Management of the Patients with Hypopharyngeal Cancer: Eight-Year Experience of Miyagi Cancer Center in Japan

Tohoku J. Exp. Med., 2005,Management 205, 65-77 of the Patients with Hypopharyngeal Cancer 65

1 MASARU TATEDA, KIYOTO SHIGA, HUMIAKI YOSHIDA, SHIGERU SAIJO, JYUNKICHI 2 YOKOYAMA, HITOSHI NISHIKAWA, YUKINORI ASADA, KAZUTO MATSUURA and 1 TOSHIMITU KOBAYASHI Department of Head and Neck Surgery, Miyagi Cancer Center, Natori, 1Department of Otolaryngology, Head and Neck Surgery, Tohoku University School of Medicine, Sendai, and 2Department of Head and Neck Surgery, Tochigi Cancer Center, Utsunomiya, Japan

TATEDA, M., SHIGA, K., YOSHIDA, H., SAIJO, S., YOKOYAMA, J., NISHIKAWA, H., ASADA, Y., MATSUURA, K. and KOBAYASHI, T. Management of the Patients with Hypopharyngeal Cancer: Eight-Year Experience of Miyagi Cancer Center in Japan. Tohoku J. Exp. Med., 2005, 205 (1), 65-77 ── The aim of this study is to evaluate the results of treatment for hypopharyngeal cancer and indicate the future prospect of the treatment. Seventy-four patients with squamous cell carcinoma of the hypopharynx admitted to Miyagi Cancer Center from 1993 through 2000 are reviewed. Sixty-four patients received radical treatment, and 10 patients received palliative treatment or no treatment. The cancer was advanced (stages III and IV) in 82% of all the patients. The overall 5-year survival rate of all the patients was 38%. The overall 5-year survival rate of 64 patients received radical treatment was 43%. The ten patients who received palliative treatment or no treatment died of cancer within 16 months. Fifty-two out of the 74 patients underwent neck dissection for the neck lymph node involvement; forty of the 52 patients underwent ipsilateral neck dissection and 12 underwent bilateral neck dissection. Four out of the 40 patients, who underwent ipsilateral neck dissection alone, developed late contralateral regional recurrence but were suc- cessfully treated by contralateral neck dissection at the time of recurrence. Twenty-three out of 74 patients had multiple primary cancers synchronously or metachronously (31%). Cause of the death of six patients out of 74 patients was confirmed to be primary cancers other than hypopharyngeal cancer, as judged by physicians in other department or other hospitals. Most of the patients died due to distant metastasis from hypopharyngeal cancer or other primary cancers. We therefore conclude that contralateral elective neck dissection which is frequently chosen for the treatment of hypopharyngeal cancer surgery is unnecessary. Even if locoregional control is accomplished, distant metastasis or multiple primary cancers emerge and make prognosis poor. To improve the prognosis, we should develop some strategy against hypopharyngeal cancer for each patient. New strategies including chemoprevention and surgery against distant metasistasis are necessary. ──── hypopharyngeal cancer; distant metastasis; multiple primary cancers; elective neck dissection © 2005 Tohoku University Medical Press

Received February 17, 2004; revision accepted for publication November 16, 2004. Address for reprints: Masaru Tateda, M.D., Department of Head and Neck Surgery, Miyagi Cancer Center Hospital, 47-1 Nodayama, Medeshima-Shiote, Natori 981-1293, Japan. e-mail: [email protected] 65 66 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 67

It is generally accepted that the prognoses of TABLE 1. Patients’ profiles and tumor character the patients with hypopharyngeal cancer are poor. istics: clinical staging according to the The main cause of poor prognosis has been high UICC criteria of 1997 frequency of advanced cancer. Although radical Characteristics n % surgery with subsequent reconstruction of the cer- Sex vical esophagus by free jejunum transfer has be- Male 65 88 come a relatively easy procedure for advanced Female 9 12 cancer recently, the survival rate in such cases re- Location mains fairly poor. In hypopharyngeal cancer, Right 34 46 there are various problematic issues such as the Left 29 39 high frequency of distant metastasis, occurrence of multiple primary cancers (Schwartz et al. 1994; Center 11 15 Ogawa et al. 1999), choice of therapy such as ra- Histological differentiation diation and surgery for the primary lesion, therapy Well 20 27 for retropharyngeal lymph node (Hasegawa and Moderate 35 47 Matsuura 1994), and indication for contralateral Poor 13 18 elective neck dissection (Nishijima et al. 1991; Unknown 6 8 Anderson et al. 1996; Lassaletta et al. 2002). We Subsite thought that these many problems are compound PS 50 68 and make survival rate decline. At our institution, PC 14 19 in principal, the choice of radical therapies of the PW 10 13 primary hypopharyngeal cancer lesion is radiation Stage (UICC1997) with chemotherapy or surgery, including partial I 3 4 pharyngectomy, and neck lymph node metastasis II 10 12 is treated by neck dissection with no contralateral III 19 12 elective neck dissection. Additional therapy is IVA 35 64 conducted in patients with multiple lymph nodes IVB 5 5 metastasis. Not all patients with hypopharyngeal IVC 2 3 cancer undergo radical treatment. Although there T classification are many reports concerning each radical treat- T1 9 11 ment (Pingree et al. 1987; Ho et al. 1993; Frank et al. 1994; Spector et al. 1995; Axon et al. 1997; T2 28 39 Eckel et al. 2001; Godballe et al. 2002; Barzan et T3 29 28 al. 2002), general results of the treatment of hypo- T4 8 22 pharyngeal cancer are unclear. Therefore we ana- N classification lyzed the results of treatment in 74 patients with N0 21 28 hypopharyngeal cancer retrospectively to clarify N1 15 10 each problem, and herein discuss appropriate N2a 5 7 treatment strategies for future prospect. N2b 20 32 N2c 8 18 SUBJECTS AND METHODS N3 5 5 Seventy-four patients with squamous cell carcinoma of the hypopharynx who were admitted to our hospital for the first time from March 1993 through December sification of the International Union Against Cancer 2000 were reviewed. We analyzed the treatment method, (UICC 1997). pTN classification was based on the path- results of treatment and survival rate. The TNM and ological findings. The T classification is classified by the stage of each patient was classified according to the clas- expanse and the invasive region of the tumor. N0 is no 66 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 67

regional lymph node metastasis. N1 is single ipsilateral advanced cancers. Details of the treatment are shown in lymph node metastasis, < 3 cm in greatest dimension. Table 2. N2a is single ipsilateral lymph node, > 3 cm but not > 6 We used the criteria of multiple primary cancer pro- cm. N2b is multiple ipsilateral lymph nodes metastasis, posed by Warren and Gates (1932). 1) Each of tumors none > 6 cm. N2c is bilateral or contralateral lymph must present a definite picture of malignancy, 2) each nodes, none > 6 cm. N3 is a lymph node > 6 cm. must be distinct, and 3) the probability that one was a Details of the patients’ characteristics are listed in metastatic lesion from the other must be excluded. Table 1. The patients consisted of 65 males and 9 fe- Multiple primary cancers were considered to be synchro- males, with ages ranging from 31 to 81 years and a mean nous when found at the same time or within a six month age of 63 years. The primary site was located on the period after diagnosis of hypopharyngeal cancer. Cancer right side of the hypopharyx in 34 patients, on the left found after six months was referred to as metachronous side in 29 patients and in the center in 11 patients. The cancer (Gluckman and Crissman 1983). Multiple prima- primary subgroup was located in the pyriform sinus (PS) ry cancers before incidence of hypopharyngeal cancer of the hypopharynx in 50 patients, in the postcricoid (PC) were evaluated based on anamneses and medical records. region in 14 patients and on the posterior pharyngeal At initial treatment, except for locoregional evaluation of wall (PW) in 10 patients. Specimens of all patients were hypopharyngeal cancer, we routinely performed flexible confirmed as squamous cell carcinoma of the hypophar- gastroscopy, radiograph or CT of the chest, ultrasonogra- ynx by histological examination. Of these, 20 were well- phy of the abdomen, and examination of occult blood in differentiated, 35 moderately differentiated, and 13 poor- feces and urine. We performed colonoscopy, urological ly differentiated; no definite confirmation of the grade of examination on demand. After treatment, follow-up vis- differentiation could be made in 6 patients. The numbers its were performed every 1-3 months. We routinely per- of patients classified as stage I, stage II, stage III, stage formed clinical examination of head and neck, including IVA, stage IVB and stage IVC were 3, 10, 19, 35, 5 and 2, MRI or CT of head and neck, flexible nasopharyngolar- respectively. Patients in the advanced stages, i.e., stage yngoscopy and radiograph of the chest. We also per- III and stage IV, constituted 82%. The T classification formed CT of the chest, flexible gastroscopy, and other was T1 for 9 patients, T2 for 28, T3 for 29, and T4 for 8. examination on demand. When the patients died of mul- The N classification was N0 for 21 patients, N1 for 15, tiple primary cancers, we confirmed no recurrence of hy- N2a for 5, N2b for 20, N2c for 8 and N3 for 5. popharyngeal cancer based on medical records including Sixty-four patients underwent radical treatment, and laboratory data, imaging, and physical examination. 10 patients underwent palliative treatment or no treat- Survival time was measured from the initiation of treatment. Fifty patients underwent surgical resection of their ment. The cause-specific survival was calculated based primary tumors, 23 patients received radiation for their on the event of patient’s death of hypopharyngreal can- primary tumors, 52 patients underwent neck dissection. cer. We calculated locoregional control rate based on the Patients with tumors evaluated worse than pN2 were event of the patient’s locoregional recurrence of hypo- treated by postoperative irradiation. Chemotherapy was pharyngeal cancer. Actual survival probabilities were used for laryngeal preservation or additional treatment of calculated using the method of Kaplan-Meier, and com-

TABLE 2. Stage and treatment strategy of patients Number of Primary Neck Stage Chemotherapy Radiation No treatment patients resection dissection I 3 3 2 3 1 0 II 10 2 2 7 9 0 III 19 17 17 10 10 0 IVA 35 26 28 16 24 3 IVB 5 0 1 5 5 0 IVC 2 2 2 1 1 0 Total 74 50 52 42 50 3 68 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 69 parisons of survival curves between all different sub- for those with stage IVB or IVC (Fig. 1). The groups were performed using the log-rank test. Informed survival rate of stage I patients was worse than consents of the patients were taken before treatment, and expected. There were significant differences be- this study was approved by the ethics committee of tween the survival rate of the patients evaluated Miyagi Cancer Center. as stage I and that of the patients evaluated as stage IVB. There were also significant differenc- RESULTS es between the survival rate of the patients evalu- The overall 5-year survival rate of all pa- ated as II, III, or IVA and that of the patients eval- tients was 38%, and the cause-specific survival uated as IVB or IVC. rate was 48%. The overall 5-year survival rate The 5-year survival rate by T classification and cause-specific survival rate of the patients was 22% for patients with T1 tumors, 44% for T2, who received radical treatment were 43% and 41% for T3, and 19% for T4 (Fig. 2A). The 56%, respectively. The ten patients who received 5-year survival rate by N classification was 45% palliative treatment or no treatment died of cancer for patients with N0 tumors, 67% for patients within 16 months. The overall survival rate at 5 with N1 tumors, 40% for patients with N2a tu- years was 33% for patients with stage I cancer, mors, 26% for patients with N2b tumors, 13% for 47% for those with stage II, 63% for those with patients with N2c tumors, and 0% for patients stage III, 28% for those with stage IVA, and 0% with N3 tumors (Fig. 2B). The survival rate was

Fig. 1. Survival curves of the patients by stage classification. There were significant differences between the survival rate of the patients evaluated as stage I and that of the patients evaluated as stage IVB (p = 0.03), and between that of the patients evaluated as II, III and that of the patients evaluated as IVB, IVC (p < 0.01). There were also significant differences between the survival rate of the patients evaluated as stage IVA and that of the patients evaluated as IVC (p = 0.01), and between the patients evaluated as IVA and that of the patients evaluated as IVC (p < 0.01). All of the patients diagnosed as IVB and IVC died of cancer within 22 months. , stage I (n = 3) 5-year survival rate of 33%; , stage II (n = 10) 5-year survival rate of 47%; , stage III (n = 19) 5-year survival rate of 63%; , stage IVA (n = 35) 5-year survival rate of 28%; , stage IVB (n = 5) 5-year survival rate of 0%; , stage IVC (n = 2) 5-year survival rate of 0%. 68 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 69

Fig. 2. Survival curves of the patients by TN classification. A: Survival curves by T classification. There was no significant difference among these 4 groups. , T1 (n = 9) 5-year survival rate of 22%; , T2 (n = 28) 5-year survival rate of 44%; , T3 (n = 29) 5-year survival rate of 41%; , T4 (n = 8) 4-year survival rate of 19%. B: Survival curves by N classification. The survival rate of the patients evaluated N0 and N1 was better than that of the patients evaluated as N2c and N3 (p < 0.01). Survival rate of the patients evaluated as N3 was worse than that of the patients evaluated as N2a and N2c (p = 0.02). The patients with N3 tumors died of cancer within 22 months. , N0 (n = 21) 5-year survival rate of 45%; , N1 (n = 15) 5-year survival rate of 67%; , N2a (n = 5) 3-year survival rate of 40%; , N2b (n = 20) 5-year survival rate of 26%; , N2c (n = 8) 5-year survival rate of 13%; , N3 (n = 5) 5-year survival rate of 0%. 70 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 71 significantly related to N classification but not -re mean onset time of 14 months (Fig. 3A). There lated to T classification. was local recurrence in 8 patients. Of these, 6 pa- In the 64 patients who received radical treat- tients had only local recurrence, one suffered from ment, disease recurred after the initial treatment both local and distant metastasis, and one experi- in 33 patients between 3 and 70 months with a enced local recurrence, regional lymph node re-

Fig. 3. The patterns of recurrence and cause of death. A: The pattern and frequency of first recurrence of the patients who received radical treatment. Distant metastasis was most frequent. Local recurrence = 8/64 (13%). Regional recurrence = 12/64 (19%). Distant metastasis = 18/64 (28%). B: The pattern of causes of deaths of all patients. ( ): palliative or no treatment. The frequency of death due to distant metastasis, the most frequent cause of death, was 56% (25/45). Death due to local lesion = 11/74 (15%). Death due to regional lesion = 15/74 (20%). Death due to distant metastasis = 25/74 (34%). 70 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 71

currence and distant metastasis. Regional lymph other department or other hospitals. node recurrence occurred in 11 patients, alone in We analyzed the survival rate and the locore- 9 patients and together with distant metastasis in 1. gional control rate of the method of primary treat- Among 18 patients with distant metastasis, 15 pa- ment. Fifty patients underwent primary resection tients showed no evidence for local and regional and 21 patients underwent radiation for their pri- lymph node recurrence between 3 and 41 months mary tumors. There were no significant differ- with a mean onset time of 14 months (Fig. 3A). ences of the survival rate and locoregional control Forty-five patients died between 1 and 98 rate between these two groups. Results of treat- months with a mean survival period of 21 months ment are shown in Table 4. Thirty-seven patients after initial treatment. Thirty-seven patients died underwent total pharyngolaryngectomy with cer- of hypopharyngeal cancer. Six patients died of vical esophagectomy (TPLE), 6 patients under- multiple primary cancers. One patient died of went total laryngectomy with partial pharyngecto- brain infarction and one other patient died of an my (TL), and 7 patients underwent partial unknown cause. The cause of the death of 11 pa- pharyngectomy (PP). The survival rate and lo- tients was local recurrence of the disease, as coregional control rate of the patients who re- judged by their clinical history. Of these, 3 pa- ceived PP were significantly lower than those of tients died of local lesions alone, 5 died of local the patients received TPLE. and regional lymph node lesions, 2 died of local Thirty-six patients received intravenous sys- lesions and distant metastasis, and 1 died of local, temic chemotherapy, including conventional regional and distant metastasis. We also con- CDDP (cisplatin), 5FU-combined therapy, and firmed that the cause of the death was regional weekly low-dose CDDP therapy. Six patients un- node recurrence of the disease. Of these, 4 pa- derwent intra-arterial CDDP chemotherapy aimed tients died of regional lymph node lesions alone, at laryngeal preservation. Thirty-two patients re- and 5 died of regional and distant metastasis (Fig. ceived no chemotherapy. There was no signifi- 3B). Distant metastasis occurred in 25 patients, cant difference among these three groups. and 17 of them died of distant metastasis and one Fifty-two patients out of 74 patients under- is still alive despite metastasis. The metastatic le- went neck dissection (ND); forty patients under- sions of these 25 patients were found in the lung went ipsilateral ND alone and 12 patients were (16 patients), the bone (2), the lung and bone (6), evaluated as N2c and underwent bilateral ND. and the lung and liver (1). Four of the patients who had undergone ipsilateral Twenty-three out of 74 patients had multiple ND alone experienced contralateral regional recur- primary cancers (31%). Four patients had triple rence between 6 and 18 months with a mean peri- primary cancer lesions and 1 patient had quadru- od of 12 months. These four patients were ple primary cancer lesions. Table 3 shows clinical salvaged from hypopharyngeal cancer by contra- course and site distribution of multiple primary lateral ND, but 1 of them died of distant metasta- cancer lesions. The most frequent site of multiple sis of gastric carcinoma 34 months after the initial primary cancers was the stomach. This was fol- treatment. Retropharyngeal node metastasis was lowed by the esophagus, larynx and colon in this found in 5 out of 74 patients (7%). All patients order. Twelve out of 74 patients had multiple pri- with retropharyngeal node metastasis died be- mary cancers before incidence of hypopharyngeal tween 3 and 13 months with a mean period of 12 cancer (16%). Nine out of 74 patients had syn- months after the initial treatment. chronous multiple primary cancer (12%). Five On initial treatment, by histological exami- out of 74 patients had metachrounous multiple nation of dissected lymph nodes, we found 2 ipsi- primary cancers after the incidentce of hypopha- lateral metastatic lymph nodes (4%) in the sub- ryngeal cancer (7%). Cause of the death of six mandibular region, 32 (62%) such nodes in the patients was confirmed to be primary cancers oth- upper jugular region, 18 (35%) such nodes in the er than hypopharyngeal cancer by physicians in mid-jugular region, 13 (25%) such nodes in the 72 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 73

TABLE 3. Clinical course and sites of multiple primary cancers Patient No. Beforea Intervalb Synchronousc Intervalb Metachronousd Cause of death 1 Stomach Alive 2 Stomach Alive 3 Stomach Hypopharynx 4 Esophagus Hypopharynx 5 Kidney Kidney 6 Lung Hypopharynx 7 Stomach 28 Hypopharynx 8 Stomach 36 Stomach 9 Stomach 36 Hypopharynx 10 Stomach 57 Hypopharynx 11 Esophagus 60 Alive 12 Esophagus 70 Hypopharynx 13 Larynx 72 Alive 14 Urinary bladder 24 Alive 15 Thyroid 300 Hypopharynx 16 8 Esophagus Esophagus 17 21 Esophagus Alive 18 21 Colon Colon 19 Esophagus 17 Mesopharynx Hypopharynx 20 Stomach 228 Unknown Gingiva 72 21 Stomach 29 Esophagus Esophagus 22 Esophagus, Stomach Alive 23 Larynx 96 12 Colon, Pancreas Pancreas a Multiple primary cancers before incidence of hypopharyngeal cancer. b Interval means the term of each cancer incident (months). c Multiple primary cancers were considered to be synchronous when found at the same time as or within a six month period after the diagnosis of hypopharyngeal cancer. d Multiple primary cancers found after six months was referred to as metachronous cancer (after). Patient No. 20 was a survivor of the atomic-bombing. lower jugular region, 6 (12%) such nodes in the agnosed as pN0 was significantly higher than paratracheal region, and one (2%) such node in those diagnosed as pN2c. The survival rate of the the supraclavicular region. Metastatic lymph patients evaluated as pN0 was higher than that of nodes were mainly located at levels II, III and IV. the patients who had 3 or more metastatic lymph In two patients, however, metastatic nodes were nodes. There was no significant difference in the found at the medial inferior site of the subman- locoregional control rate among these groups. dibular gland. Contralateral lymph node metastasis was found in 10 patients histologically. DISCUSSION We analyzed the survival rate and the locore- This is a retrospective mono-institutional regional control rate based on the pN classification view of all patients diagnosed with hypopharyn- (Table 5). The 5-year survival rate of tumors di- geal cancer and admitted to Miyagi Cancer 72 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 73

TABLE 4. Results of treatment 5-year survival rate 5-year locoreginal n (%) control rate (%) Treatment of primary lesiona Primary resection 50 41 73 Radiation 21 32 48 Method of primary resection PP 7 14b 43c TL 6 33 80 TLP 37 47b 79c Chemotherapyd Intravenous 36 37 64 Intraarterial 6 50 50 No chemotherapy 32 37 65 a Excluding 3 patients received no treatment. There was no significant difference between two groups. b Survival rate of the patients received PP was significantly worse than those of the patients received TLP (p = 0.02). c Locoregional control rate of the patients who received PP was significantly worse than those of the patients who received TLP (p = 0.01). d There was no significant difference among the three groups.

TABLE 5. Results of pN classification 5-year survival rate 5-year locoregional n (%) control rate (%) pN classificationa pN0 10 70b 80 pN1 5 80 80 pN2a 5 40 62 pN2b 22 35 60 pN2c 10 15b 47 Pathological number of metastatic cervical lymph nodesc 0 10 70d 80 1 10 60 80 2 7 43 50 ≧3 25 24d 65 a There was no significant difference among the locoregional control rates of pN classification. b Survival rate of the patients evaluated as pN0 was better than that of the patients evaluated as pN2c (p = 0.03). c There was no significant difference among the 5-year locoregional control rates of the 4 groups. d Survival rate of the patients evaluated the pN0 was better than that of the patients who had 3 or more metastatic lymph nodes (p = 0.04). 74 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 75

Center. The overall survival rate reported in the the patients who received PP had a worse survival literature is approximately 10% - 50%, with poor- rate than those who were treated with other meth- er results in advanced stages (Pingree et al. 1987; ods of primary resection. In 7 patients who un- Ho et al. 1993; Spector et al. 1995; Wahlberg et derwent PP, there was local recurrence in 2 cases, al. 1998; Godballe et al. 2002; Barzan et al. regional recurrence in 2 cases, and distant metas- 2002). The overall 5-year survival rate of all pa- tasis in 1 case. Although some studies have re- tients in our study was 38%, and the cause-spe- ported that larynx-sparing surgical procedures do cific survival rate was 48%. The overall 5-year not adversely affect survival (Eckel et al. 2001; survival rate and cause-specific survival rate of Barzan et al. 2002), another study found that pa- the patients who received radical treatment in- tients so treated had a worse prognosis (Czaja et cluding TPLE, following reconstruction by free al. 1997). In the present study, results of PP for jejunal transfer were 43% and 56%, respectively. laryngeal preservation were unsatisfactory. The main failure was distant metastasis indicating Indications for PP and procedures including tran- that a new strategy, including chemotherapy and soral resection or pharyngotomy are controversial surgery, against distant metastasis is necessary to (Zeitels et al. 1994; Steiner et al. 2001). When a improve the survival rates. patient needs to undergo partial resection of a pri- Reports in the literature on multiple primary mary tumor, indication for PP must be carefully cancer of the hypopharynx are relatively few. The evaluated and additional therapies, including post- incidence of multiple primary cancers of the hy- operative radiotherapy, are thought to be neces- popharynx has been reported to be approximately sary. 10% - 20% in Japan (Ogawa et al. 1999), and the The standard treatment of advanced hypo- estimated 5-year metachronous cancer incidence pharyngeal cancer is surgery and postoperative rate has been found to be 34.4% (Schwartz et al. radiotherapy (Vandenbrouck et al. 1977; Pingree 1994). In our study, 23 out of 74 patients had et al. 1987; Frank et al. 1994; Axon et al. 1997; multiple primary cancers (31%). Six patients died Hoffman et al. 1997; Eckel et al. 2001), while of multiple primary cancers other than hypopha- chemoradiotherapy aimed at larynx-preservation ryngeal cancer. Nine out of 74 patients had syn- has recently been reported (Kraus et al. 1994; chronous multiple primary cancer (12%). Five Clayman et al. 1995; Lefebvre et al. 1996; out of 74 patients had metachrounous multiple Zelefsky et al. 1996; Samant et al. 1999). Not all primary cancers (7%). Although the incidence of patients with hypopharyngeal cancer are treated multiple primary cancers without other previous by surgery for various reasons such as unresect- cancer was relatively low at this time, it is in- able primary cancer or lymph node metastasis, creasing (Ogawa et al. 1999), and thus long-term patient refusal, and severe cardiopulmonary disor- follow-up is needed. Regular examination includ- der (Eckel et al. 2001). In our study, although re- ing gastroscopy is important after initial treat- sults of primary resection were better than those ment. of radiation, there was no significant difference. Treatment of primary tumors, including sur- If treatment results of surgery or radiotherapy are gery and radiation, is decided based on the pa- not significantly different, we need to have multi- tient’s condition and after consultation with the ple strategies to treat hypopharyngeal cancer and patient. In our results, the survival rate and lo- explain general results and complications of each coregional control rate of the patients who re- treatment to the patients. ceived surgery tended to be higher than those of In our study chemotherapy had no influence the patients who received radiation, but there was on survival and locoregional control rates. no significant difference between the two groups. Concurrent low-dose chemotherapy and intra- In our results, the survival rate of the patients with arterial chemotherapy were used for laryngeal stage I or T1 tumors was worse than that of the preservation. It has been reported that concomi- patients in other groups, as shown by the fact that tant or alternating chemotherapy in addition to ra- 74 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 75

diotherapy results in slightly significant benefits In conclusion, the overall 5-year survival and is useful for larynx preservation. The low rate of our patients was 38%. The indication for significance of the resulting benefits, however, -in and strategy of PP were decided carefully. dicates that this procedure must be further investi- Contralateral elective neck dissection is unneces- gated (Pignon et al. 2000). The efficacy of intra- sary. Regular examination to detect second pri- arterial chemotherapy should be further elucidated mary malignancy is necessary. The main failure by follow up and accumulation of cases in the fu- of hypopharyngeal cancer was distant metastasis. ture. At our institution, intravenous conventional To improve general results, we should develop chemotherapy as neoadjuvant chemotherapy or some strategy against hypopharyngeal cancer. adjuvant chemotherapy in patients who receive New strategies including chemoprevention and radical resection needs to be reconsidered. surgery against distant metasistasis are necessary. Elective contralateral neck dissection is controversial (Nishijima et al. 1991; Anderson et al. References 1996; Lassaletta et al. 2002). Four of our patients Andersen, P.E., Cambronero, E., Shaha, A.R. & Shah, experienced contralateral regional recurrence, but J.P. (1996) The extent of neck disease after re- they were salvaged by ND at the time of recur- gional failure during observation of the N0 rence. Although we presently consider elective neck. Am. J. Surg., 172, 689-691. Axon, P.R., Woolfold, T.J., Hargreaves, S.P., Yates, P., contralateral neck dissection to be unnecessary, its Birzgalis, A.R. & Farrington, W.T. (1997) A advisability shoud be reconsidered based on re- comparison of surgery and radiotherapy in the sults of patient follow-up. It is well documented management of post-cricoid carcinoma. Clin. that regional lymph node metastasis of hypopha- Otolaryngol., 22, 370-374. ryngeal cancer is usually located at levels II, III Barzan, L., Talamini, R., Politi, D., Minatel, E., Gobitti, C. & Franchin, G. (2002) Squamous and IV (Candela et al. 1990; Wenig and cell carcinoma of the hypopharynx treated with Applebaum 1991). In our results, regional metas- surgery and radiotherapy. J. Laryngol. Otol., tasis was mainly located at these levels in the pa- 116, 24-28. tients who underwent initial neck dissection. Two Candela, F.C., Kothari, K. & Shah, J.P. (1990) Pat- patients who had a metastatic submandibular terns of cervical node metastases from squamous carcinoma of the oropharynx and hypo- lymph node (level I), however, also experienced pharynx. Head Neck, 12, 197-203. multiple lymph node metastases in other region Clayman, G.L., Weber, R.S., Guillamondegui, O., including the retro-space of submandibular gland Byers, R.M., Wolf, P.F., Frankenthaler, R.A., and the region near the hyoid bone. The histopa- Morrison, W.H., Garden, A.S., Hong, W.K. & thology of the one patient with metastasis to the Goepfert, H. (1995) Laryngeal preservation for submandibular lymph node was basaloid squa- advanced laryngeal and hypopharyngeal cancers. Arch. Otolaryngol. Head Neck Surg., 121, mous cell carcinoma with a poor prognosis. 219-223. Retropharyngeal node metastasis was found in 5 Czaja, J.M. & Gluckman, J.L. (1997) Surgical man- patients. All patients with retropharyngeal node agement of early-stage hypopharyngeal carci- metastasis died of cancer. Survival of the patients noma. Ann. Otol. Rhinol. Laryngol., 106, with retropharyngeal node metastasis was signifi- 909-913. Eckel, H.E., Staar, S., Volling, P., Sittel, C., Damm, M. cantly worse than that of the patients with no ret- & Jungehuelsing, M. (2001) Surgical treatment ropharyngeal node metastasis (data not shown). for hypopharynx carcinoma: feasibility, mortal- Generally, the N classification, pN classifica- ity, and results. Otolaryngol. Head Neck Surg., tion and number of pathological metastatic lymph 124, 561-569. nodes have been shown to be important prognos- Frank, J.L., Garb, J.L., Kay, S., McClish, D.K., Bethke, K.P., Lind, D.S., Mellis, M., Slomka, tic factors (Ono et al. 1985; Barzan et al. 2002). W., Sismanis, A. & Neifeld, J.P. (1994) Postop- In our results, the 5-year survival rate was signifi- erative radiotherapy improves survival in squa- cantly related to the pN classification and the mous cell carcinoma of the hypopharynx. Am. J. number of pathological metastatic nodes. Surg., 168, 476-480. 76 M. Tateda et al. Management of the Patients with Hypopharyngeal Cancer 77

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