reactions.
- Received October 3, 2013.
- Revision received November 8, 2013.
- Accepted November 11, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
