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Concurrent chemoradiotherapy for T4 patients with hypopharyngeal and laryngeal squamous cell carcinomas
Auris Nasus Larynx 34 (2007) 499–504 www.elsevier.com/locate/anl
Concurrent chemoradiotherapy for T4 patients with hypopharyngeal and laryngeal squamous cell carcinomas Goshi Nishimura a,*, Mamoru Tsukuda a,b, Choichi Horiuchi a, Kenichi Satake a, Takafumi Yoshida a, Junichi Nagao a, Mariko Kawakami a, Norio Kondo a, Yasuhiro Arai a, Takahide Taguchi a, Hideki Matsuda b, Yasukazu Mikami b a
Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan b Department of Biology and Function in the Head and Neck, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan Received 1 November 2006; accepted 10 February 2007 Available online 28 June 2007
Abstract Objectives: Concurrent chemoradiotherapy (CCR) was given for the previously untreated T4 hypopharyngeal and laryngeal squamous cell carcinoma patients and the response and survival rates were evaluated. Patients and methods: A total of 23 patients, namely, 15 for hypopharynx and 8 for larynx were eligible. These patients were given cisplatin and 5-fluorouracil based chemotherapeutic regimens with conventional radiotherapy for a total dose of 66.6–70.2 Gy. Results: Ten out of the 15 hypopharyngeal carcinoma patients and 4 out of the 8 laryngeal carcinoma patients showed a complete response at the primary sites. The 5-year disease-specific survival rate was 59.4% in all the patients, 51.9% in the hypopharyngeal carcinoma patients, and 71.0% in the laryngeal patients. Seven out of the 12 resectable hypopharyngeal carcinoma patients and 4 out of 8 laryngeal carcinoma patients were able to do without total laryngectomy. Conclusions: Based on these results, the survival rate in the hypopharyngeal and laryngeal T4 carcinoma patients treated by CCR seems to be satisfactory and the possibility of organ preservation for the advanced patients is indicated. # 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Concurrent chemoradiotherapy; T4; Hypopharyngeal carcinoma; Laryngeal carcinoma
1. Introduction Most of head and neck cancers are histopathologically squamous cell carcinomas. The definitive treatment modality for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) is radiotherapy and/or surgical resection. Because of the anatomical features in the head and neck, organ preservation is important to keep the functions, e.g. phonation and deglutition, and to minimize the aesthetic appearance changes. To preserve these functions, recent papers have described the efficacy of concurrent chemoradiotherapy (CCR) and neoadjuvant (induction) chemother* Corresponding author. Tel.: +81 45 787 2687; fax: +81 45 783 2580. E-mail address: [email protected] (G. Nishimura).
apy followed by definitive radiotherapy for the advanced HNSCC patients [1–5]. The most important factor to improve the outcome of the patients with HNSCC is being diagnosed at early stages. However, most of the HNSCC patients (70–80%) have advanced stages on the first visit and advanced patients are frequently unresectable. The regimens for CCR were various and not standardized. In consideration of the high response rate in the clinical use of neoadjuvant chemotherapy, we have given cisplatin (CDDP) and 5fluorouracil (5-FU) based regimens [4,5]. The benefits of CCR including a potential chemotherapeutic regimen, which shows a strong anti-tumor effect by itself, are thought to be the improvement in the locoregional control by the synergistic effects of radiotherapy and chemotherapy, and the eradication of micro-metastasis by systemic
0385-8146/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.anl.2007.02.004
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chemotherapy. The disadvantages of the potential chemoradiotherapy are the high incidence rate of severe adverse effects and the need for long-term hospitalization. Another matter to be taken note of is the limitation of application, which means the tolerability of the patients for the potential chemoradiotherapy. One of the characteristics of HNSCC patients is the poor life habit, e.g. heavy smoking, heavy drinking and low nutrition. These habits induce poor general conditions and complications, which leads to the limitation of the potential chemoradiotherapy application. Here, we assess the efficacy of chemoradiotherapy including potential regimens for the most advanced patients, i.e. T4 cases, of hypopharyngeal and laryngeal carcinomas.
2.0 Gy for the high-risk cases of airway obstruction. The standard radiotherapy given for the parallel opposed lateral fields, encompassing the primary tumor and neck lymph nodes. After a total dose of about 40 Gy, all the patients were clinically re-evaluated by endoscope, CT scan and/or MRI. The patients with a 50% or greater decrease in the product of two perpendicular diameters of primary and neck tumor continued radiotherapy with a second course of chemotherapy and completed radiotherapy for a total dose of 66.6– 70.2 Gy. For non-responders and recurrent patients after this therapy, definitive surgery was recommended for the resectable cases. 2.3. Response assessment
2. Patients and methods 2.1. Eligibility criteria Eligibility criteria included the followings: untreated patients with squamous cell carcinoma of the hypopharynx or larynx; disease that was measurable in at least one dimension; T4 disease according to the 1997 staging system of the Union International Contre le Cancer (UICC) without distant metastasis and active other carcinomas, the staging evaluated by endoscope, computed tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasonographic (US) findings of the neck; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; life expectancy >3 months. Surgical respectable criteria excluded the patients with invasion to the prevertebral muscle and the common or internal carotid artery (i.e., those showing positive results on the artery occlusion test). 2.2. Treatment schedule Concurrent chemoradiotherapy was given for the patients according to the following criteria; age between 20 and 75 years; sufficient bone marrow function (neutrophil count of >2000 cell/mm3 and platelet count of >100,000/mm3); without significant abnormalities in the liver, heart, lungs, and kidneys (24 h creatinine clearance rate >65 ml/min/ 1.73 m2); without active peptic ulcer diseases. The chemotherapy regimen consisted of a combination of three drugs; CDDP (60–70 mg/m2, day 4), 5-FU (600 mg/ (m2 day), days 1–5), and docetaxel (TXT; 50 mg/m2, day 1) [4], or four drugs; CDDP (60–70 mg/m2, day 4), 5-FU (600 mg/(m2 day), days 1–5), methotrexate (MTX; 30 mg/ m2, day 1), and leucovorin (LV; 20 mg/m2, days 1–5) [5]. Both regimens showed high response rates and improved survival rates, and now we are evaluating the randomized trial between these regimens. Two cycles of these regimens were given every 4 weeks during radiotherapy. Radiotherapy was given 5 days a week using a single daily fraction of 1.8 or 2.0 Gray (Gy) with 6 MV X-ray linear accelerators. The daily radiation dose was 1.8 Gy for usual patients, and
At 4 weeks after the end of chemoradiotherapy, the clinical response was assessed for each patient according to the combined findings of CT scan, MRI, and US. A complete response (CR) was defined as the complete disappearance of all measurable lesions for at least 4 weeks. A partial response (PR) was defined as a 50% or greater decrease in the product of two perpendicular diameters of each and all measurable lesions for at least 4 weeks. The patients in whom the disease did not fulfill the criteria for PR were considered as having no change (NC) or a stable disease. The pathological responses to this chemoradiotherapy were confirmed by biopsy at the primary site in all the patients. In the patients with N1–3 lymph node disease, fine needle aspiration cytology of the neck lymph nodes was performed. The patients with less than CR of the primary and neck tumor (evaluated by histopathology) were under consideration for a planned surgery 6–8 weeks after the end of the chemoradiotherapy. The 5-year disease-specific survival rate was calculated by the Kaplan–Meier method and was statistically analyzed by the Wilcoxon test. 2.4. Toxicity assessment Toxicity was assessed during the treatment and 4 weeks after treatment using the 1998 National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0.
3. Results 3.1. Patient population Between January 1999 and December 2006, we treated 89 hypopharyngeal carcinoma patients and 121 laryngeal carcinoma patients. In these patients, a total of 23 patients were eligible, namely, 15 (12 resectable and 3 unresectable cases) in hypopharyngeal carcinoma and 8 (all resectable cases) in laryngeal carcinoma (supraglottic type, 4 cases; glottic type, 4 cases) (Table 1). The median follow-up time for all patients was 44.8 months (range: 5–96 months). One
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Table 1 Patient characteristics (n = 23)
N/A; not applicant.
hypopharyngeal carcinoma patient, who indicated NC, was died at 5 months after the treatment, and other patients can be followed more than 12 months. In all, 20 patients were male and 3 female, the average age being 59.1 years (range: 40–73 years). 3.2. Toxicity The degrees of toxicity for all patients are listed in Table 2. Grade 4 toxicities occurred in 3 of 23 patients (14%) during CCR. Neutropenia, mucositis, dermatitis, and nausea/vomiting were the most common toxicities observed. The toxicities were all tolerable and no fatal case was observed.
3.3. Treatment response The response rate and recurrence rate of CR cases were summarized in Table 3, with subdivided hypopharyngeal carcinoma patients in all eligible patients and resectable patients. In all, 14 out of 23 T4 hypopharyngeal and laryngeal carcinoma patients (60.9%) showed pathological CR at the primary sites, and 9 out of 17 patients with node positive patients (52.9%) showed cytological CR at the lymph nodes. In the resectable cases, 12 out of 20 patients (60.0%) showed CR at the primary sites, and 7 out of 14 patients with node positive patients (50.0%) showed CR at the lymph nodes. The recurrence rate at the primary site was
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Table 2 Toxicity (n = 23)
Table 3 Response rate and recurrence rate of CR cases at the primary sites and lymph nodes
28.6% (4 out of 14 CR patients) and that of lymph nodes in the neck was 11.1% (1 of 9 CR patients) in all the cases. In the resectable cases, the recurrence rate was 33.3% (4 of 12) at the primary site and 14.3% (1 of 7) at the lymph nodes. Salvage primary dissection was performed for 5 patients with hypopharyngeal carcinoma and 4 patients with laryngeal carcinoma. All organ-preserved patients were satisfied with phonation and feeding without difficulty for the daily fife.
was no statistical difference between these cases. Laryngeal carcinoma patients were all resectable and the 5-year disease-specific survival rate was 71.0%. The disease specific cause of death was as follows; hypopharynx, three at the primary site and two at the distant metastasis; larynx, one at the lymph node and two at the distant metastasis.
3.4. Survival
HNSCC is found at 5% of the newly diagnosed cancers, there being 400,000 new cases every year. Although the early stage HNSCC is potentially curable by surgery and/or radiotherapy, which relapse rate is 10–40%, 70–80% of the patients with HNSCC are diagnosed at the advanced stage (stage III and IV) on their first visit. For the unresectable cases, chemotherapy and/or radiotherapy is regarded as the standard therapy. The management of resectable HNSCC has changed significantly over the past century [6]. Surgery followed by radiotherapy is the most accepted treatment for
The Kaplan–Meier disease-specific survival rate was shown in Fig. 1. The 5-year disease-specific survival rate was 59.4% in all the cases, 60.1% in the resectable cases and 50.0% in the unresectable cases. There was no statistical difference between the resectable and unresectable cases. The 5-year disease-specific survival rate of hypopharyngeal carcinoma was 51.9% in all the cases, 51.6% in the resectable cases, and 50.0% in the unresectable cases. There
4. Discussion
G. Nishimura et al. / Auris Nasus Larynx 34 (2007) 499–504
Fig. 1. Kaplan–Meier disease-specific survival curves. Solid line, overall; Dotted line, resectable case; Double-dotted line, unresectable case.
the resectable cases. However, the cure rate has not exceeded 30%, with the high rate of locoregional failure (60%) or distant metastasis (20%) [7]. CDDP-based induction chemotherapy has been used since the 1970s and has the benefit of organ preservation and reduction of the distant metastasis rate, albeit with a controversy regarding the survival elongation [8–11]. 5-FU is frequently administrated as the base of chemotherapy regimens since it has a synergistic interaction with many anti-neoplastic agents. Induction chemotherapy with CDDP and 5-FU (PF regimen) has been the standard therapy for the locoregionally advanced and recurrent HNSCC [11]. In the randomized trails of induction chemotherapy, the response rate of CDDP plus 5-FU regimen ranged from 60 to 80% and the clinical CR rates ranged from 20 to 30% [12]. With a report of the Department of Veterans Affairs Laryngeal Cancer Study Group showing the efficacy of chemoradiotherapy [13], there has been a continuous shift toward chemoradiotherapy in the management of advanced HNSCC. The CCR regimen has not been standardized yet. Radiation methods frequently used are conventional radiotherapy, hyperfractionation radiotherapy and accelerated fractionation radiotherapy. And chemotherapeutic agents used preferably are CDDP, 5-FU, carboplatin and taxanes. The administration doses of these agents differ from high to low doses. The administration method is multifarious:
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intravenously systemic administration, trans-orally systemic administration and intra-arterially selective administration [13–15]. We have given a modified PF regimen at high doses (CDDP at 60–70 mg/m2 on day 4 and 5-FU at 600 mg/(m2 day) for 120 h from day 1 to day 5) via intra-venous administration for the advanced patients without complications, because of the possibility of the synergistic effect on the locoregional control by radiotherapy and the potential chemotherapy, and the eradication of micro-metastasis by potential chemotherapeutic agents. Furthermore, we modified the PF regimen, i.e. the combination with MTX and LV in addition to CDDP administration after 5-FU [5] or combination with TXT and PF [4], because, the CDDP administration after the starting of 5-FU infusion showed a higher CR rate than the conventional PF regimen, and the combination of MTX and 5-FU showed synergistic cytotoxic effects and the co-administration of LV indicated the enhancement of 5-FU cytotoxicity [16–19]. On the other hand, the chemotherapeutic effect of TXT itself differs from the cytotoxic mechanism of CDDP and 5-FU [20]. We have been using the conventional radiotherapy method in order to reduce the synergistic adverse effects of radiotherapy combined with these chemotherapeutic agents. All these regimens are tolerable if a sufficient attention is paid to the adverse effects. The 5-year disease-specific survival rate in T4 cases, previously reported, was as follows; hypopharynx, 20.5– 25%; larynx, 64–75% [21–24]. In our cases, the 5-year disease-specific survival rate was 51.9% in hypopharyngeal carcinoma and 71.0% in laryngeal carcinoma. Although it is hard to compare these results statistically, the present study shows a more than 25 points higher rate in the hypopharynx and almost same rate in the larynx. Five out of 12 resectable hypopharyngeal carcinoma patients (41.7%) underwent pharyngolaryngo-esophagectomy, and 4 out of 8 resectable laryngeal carcinoma patients (50.0%) underwent total laryngectomy. In other words, the larynx could be preserved in 11 out of 20 resectable T4 hypopharyngeal or laryngeal carcinoma patients (55.0%). The complications of surgery after the present chemoradiotherapy were permissible. The better survival rate might be the benefit of the impact chemotherapeutic regimen. The present study shows the possibility of the organ preservation for T4 patients with CCR as well. In conclusion, CCR in the present study is worthy of being given with the possibility of the survival elongation and the organ preservation to maintain the quality of life for hypopharyngeal and laryngeal carcinoma T4 patients. To get final results, further investigation into the efficacy of CCR using a large number of patients is needed.
References [1] Urba SG, Moon J, Giri PG, Adelstein DJ, Hanna E, Yoo GH, et al. Organ preservation for advanced resectable cancer of the base of
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G. Nishimura et al. / Auris Nasus Larynx 34 (2007) 499–504 tongue and hypopharynx: a Southwest Oncology Group Trial. J Clin Oncol 2005;23:88–95. Fountzilas G, Ciuleanu E, Dafni U, Plataniotis G, Kalogera-Fountzila A, Samantas E, et al. Concomitant radiochemotherapy vs. radiotherapy alone in patients with head and neck cancer: a Hellenic Cooperative Oncology Group Phase III Study. Med Oncol 2004;21:95–107. Seiwert TY, Cohen EEW. State-of-the-art management of locally advanced head and neck cancer. Br J Cancer 2005;92:1341–8. Katori H, Tsukuda M, Mochimatsu I, Ishitoya J, Kawai S, Mikami Y, et al. Phase I trial of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Br J Cancer 2004;90:348–52. Taguchi T, Tsukuda M, Mikami Y, Matsuda H, Horiuchi C, Yoshida T, et al. Concurrent chemoradiotherapy with cisplatin, 5-fluorouracil, methotrexate, and leucovorin in patients with advanced resectable squamous cell carcinoma of the larynx and hypopharynx. Acta OtoLaryngol 2006;126:408–13. Forastiere A, Koch W, Trotti A, Sidransky D. Medical progress: head and neck cancer. N Engl J Med 2001;345:1890–900. Vokes EE, Weichseblaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med 1993;328:184–94. Munro AJ. An overview of randomized controlled trials of adjuvant chemotherapy in head and neck cancer. Br J Cancer 1995;71:83–91. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region. A meta-analysis of prospective and randomized trials. J Clin Oncol 1996;14:838–47. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoragional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACHNC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355:949–55. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324:1685–90. Al-Sarraf M. Treatment of locally advanced head and neck cancer: historical and critical review. Cancer Cont 2002;9:387–99. Robbins KT, Kumar P, Harris J, McCulloch T, Cmelak A, Sofferman R, et al. Supradose intra-arterial cisplat;in and concurrent radiation
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Concurrent chemoradiotherapy for T4 patients with hypopharyngeal and laryngeal squamous cell carcinomas Goshi Nishimura a,*, Mamoru Tsukuda a,b, Choichi Horiuchi a, Kenichi Satake a, Takafumi Yoshida a, Junichi Nagao a, Mariko Kawakami a, Norio Kondo a, Yasuhiro Arai a, Takahide Taguchi a, Hideki Matsuda b, Yasukazu Mikami b a
Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan b Department of Biology and Function in the Head and Neck, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan Received 1 November 2006; accepted 10 February 2007 Available online 28 June 2007
Abstract Objectives: Concurrent chemoradiotherapy (CCR) was given for the previously untreated T4 hypopharyngeal and laryngeal squamous cell carcinoma patients and the response and survival rates were evaluated. Patients and methods: A total of 23 patients, namely, 15 for hypopharynx and 8 for larynx were eligible. These patients were given cisplatin and 5-fluorouracil based chemotherapeutic regimens with conventional radiotherapy for a total dose of 66.6–70.2 Gy. Results: Ten out of the 15 hypopharyngeal carcinoma patients and 4 out of the 8 laryngeal carcinoma patients showed a complete response at the primary sites. The 5-year disease-specific survival rate was 59.4% in all the patients, 51.9% in the hypopharyngeal carcinoma patients, and 71.0% in the laryngeal patients. Seven out of the 12 resectable hypopharyngeal carcinoma patients and 4 out of 8 laryngeal carcinoma patients were able to do without total laryngectomy. Conclusions: Based on these results, the survival rate in the hypopharyngeal and laryngeal T4 carcinoma patients treated by CCR seems to be satisfactory and the possibility of organ preservation for the advanced patients is indicated. # 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Concurrent chemoradiotherapy; T4; Hypopharyngeal carcinoma; Laryngeal carcinoma
1. Introduction Most of head and neck cancers are histopathologically squamous cell carcinomas. The definitive treatment modality for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) is radiotherapy and/or surgical resection. Because of the anatomical features in the head and neck, organ preservation is important to keep the functions, e.g. phonation and deglutition, and to minimize the aesthetic appearance changes. To preserve these functions, recent papers have described the efficacy of concurrent chemoradiotherapy (CCR) and neoadjuvant (induction) chemother* Corresponding author. Tel.: +81 45 787 2687; fax: +81 45 783 2580. E-mail address: [email protected] (G. Nishimura).
apy followed by definitive radiotherapy for the advanced HNSCC patients [1–5]. The most important factor to improve the outcome of the patients with HNSCC is being diagnosed at early stages. However, most of the HNSCC patients (70–80%) have advanced stages on the first visit and advanced patients are frequently unresectable. The regimens for CCR were various and not standardized. In consideration of the high response rate in the clinical use of neoadjuvant chemotherapy, we have given cisplatin (CDDP) and 5fluorouracil (5-FU) based regimens [4,5]. The benefits of CCR including a potential chemotherapeutic regimen, which shows a strong anti-tumor effect by itself, are thought to be the improvement in the locoregional control by the synergistic effects of radiotherapy and chemotherapy, and the eradication of micro-metastasis by systemic
0385-8146/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.anl.2007.02.004
500
G. Nishimura et al. / Auris Nasus Larynx 34 (2007) 499–504
chemotherapy. The disadvantages of the potential chemoradiotherapy are the high incidence rate of severe adverse effects and the need for long-term hospitalization. Another matter to be taken note of is the limitation of application, which means the tolerability of the patients for the potential chemoradiotherapy. One of the characteristics of HNSCC patients is the poor life habit, e.g. heavy smoking, heavy drinking and low nutrition. These habits induce poor general conditions and complications, which leads to the limitation of the potential chemoradiotherapy application. Here, we assess the efficacy of chemoradiotherapy including potential regimens for the most advanced patients, i.e. T4 cases, of hypopharyngeal and laryngeal carcinomas.
2.0 Gy for the high-risk cases of airway obstruction. The standard radiotherapy given for the parallel opposed lateral fields, encompassing the primary tumor and neck lymph nodes. After a total dose of about 40 Gy, all the patients were clinically re-evaluated by endoscope, CT scan and/or MRI. The patients with a 50% or greater decrease in the product of two perpendicular diameters of primary and neck tumor continued radiotherapy with a second course of chemotherapy and completed radiotherapy for a total dose of 66.6– 70.2 Gy. For non-responders and recurrent patients after this therapy, definitive surgery was recommended for the resectable cases. 2.3. Response assessment
2. Patients and methods 2.1. Eligibility criteria Eligibility criteria included the followings: untreated patients with squamous cell carcinoma of the hypopharynx or larynx; disease that was measurable in at least one dimension; T4 disease according to the 1997 staging system of the Union International Contre le Cancer (UICC) without distant metastasis and active other carcinomas, the staging evaluated by endoscope, computed tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasonographic (US) findings of the neck; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; life expectancy >3 months. Surgical respectable criteria excluded the patients with invasion to the prevertebral muscle and the common or internal carotid artery (i.e., those showing positive results on the artery occlusion test). 2.2. Treatment schedule Concurrent chemoradiotherapy was given for the patients according to the following criteria; age between 20 and 75 years; sufficient bone marrow function (neutrophil count of >2000 cell/mm3 and platelet count of >100,000/mm3); without significant abnormalities in the liver, heart, lungs, and kidneys (24 h creatinine clearance rate >65 ml/min/ 1.73 m2); without active peptic ulcer diseases. The chemotherapy regimen consisted of a combination of three drugs; CDDP (60–70 mg/m2, day 4), 5-FU (600 mg/ (m2 day), days 1–5), and docetaxel (TXT; 50 mg/m2, day 1) [4], or four drugs; CDDP (60–70 mg/m2, day 4), 5-FU (600 mg/(m2 day), days 1–5), methotrexate (MTX; 30 mg/ m2, day 1), and leucovorin (LV; 20 mg/m2, days 1–5) [5]. Both regimens showed high response rates and improved survival rates, and now we are evaluating the randomized trial between these regimens. Two cycles of these regimens were given every 4 weeks during radiotherapy. Radiotherapy was given 5 days a week using a single daily fraction of 1.8 or 2.0 Gray (Gy) with 6 MV X-ray linear accelerators. The daily radiation dose was 1.8 Gy for usual patients, and
At 4 weeks after the end of chemoradiotherapy, the clinical response was assessed for each patient according to the combined findings of CT scan, MRI, and US. A complete response (CR) was defined as the complete disappearance of all measurable lesions for at least 4 weeks. A partial response (PR) was defined as a 50% or greater decrease in the product of two perpendicular diameters of each and all measurable lesions for at least 4 weeks. The patients in whom the disease did not fulfill the criteria for PR were considered as having no change (NC) or a stable disease. The pathological responses to this chemoradiotherapy were confirmed by biopsy at the primary site in all the patients. In the patients with N1–3 lymph node disease, fine needle aspiration cytology of the neck lymph nodes was performed. The patients with less than CR of the primary and neck tumor (evaluated by histopathology) were under consideration for a planned surgery 6–8 weeks after the end of the chemoradiotherapy. The 5-year disease-specific survival rate was calculated by the Kaplan–Meier method and was statistically analyzed by the Wilcoxon test. 2.4. Toxicity assessment Toxicity was assessed during the treatment and 4 weeks after treatment using the 1998 National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0.
3. Results 3.1. Patient population Between January 1999 and December 2006, we treated 89 hypopharyngeal carcinoma patients and 121 laryngeal carcinoma patients. In these patients, a total of 23 patients were eligible, namely, 15 (12 resectable and 3 unresectable cases) in hypopharyngeal carcinoma and 8 (all resectable cases) in laryngeal carcinoma (supraglottic type, 4 cases; glottic type, 4 cases) (Table 1). The median follow-up time for all patients was 44.8 months (range: 5–96 months). One
G. Nishimura et al. / Auris Nasus Larynx 34 (2007) 499–504
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Table 1 Patient characteristics (n = 23)
N/A; not applicant.
hypopharyngeal carcinoma patient, who indicated NC, was died at 5 months after the treatment, and other patients can be followed more than 12 months. In all, 20 patients were male and 3 female, the average age being 59.1 years (range: 40–73 years). 3.2. Toxicity The degrees of toxicity for all patients are listed in Table 2. Grade 4 toxicities occurred in 3 of 23 patients (14%) during CCR. Neutropenia, mucositis, dermatitis, and nausea/vomiting were the most common toxicities observed. The toxicities were all tolerable and no fatal case was observed.
3.3. Treatment response The response rate and recurrence rate of CR cases were summarized in Table 3, with subdivided hypopharyngeal carcinoma patients in all eligible patients and resectable patients. In all, 14 out of 23 T4 hypopharyngeal and laryngeal carcinoma patients (60.9%) showed pathological CR at the primary sites, and 9 out of 17 patients with node positive patients (52.9%) showed cytological CR at the lymph nodes. In the resectable cases, 12 out of 20 patients (60.0%) showed CR at the primary sites, and 7 out of 14 patients with node positive patients (50.0%) showed CR at the lymph nodes. The recurrence rate at the primary site was
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Table 2 Toxicity (n = 23)
Table 3 Response rate and recurrence rate of CR cases at the primary sites and lymph nodes
28.6% (4 out of 14 CR patients) and that of lymph nodes in the neck was 11.1% (1 of 9 CR patients) in all the cases. In the resectable cases, the recurrence rate was 33.3% (4 of 12) at the primary site and 14.3% (1 of 7) at the lymph nodes. Salvage primary dissection was performed for 5 patients with hypopharyngeal carcinoma and 4 patients with laryngeal carcinoma. All organ-preserved patients were satisfied with phonation and feeding without difficulty for the daily fife.
was no statistical difference between these cases. Laryngeal carcinoma patients were all resectable and the 5-year disease-specific survival rate was 71.0%. The disease specific cause of death was as follows; hypopharynx, three at the primary site and two at the distant metastasis; larynx, one at the lymph node and two at the distant metastasis.
3.4. Survival
HNSCC is found at 5% of the newly diagnosed cancers, there being 400,000 new cases every year. Although the early stage HNSCC is potentially curable by surgery and/or radiotherapy, which relapse rate is 10–40%, 70–80% of the patients with HNSCC are diagnosed at the advanced stage (stage III and IV) on their first visit. For the unresectable cases, chemotherapy and/or radiotherapy is regarded as the standard therapy. The management of resectable HNSCC has changed significantly over the past century [6]. Surgery followed by radiotherapy is the most accepted treatment for
The Kaplan–Meier disease-specific survival rate was shown in Fig. 1. The 5-year disease-specific survival rate was 59.4% in all the cases, 60.1% in the resectable cases and 50.0% in the unresectable cases. There was no statistical difference between the resectable and unresectable cases. The 5-year disease-specific survival rate of hypopharyngeal carcinoma was 51.9% in all the cases, 51.6% in the resectable cases, and 50.0% in the unresectable cases. There
4. Discussion
G. Nishimura et al. / Auris Nasus Larynx 34 (2007) 499–504
Fig. 1. Kaplan–Meier disease-specific survival curves. Solid line, overall; Dotted line, resectable case; Double-dotted line, unresectable case.
the resectable cases. However, the cure rate has not exceeded 30%, with the high rate of locoregional failure (60%) or distant metastasis (20%) [7]. CDDP-based induction chemotherapy has been used since the 1970s and has the benefit of organ preservation and reduction of the distant metastasis rate, albeit with a controversy regarding the survival elongation [8–11]. 5-FU is frequently administrated as the base of chemotherapy regimens since it has a synergistic interaction with many anti-neoplastic agents. Induction chemotherapy with CDDP and 5-FU (PF regimen) has been the standard therapy for the locoregionally advanced and recurrent HNSCC [11]. In the randomized trails of induction chemotherapy, the response rate of CDDP plus 5-FU regimen ranged from 60 to 80% and the clinical CR rates ranged from 20 to 30% [12]. With a report of the Department of Veterans Affairs Laryngeal Cancer Study Group showing the efficacy of chemoradiotherapy [13], there has been a continuous shift toward chemoradiotherapy in the management of advanced HNSCC. The CCR regimen has not been standardized yet. Radiation methods frequently used are conventional radiotherapy, hyperfractionation radiotherapy and accelerated fractionation radiotherapy. And chemotherapeutic agents used preferably are CDDP, 5-FU, carboplatin and taxanes. The administration doses of these agents differ from high to low doses. The administration method is multifarious:
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intravenously systemic administration, trans-orally systemic administration and intra-arterially selective administration [13–15]. We have given a modified PF regimen at high doses (CDDP at 60–70 mg/m2 on day 4 and 5-FU at 600 mg/(m2 day) for 120 h from day 1 to day 5) via intra-venous administration for the advanced patients without complications, because of the possibility of the synergistic effect on the locoregional control by radiotherapy and the potential chemotherapy, and the eradication of micro-metastasis by potential chemotherapeutic agents. Furthermore, we modified the PF regimen, i.e. the combination with MTX and LV in addition to CDDP administration after 5-FU [5] or combination with TXT and PF [4], because, the CDDP administration after the starting of 5-FU infusion showed a higher CR rate than the conventional PF regimen, and the combination of MTX and 5-FU showed synergistic cytotoxic effects and the co-administration of LV indicated the enhancement of 5-FU cytotoxicity [16–19]. On the other hand, the chemotherapeutic effect of TXT itself differs from the cytotoxic mechanism of CDDP and 5-FU [20]. We have been using the conventional radiotherapy method in order to reduce the synergistic adverse effects of radiotherapy combined with these chemotherapeutic agents. All these regimens are tolerable if a sufficient attention is paid to the adverse effects. The 5-year disease-specific survival rate in T4 cases, previously reported, was as follows; hypopharynx, 20.5– 25%; larynx, 64–75% [21–24]. In our cases, the 5-year disease-specific survival rate was 51.9% in hypopharyngeal carcinoma and 71.0% in laryngeal carcinoma. Although it is hard to compare these results statistically, the present study shows a more than 25 points higher rate in the hypopharynx and almost same rate in the larynx. Five out of 12 resectable hypopharyngeal carcinoma patients (41.7%) underwent pharyngolaryngo-esophagectomy, and 4 out of 8 resectable laryngeal carcinoma patients (50.0%) underwent total laryngectomy. In other words, the larynx could be preserved in 11 out of 20 resectable T4 hypopharyngeal or laryngeal carcinoma patients (55.0%). The complications of surgery after the present chemoradiotherapy were permissible. The better survival rate might be the benefit of the impact chemotherapeutic regimen. The present study shows the possibility of the organ preservation for T4 patients with CCR as well. In conclusion, CCR in the present study is worthy of being given with the possibility of the survival elongation and the organ preservation to maintain the quality of life for hypopharyngeal and laryngeal carcinoma T4 patients. To get final results, further investigation into the efficacy of CCR using a large number of patients is needed.
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