- Email: [email protected]
Long-term results after esophagectomy for squamous cell carcinoma of the esophagus associated with head and neck cancer
Long-Term Results after Esophagectomy for Squamous Cell Carcinoma of the Esophagus Associated with Head and Neck Cancer Philippe Wind, MD, Marie-He´le`ne Roullet, MD, David Quinaux, MD, Olivier Laccoureye, MD, Daniel Brasnu, MD, Paul-Henri Cugnenc MD, Paris, France
BACKGROUND: Esophageal squamous cell carcinomas are frequently associated with head and neck cancers. The poor prognosis of each cancer, and their proximity, often limit the treatment options. This study was conducted to determine the characteristics and long-term outcome of such dual cancers. PATIENTS AND METHODS: We included 75 patients with esophageal carcinoma, of whom 25 had a synchronous head and neck malignancy. Curative treatment was possible in every case. The patients were divided into “solitary cancer” and “synchronous cancer” groups. RESULTS: The gender distribution, tumor location, and histological findings were similar in the two groups. Patients in the synchronous cancer group were younger than those in the solitary group (P <0.0042). The operative mortality and pulmonary morbidity rates were not significantly different in the two groups. The rate of cervical anastomotic leaks was higher in the synchronous group (P <0.05). The mean follow-up was 83 ⴞ 50 months. Five-year survival rates were not significantly different in the two groups (14.3% ⴞ 5.7% in the solitary group and 17.5% ⴞ 7.9% in the synchronous group). CONCLUSIONS: With aggressive treatment, the survival of patients with synchronous esophageal and head and neck cancers was similar to that of patients with isolated esophageal cancer. Am J Surg. 1999;178:251–255. © 1999 by Excerpta Medica, Inc.
N
ine out of 10 esophageal cancers are squamous cell carcinomas.1 This malignancy is generally encountered in men between 55 and 70 years with a history of drinking and smoking.2 Esophagectomy is still the standard treatment and yields an overall 5-year survival rate of 20%. However, fewer than 60% of esophageal carcinomas are resectable at the time of diagnosis.1
From the Departments of Gastrointestinal Surgery (PW, MHR, DQ, PHC) and Head and Neck Surgery (OL, DB), Hospital Laennec, Paris, France. Requests for reprints should be addressed to Philippe Wind, Hopital Laennec, 42 rue de Se`vres, 75007 Paris, France. Manuscript submitted October 20, 1998, and accepted in revised form June 22, 1999.
© 1999 by Excerpta Medica, Inc. All rights reserved.
Given their shared epidemiologic factors,3 squamous cell carcinoma of the esophagus is frequently associated with head and neck cancers.4 Moreover, in patients with head and neck cancer, routine endoscopy of the gastrointestinal tract5 and long-term posttherapeutic follow-up has resulted in more frequent detection of synchronous or metachronous second primary carcinomas of the esophagus.6 The management and clinical course of these patients with multiple squamous cell carcinomas are poorly documented.7 The poor prognosis of each carcinoma taken individually, and their anatomic proximity, limit the therapeutic possibilities.8 We devised an aggressive treatment regimen aimed at curing simultaneous primary carcinomas of the esophagus and of the head and neck. The study was conducted to determine the characteristics and long-term outcome of primary esophageal squamous cell carcinoma simultaneously associated with head and neck cancer. The results were compared with those obtained in patients with an isolated esophageal tumor.
PATIENTS AND METHODS Inclusion Criteria and Group Definitions We included (1) patients who underwent curative resection for isolated squamous cell carcinoma of the esophagus, and (2) patients with simultaneous primary squamous cell carcinoma of the esophagus and head and neck cancer, in whom complete remission was achieved in both locations. Patients with pharyngeal cancers involving the cervical esophagus and those with adenocarcinomas of the esophagus or cardia were not included in the study. From 1986 to 1995, 173 patients with carcinoma of the esophagus or cardia were admitted to our surgical department. Forty-one of these patients had adenocarcinoma of the cardia or lower esophagus. Among the remaining 132 patients who had squamous cell carcinoma of the esophagus, 75 met the inclusion criteria. The patients were divided into two groups, as follows. The “solitary” cancer group comprised 50 patients with solitary esophageal squamous cell carcinoma at diagnosis. The “synchronous” cancer group comprised 25 patients with synchronous multiple carcinomas of the esophagus and of the head and neck. The location of the head and neck tumors was as follows: oral cavity n ⫽ 4, oropharynx n ⫽ 9, piriform sinus n ⫽ 10, and larynx n ⫽ 3 (1 patient had 2 head and neck cancers). Preoperative Staging The esophageal tumor was located by endoscopy. Preoperative staging included panendoscopy of the airways and 0002-9610/99/$–see front matter PII S0002-9610(99)00163-4
251
LONG-TERM RESULTS AFTER ESOPHAGECTOMY/WIND ET AL
TABLE I Operative Techniques for Esophagectomy
Subtotal esophagectomy Approach Right thoracotomy Transhiatal Reconstruction Gastric tube Colon Anastomosis Cervical Thoracic Esopharyngolaryngectomy Reconstruction Gastric tube Colon
Solitary Cancer Group (n ⴝ 50)
Synchronous Cancer Group (n ⴝ 25)
Total (n ⴝ 75)
P
47
16
63
⬍0.01
26 21
6 10
31 32
⬍0.3
46 1
15 1
61 2
⬍0.5
45 2 3
16 — 9
61 2 12
⬍0.5
— 3
1 8
digestive tract, barium contrast, chest computed tomography (CT), ultrasonography of the upper abdomen, pulmonary functions tests and, recently, endosonography. The depth of tumor invasion, lymph node involvement, distant metastasis, and tumor stage were defined according to the UICC TNM classification. Management of Patients with Synchronous Tumors Whenever possible, the basic therapeutic plan consisted of first curing the head and neck cancer and then resecting the esophagus. All patients with synchronous head and neck cancers received chemotherapy first (ie, 5-fluorouracil and cisplatinum for three courses). They were then divided into four groups depending on the treatment of their head and neck cancer, as follows: (1) those (n ⫽ 2) whose head and neck cancer was exclusively treated with chemotherapy or chemo-radiation therapy; (2) those (n ⫽ 7) whose head and neck tumor was resected by the peroral approach; (3) those (n ⫽ 9) who then underwent major surgery with cervical incision (ie, mandibulectomy n ⫽ 1, mandibulectomy associated with oropharyngectomy n ⫽ 2, partial pharyngectomy n ⫽ 3 or partial laryngectomy n ⫽ 3); and (4) those (n ⫽ 8) in whom pharyngolaryngectomy was necessary afterwards. For patients who underwent nonsurgical treatment or endobuccal surgery, esophagectomy was delayed by 2 to 4 weeks. For patients with major head and neck surgery, esophageal resection was delayed by 2 months. In the interval, patients with severe weight loss or dysphagia received enteral nutrition. Esophageal Resection Before esophagectomy, in the synchronous group, previous therapy for head and neck cancer included cervical incision in 12 patients and cervical radiation therapy in 2 patients. Esophagectomy was always performed under general anesthesia. A double-lumen endobronchial tube was used perioperatively in case of right thoracotomy. Subtotal esophagectomy was performed either via a fifth intercostal space thoracotomy or via a transhiatal approach after ventral phrenic division. The stomach was mobilized conventionally via an abdominal incision. The gastric tube was 252
⬍0.01
placed in the posterior mediastinum. Esophagogastric anastomosis was constructed using a circular stapler in the thorax or was hand-sewn at the cervical level. When total esopharyngolaryngectomy was necessary, gastric tube reconstruction or colon interposition was used for anastomosis on the pharynx. A feeding jejunostomy was constructed in every case. Details of esophageal surgery are given in Table I. Patient Outcome Operative mortality was defined as death during hospitalization or within 1 month after surgery. Postoperative complications were diagnosed by routine clinical examination and usual radiological techniques, including ultrasound and CT scan when necessary. Anastomotic leakage was diagnosed by cervical inspection or by meglumine diatrizoate (Gastrographin) ingestion. Follow-up information was obtained through outpatient visits or telephone interviews with the regular physician. Statistical Analysis We used the SPSS statistical software package for Windows. Descriptive data are given as means and one standard deviation. Data were compared by using the MannWhitney U or chi-square tests as appropriate. Life tables were drawn by the Kaplan-Meier method, and differences in survival were calculated by the log-rank test. In multivariate analysis, the stepwise Cox proportional hazards model was used to assess the impact of various factors on survival. A P value of less than 0.05 was regarded as statistically significant.
RESULTS Clinical and pathologic background data are shown in Table II. The gender distribution, tumor location, and histological findings were similar in the two groups. Mean age was significantly higher in the solitary carcinoma group (P ⫽ 0.0042). Six patients died in the postoperative period, 2 of liver dysfunction (patients with cirrhosis), 3 of pulmonary infection, and 1 of mediastinitis due to cervical anastomotic
THE AMERICAN JOURNAL OF SURGERY® VOLUME 178 SEPTEMBER 1999
LONG-TERM RESULTS AFTER ESOPHAGECTOMY/WIND ET AL
TABLE II Clinicopathologic Background Factors of 50 Patients with an Isolated Esophageal Carcinoma and 25 Patients with Synchronous Esophageal and Head and Neck Cancers Solitary Group (n ⴝ 50) Gender ratio (M/F) 38/12 Age (years) 60.3 ⫾ 8.5 Esophageal tumor location Upper esophagus 11 (22) Middle esophagus 34 (68) Lower esophagus 5 (10) pT stage of esophageal cancer ⬍pT3 21 (42) p(T3) 29 (58) pN stage of esophageal cancer p(N⫺) 33 (66) p(N⫹) 17 (34)
Synchronous Group (n ⴝ 25)
P
21/4 54.9 ⫾ 7.1
⬍0.5 0.0042
6 (24) 15 (60) 4 (16)
⬍0.9 ⬍0.5 ⬍0.5
16 (64) 9 (36)
⬍0.1 ⬍0.1
13 (52) 12 (48)
⬍0.2 ⬍0.2
Figure 1. Survival (Kaplan-Meier) after esophagectomy of patients in the solitary and synchronous cancer groups according to esophageal depth invasion (P ⫽ 0.0002).
Values in parentheses are percentages. M/F ⫽ Male/Female.
TABLE III Postoperative Complications after Esophagectomy in 75 Patients with a Solitary Esophageal Carcinoma or with an Esophageal Carcinoma with an Associated Synchronous Head and Neck Cancer
Postoperative mortality Anastomotic leaks Pneumonia Tracheotomy Chylothorax Recurrent nerve palsy Oral feeding delay (days) Length of hospital stay (days)
Solitary Group (n ⴝ 50)
Synchronous Group (n ⴝ 25)
5 (10) 7 (14) 11 (22) 5 (10) 3 (6) 3 (6)
1 (4) 10 (40) 4 (17) 3 (12) — 3 (6)
P ⬍0.5 0.05 ⬍0.9 ⬍0.9 ⬍0.3 ⬍0.5
14 ⫾ 9.5
21.7 ⫾ 15.5
0.0271
28.7 ⫾ 14.6
29.9 ⫾ 13.1
0.5785
Values in parentheses are percentages.
leakage. Postoperative complications are listed in Table III. The rate of anastomotic leakage (P ⬍0.05) and the duration before oral feeding (P ⫽ 0.0266) were significantly higher in the synchronous carcinoma group. The length of hospital stay was similar in the two groups. Follow-up information was available for all the patients. The mean follow-up was 83 ⫾ 50 months (range 25 to 154). In the solitary group, 34 patients died during followup, 31 (91.2%) of esophageal carcinoma relapse and 3 (8.8%) of causes unrelated to cancer. In the synchronous group, 19 patients died, 9 (47.4%) of head and neck cancer relapse, 2 (10.5%) of a new head and neck cancer, 6 (31.6%) of esophageal carcinoma relapse, and 2 (10.5%) of causes unrelated to cancer. Five-year survival rates, including postoperative mortality, were not significantly different (P ⫽ 0.8660) in the two groups (14.3% ⫾ 5.7% in the solitary group and 17.5%
Figure 2. Survival (Kaplan-Meier) after esophagectomy of patients in solitary and synchronous cancer groups according to node involvement (P ⫽ 0.0373).
⫾ 7.9% in the synchronous group). The depth of esophageal tumor invasion (P ⫽ 0.0002; Figure 1) and node involvement (P ⫽ 0.0373; Figure 2) were significant prognostic factors. In multivariate survival analysis (Table IV), the only significant predictive factor was the depth of esophageal tumor invasion (P ⫽ 0.0019).
COMMENTS In this study only patients who underwent potentially curative treatment for both cancers were studied. Longterm survival was similar in the synchronous cancers group and the solitary esophageal carcinoma group. Squamous cell carcinoma of the esophagus and head and neck cancers are associated in 12% to 17% of cases.9,10 The risk varies with the anatomic location of the neck cancer, with an increased incidence in patients with cancer of the oral cavity and hypopharynx.11,12 The concept of “field cancerization,” originally forwarded by Slaughter et al13 to explain the high local recurrence rate of oral cancers, also seems to explain the high rate of multiple synchronous and metachronous carcinomas of the upper aerodigestive digestive tract.14,15 There may be a panmucosal disease of the aerodigestive tract in which heavy use of tobacco and alcohol have a regional carcinogenic effect.3
THE AMERICAN JOURNAL OF SURGERY® VOLUME 178 SEPTEMBER 1999
253
LONG-TERM RESULTS AFTER ESOPHAGECTOMY/WIND ET AL
TABLE IV Univariate and Multivariate Overall Survival Analysis of 75 Patients with an Esophageal Carcinoma Prognosis Factors Group Depth invasion ⬍pT3 Depth invasion pT3 N stage: pN⫺ N stage: pN⫹
Group
5-Year Survival (%)
Univariate Analysis P
Multivariate Analysis P
Solitary Synchronous Solitary Synchronous Solitary Synchronous Solitary Synchronous Solitary Synchronous
14.3 ⫾ 5.7 17.5 ⫾ 7.9 32 ⫾ 11.5 27.5 ⫾ 11.6 0 0 20.9 ⫾ 8 31.2 ⫾ 14.8 0 7.1 ⫾ 6.9
0.8660
0.4375
0.0002
0.0019
0.0373
0.3408
In the current study, patients with synchronous cancers were younger than those with solitary esophageal carcinoma. The explanation could be a particular genetic susceptibility to multiple cancers,16 increased exposure to carcinogenic factors, or earlier diagnosis of the esophageal carcinoma owing to routine panendoscopy in patients with head and neck cancer.5 The location of the esophageal cancer in patients with multiple carcinomas was similar to that in patients with solitary esophageal carcinoma, confirming the findings of other studies.12,17 As report by others,17,18 patients with synchronous multiple cancers were more likely to have esophageal cancer limited to the esophageal wall, but the difference was not statistically significant in our study. The rate of lymph node involvement in the two groups must be analyzed cautiously, as different surgical procedures were used for esophagectomy. Moreover, some patients in the synchronous group underwent cervical lymph node dissection at the time of head and neck cancer surgery. As a result, cervical lymph node metastases could not be accurately attributed to the esophageal or head and neck cancer. The grim prognosis of double primary esophageal and head and neck carcinomas and their anatomic proximity19 –21 often limit the therapeutic possibilities for both cancers.22 As a result, esophageal resection is probably considered less often than for solitary tumors. In this study, except for total esopharyngolaryngectomy when required, we aimed to use the same therapeutic approach for each lesion as that used for single distinctive primary lesions. Esophagectomy was delayed to avoid an extensive surgical procedure for two cancers in adjacent sites. Theoretically, the radical therapy previously applied to the head and neck cancer may also obviate further treatment. Cervical dissection is rendered difficult after previous cervical incision or cervical radiation therapy. Anastomotic leakage and recurrent nerve paralysis rates are potentially increased. Precarious phonation or swallowing function after conservative laryngeal surgery may be worsened by esophageal surgery involving recurrent cervical incision. All these factors increase pulmonary complications, which in turn increase mortality and morbidity after oesophagectomy.23 In addition, the esophageal tumor may progress during head and neck cancer therapy. In the interval, neoadjuvant chemoradiation therapy can be undertaken, but a recent study24 suggested that it did not improve overall survival, while 254
increasing mortality after esophagectomy. Esophageal resection as first-step therapy carries similar disadvantages, because esophagectomy has its own complications25 that can also compromise or delay the treatment of the head and neck cancer. Moreover, esophagectomy is impossible when the head and neck cancer causes airway obstruction. In this study the initial head and neck cancer treatment allowed us to conduct esophagectomy in selected patients who had potentially been cured, and to reduce the influence of the head and neck cancer treatment on esophagectomy. The interval between the treatment of each cancer depended on the modalities of the head and neck cancer therapy. This interval also allowed for an improvement in the patient’s general condition (including tobacco and alcohol withdrawal) before esophagectomy. The mortality and pulmonary morbidity rates after esophagectomy in patients with synchronous tumors were similar to those in patients with solitary esophageal carcinoma. The only complication that occurred more frequently was cervical anastomotic leakage in the synchronous group, probably resulting from recent cervical incision or cervical radiation therapy. This complication delayed oral feeding but did not affect the length of the hospital stay. For tumors arising in the middle or lower thoracic esophagus, intrathoracic anastomosis avoids repeated cervical incision and reduces the interval between the treatment of the two cancers. Esophagectomy for squamous cell carcinoma of the esophagus gives a 15% to 25% 5-year survival rate,1,26 the main prognostic factors being tumor penetration in the esophageal wall and lymph node involvement.27,28 In this study, 5-year survival rates were similar in the two groups. Nevertheless, two restrictions must be taken into account. First, all patients in the synchronous group received neoadjuvant chemotherapy for their head and neck cancer, although this is known to have no impact on survival after esophageal cancer resection.29,30 Secondly, although the difference was not statistically significant, the synchronous group comprised more patients with tumors limited to the esophageal wall. However, among the prognostic factors studied in multivariate analysis, the simultaneous presence of a head and neck tumor did not affect survival. Therefore, despite the high rate of cervical anastomotic leakage, esophagectomy is feasible in patients with synchronous tumors, with acceptable mortality and long-term outcome.
THE AMERICAN JOURNAL OF SURGERY® VOLUME 178 SEPTEMBER 1999
LONG-TERM RESULTS AFTER ESOPHAGECTOMY/WIND ET AL
REFERENCES 1. Mu¨ller JM, Erasmi H, Stelzner M, et al. Surgical therapy of esophageal carcinoma. Br J Surg. 1990;77:845– 857. 2. Munoz N. Epidemiological aspects of oesophageal cancer. Endoscopy. 1993;25:609 – 612. 3. Wynder E, Mushinski M, Spivak J. Tobacco and alcohol consumption in relation to development of multiple primary cancers. Cancer. 1977;40:1872–1878. 4. Choy A, Hasselt CAV, Chisholm EM, et al. Multiple primary cancers in Hong Kong chinese patients with squamous cell cancer of the head or neck. Cancer. 1992;70:815– 820. 5. Ina H, Shibuya H, Ohashi I, Kitagawa M. The frequency of a concomitant early esophageal cancer in male patients with oral or oropharyngeal cancer. Cancer. 1994;73:2038 –2041. 6. Day GL, Blot WJ. Second primary tumors in patients with oral cancer. Cancer. 1992;70:14 –19. 7. Tachimori Y, Watanabe H, Kato H, et al. Treatment for synchronous and metachronous carcinomas of the head and neck and esophagus. J Surg Oncol. 1990;45:43– 45. 8. Gluckman JL, Crissman JD. Survival rates in 548 patients with multiple neoplasms of the upper aerodigestive tract. Laryngoscope. 1983;93:71–74. 9. Fogel T, Harrison L, Son Y. Subsequent upper aerodigestive malignancies following treatement of esophageal cancer. Cancer. 1985;55:1882–1885. 10. Hoar S, Wilson J, Blot W, et al. Second cancer following cancer of the digestive system in Connecticut, 1935–1982. Natl Cancer Inst Monograph. 1985;68:49 – 82. 11. Tepperman B, Fitzpatrick P. Second respiratory and upper digestive tract cancers after oral cancer. Lancet. 1981;12:547–549. 12. Shibuya H, Wakita T, Nakagawa T, et al. The relation between an esophageal cancer and associated cancers in adjacent organs. Cancer. 1995;76:101–105. 13. Slaughter D, Southwick H, Smejkal W. “Field cancerization” in oral stratified squamous epithelium. Cancer. 1953;6:963–968. 14. Shibuya H, Hisamitsu S, Shioiri S, et al. Multiple primary cancer risk in patients with squamous cell carcinoma of the oral cavity. Cancer. 1987;60:3083–3086. 15. Guirt FM, Matthews B, Koufman J. Multiple simultaneous tumors in patients with head and neck cancer. Cancer. 1982;50: 1195–1199. 16. Yokoyama A, Muramatsu T, Ohmori T, et al. Multiple primary esophageal and concurrent upper aerodigestive tract cancer and the
aldehyde dehydrogenase-2 of Japanese alcoholics. Cancer. 1996;77: 1986 –1990. 17. Takiyama W, Moriwaki S, Mandai K, Takashima S. Relationship of esophageal dysplasia to associated head and neck cancer in patients with esophageal carcinoma. Jpn J Oncol. 1996;26:12–17. 18. Shiozaki H, Tahara H, Kobayaschi K, et al. Endoscopic screening of early esophageal cancer with the lugol dye method in patients with head and neck cancers. Cancer. 1990;66:2068 –2071. 19. Asamura H, Kato H, Watanabe H, et al. Combined gastric pull-up and microvascular jejunal transfer procedure after pharyngolaryngoesophagectomy. Ann Thorac Surg. 1989;48:423– 425. 20. Sun K, Matsubara T, Ueda M. Surgical treatment for primary esophageal cancer developing after pharyngolaryngectomy for head and neck cancer. Surgery. 1997;122:15–19. 21. Yoshino K, Endo M, Nara S, Ishikawa N. Surgery for synchronous double cancer in the hypopharynx and thoracic esophagus. Hepato-gastroenterology. 1995;42:275–278. 22. Panosetti E, Luboinski B, Mamelle G, Richard JM. Multiple synchronous and metachronous cancers of the upper aerodigestive tract: a nine year study. Laryngoscope. 1989;99:1267–1273. 23. Tsutsui S, Moriguchi S, Morita M, et al. Multivariate analysis of postoperative complications after esophageal resection. Ann Thorac Surg. 1992;53:1052–1056. 24. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous cell cancer of the esophagus. NEJM. 1997;337:161–167. 25. Law S, Fok M, Wong J. Risk analysis in resection of squamous cell carcinoma of the esophagus. World J Surg. 1994;18:339 –346. 26. Watson A. Operable esophageal cancer: current results from the west. World J Surg. 1994;18:361–366. 27. Killinger WA, Rice TW, Adelstein DJ, et al. Stage II esophageal carcinoma: the significance of T and N. J Thorac Cardiovasc Surg. 1996;111:935–940. 28. Ide H, Nakamura T, Hayashi K, et al. Esophageal squamous cell carcinoma: pathology and prognosis. World J Surg. 1994;18:321– 330. 29. Roth JA, Pass HI, Flanagan MM, et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg. 1988;96:242–248. 30. Schlag P. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. Arch Surg. 1992;127: 1446 –1450.
THE AMERICAN JOURNAL OF SURGERY® VOLUME 178 SEPTEMBER 1999
255
BACKGROUND: Esophageal squamous cell carcinomas are frequently associated with head and neck cancers. The poor prognosis of each cancer, and their proximity, often limit the treatment options. This study was conducted to determine the characteristics and long-term outcome of such dual cancers. PATIENTS AND METHODS: We included 75 patients with esophageal carcinoma, of whom 25 had a synchronous head and neck malignancy. Curative treatment was possible in every case. The patients were divided into “solitary cancer” and “synchronous cancer” groups. RESULTS: The gender distribution, tumor location, and histological findings were similar in the two groups. Patients in the synchronous cancer group were younger than those in the solitary group (P <0.0042). The operative mortality and pulmonary morbidity rates were not significantly different in the two groups. The rate of cervical anastomotic leaks was higher in the synchronous group (P <0.05). The mean follow-up was 83 ⴞ 50 months. Five-year survival rates were not significantly different in the two groups (14.3% ⴞ 5.7% in the solitary group and 17.5% ⴞ 7.9% in the synchronous group). CONCLUSIONS: With aggressive treatment, the survival of patients with synchronous esophageal and head and neck cancers was similar to that of patients with isolated esophageal cancer. Am J Surg. 1999;178:251–255. © 1999 by Excerpta Medica, Inc.
N
ine out of 10 esophageal cancers are squamous cell carcinomas.1 This malignancy is generally encountered in men between 55 and 70 years with a history of drinking and smoking.2 Esophagectomy is still the standard treatment and yields an overall 5-year survival rate of 20%. However, fewer than 60% of esophageal carcinomas are resectable at the time of diagnosis.1
From the Departments of Gastrointestinal Surgery (PW, MHR, DQ, PHC) and Head and Neck Surgery (OL, DB), Hospital Laennec, Paris, France. Requests for reprints should be addressed to Philippe Wind, Hopital Laennec, 42 rue de Se`vres, 75007 Paris, France. Manuscript submitted October 20, 1998, and accepted in revised form June 22, 1999.
© 1999 by Excerpta Medica, Inc. All rights reserved.
Given their shared epidemiologic factors,3 squamous cell carcinoma of the esophagus is frequently associated with head and neck cancers.4 Moreover, in patients with head and neck cancer, routine endoscopy of the gastrointestinal tract5 and long-term posttherapeutic follow-up has resulted in more frequent detection of synchronous or metachronous second primary carcinomas of the esophagus.6 The management and clinical course of these patients with multiple squamous cell carcinomas are poorly documented.7 The poor prognosis of each carcinoma taken individually, and their anatomic proximity, limit the therapeutic possibilities.8 We devised an aggressive treatment regimen aimed at curing simultaneous primary carcinomas of the esophagus and of the head and neck. The study was conducted to determine the characteristics and long-term outcome of primary esophageal squamous cell carcinoma simultaneously associated with head and neck cancer. The results were compared with those obtained in patients with an isolated esophageal tumor.
PATIENTS AND METHODS Inclusion Criteria and Group Definitions We included (1) patients who underwent curative resection for isolated squamous cell carcinoma of the esophagus, and (2) patients with simultaneous primary squamous cell carcinoma of the esophagus and head and neck cancer, in whom complete remission was achieved in both locations. Patients with pharyngeal cancers involving the cervical esophagus and those with adenocarcinomas of the esophagus or cardia were not included in the study. From 1986 to 1995, 173 patients with carcinoma of the esophagus or cardia were admitted to our surgical department. Forty-one of these patients had adenocarcinoma of the cardia or lower esophagus. Among the remaining 132 patients who had squamous cell carcinoma of the esophagus, 75 met the inclusion criteria. The patients were divided into two groups, as follows. The “solitary” cancer group comprised 50 patients with solitary esophageal squamous cell carcinoma at diagnosis. The “synchronous” cancer group comprised 25 patients with synchronous multiple carcinomas of the esophagus and of the head and neck. The location of the head and neck tumors was as follows: oral cavity n ⫽ 4, oropharynx n ⫽ 9, piriform sinus n ⫽ 10, and larynx n ⫽ 3 (1 patient had 2 head and neck cancers). Preoperative Staging The esophageal tumor was located by endoscopy. Preoperative staging included panendoscopy of the airways and 0002-9610/99/$–see front matter PII S0002-9610(99)00163-4
251
LONG-TERM RESULTS AFTER ESOPHAGECTOMY/WIND ET AL
TABLE I Operative Techniques for Esophagectomy
Subtotal esophagectomy Approach Right thoracotomy Transhiatal Reconstruction Gastric tube Colon Anastomosis Cervical Thoracic Esopharyngolaryngectomy Reconstruction Gastric tube Colon
Solitary Cancer Group (n ⴝ 50)
Synchronous Cancer Group (n ⴝ 25)
Total (n ⴝ 75)
P
47
16
63
⬍0.01
26 21
6 10
31 32
⬍0.3
46 1
15 1
61 2
⬍0.5
45 2 3
16 — 9
61 2 12
⬍0.5
— 3
1 8
digestive tract, barium contrast, chest computed tomography (CT), ultrasonography of the upper abdomen, pulmonary functions tests and, recently, endosonography. The depth of tumor invasion, lymph node involvement, distant metastasis, and tumor stage were defined according to the UICC TNM classification. Management of Patients with Synchronous Tumors Whenever possible, the basic therapeutic plan consisted of first curing the head and neck cancer and then resecting the esophagus. All patients with synchronous head and neck cancers received chemotherapy first (ie, 5-fluorouracil and cisplatinum for three courses). They were then divided into four groups depending on the treatment of their head and neck cancer, as follows: (1) those (n ⫽ 2) whose head and neck cancer was exclusively treated with chemotherapy or chemo-radiation therapy; (2) those (n ⫽ 7) whose head and neck tumor was resected by the peroral approach; (3) those (n ⫽ 9) who then underwent major surgery with cervical incision (ie, mandibulectomy n ⫽ 1, mandibulectomy associated with oropharyngectomy n ⫽ 2, partial pharyngectomy n ⫽ 3 or partial laryngectomy n ⫽ 3); and (4) those (n ⫽ 8) in whom pharyngolaryngectomy was necessary afterwards. For patients who underwent nonsurgical treatment or endobuccal surgery, esophagectomy was delayed by 2 to 4 weeks. For patients with major head and neck surgery, esophageal resection was delayed by 2 months. In the interval, patients with severe weight loss or dysphagia received enteral nutrition. Esophageal Resection Before esophagectomy, in the synchronous group, previous therapy for head and neck cancer included cervical incision in 12 patients and cervical radiation therapy in 2 patients. Esophagectomy was always performed under general anesthesia. A double-lumen endobronchial tube was used perioperatively in case of right thoracotomy. Subtotal esophagectomy was performed either via a fifth intercostal space thoracotomy or via a transhiatal approach after ventral phrenic division. The stomach was mobilized conventionally via an abdominal incision. The gastric tube was 252
⬍0.01
placed in the posterior mediastinum. Esophagogastric anastomosis was constructed using a circular stapler in the thorax or was hand-sewn at the cervical level. When total esopharyngolaryngectomy was necessary, gastric tube reconstruction or colon interposition was used for anastomosis on the pharynx. A feeding jejunostomy was constructed in every case. Details of esophageal surgery are given in Table I. Patient Outcome Operative mortality was defined as death during hospitalization or within 1 month after surgery. Postoperative complications were diagnosed by routine clinical examination and usual radiological techniques, including ultrasound and CT scan when necessary. Anastomotic leakage was diagnosed by cervical inspection or by meglumine diatrizoate (Gastrographin) ingestion. Follow-up information was obtained through outpatient visits or telephone interviews with the regular physician. Statistical Analysis We used the SPSS statistical software package for Windows. Descriptive data are given as means and one standard deviation. Data were compared by using the MannWhitney U or chi-square tests as appropriate. Life tables were drawn by the Kaplan-Meier method, and differences in survival were calculated by the log-rank test. In multivariate analysis, the stepwise Cox proportional hazards model was used to assess the impact of various factors on survival. A P value of less than 0.05 was regarded as statistically significant.
RESULTS Clinical and pathologic background data are shown in Table II. The gender distribution, tumor location, and histological findings were similar in the two groups. Mean age was significantly higher in the solitary carcinoma group (P ⫽ 0.0042). Six patients died in the postoperative period, 2 of liver dysfunction (patients with cirrhosis), 3 of pulmonary infection, and 1 of mediastinitis due to cervical anastomotic
THE AMERICAN JOURNAL OF SURGERY® VOLUME 178 SEPTEMBER 1999
LONG-TERM RESULTS AFTER ESOPHAGECTOMY/WIND ET AL
TABLE II Clinicopathologic Background Factors of 50 Patients with an Isolated Esophageal Carcinoma and 25 Patients with Synchronous Esophageal and Head and Neck Cancers Solitary Group (n ⴝ 50) Gender ratio (M/F) 38/12 Age (years) 60.3 ⫾ 8.5 Esophageal tumor location Upper esophagus 11 (22) Middle esophagus 34 (68) Lower esophagus 5 (10) pT stage of esophageal cancer ⬍pT3 21 (42) p(T3) 29 (58) pN stage of esophageal cancer p(N⫺) 33 (66) p(N⫹) 17 (34)
Synchronous Group (n ⴝ 25)
P
21/4 54.9 ⫾ 7.1
⬍0.5 0.0042
6 (24) 15 (60) 4 (16)
⬍0.9 ⬍0.5 ⬍0.5
16 (64) 9 (36)
⬍0.1 ⬍0.1
13 (52) 12 (48)
⬍0.2 ⬍0.2
Figure 1. Survival (Kaplan-Meier) after esophagectomy of patients in the solitary and synchronous cancer groups according to esophageal depth invasion (P ⫽ 0.0002).
Values in parentheses are percentages. M/F ⫽ Male/Female.
TABLE III Postoperative Complications after Esophagectomy in 75 Patients with a Solitary Esophageal Carcinoma or with an Esophageal Carcinoma with an Associated Synchronous Head and Neck Cancer
Postoperative mortality Anastomotic leaks Pneumonia Tracheotomy Chylothorax Recurrent nerve palsy Oral feeding delay (days) Length of hospital stay (days)
Solitary Group (n ⴝ 50)
Synchronous Group (n ⴝ 25)
5 (10) 7 (14) 11 (22) 5 (10) 3 (6) 3 (6)
1 (4) 10 (40) 4 (17) 3 (12) — 3 (6)
P ⬍0.5 0.05 ⬍0.9 ⬍0.9 ⬍0.3 ⬍0.5
14 ⫾ 9.5
21.7 ⫾ 15.5
0.0271
28.7 ⫾ 14.6
29.9 ⫾ 13.1
0.5785
Values in parentheses are percentages.
leakage. Postoperative complications are listed in Table III. The rate of anastomotic leakage (P ⬍0.05) and the duration before oral feeding (P ⫽ 0.0266) were significantly higher in the synchronous carcinoma group. The length of hospital stay was similar in the two groups. Follow-up information was available for all the patients. The mean follow-up was 83 ⫾ 50 months (range 25 to 154). In the solitary group, 34 patients died during followup, 31 (91.2%) of esophageal carcinoma relapse and 3 (8.8%) of causes unrelated to cancer. In the synchronous group, 19 patients died, 9 (47.4%) of head and neck cancer relapse, 2 (10.5%) of a new head and neck cancer, 6 (31.6%) of esophageal carcinoma relapse, and 2 (10.5%) of causes unrelated to cancer. Five-year survival rates, including postoperative mortality, were not significantly different (P ⫽ 0.8660) in the two groups (14.3% ⫾ 5.7% in the solitary group and 17.5%
Figure 2. Survival (Kaplan-Meier) after esophagectomy of patients in solitary and synchronous cancer groups according to node involvement (P ⫽ 0.0373).
⫾ 7.9% in the synchronous group). The depth of esophageal tumor invasion (P ⫽ 0.0002; Figure 1) and node involvement (P ⫽ 0.0373; Figure 2) were significant prognostic factors. In multivariate survival analysis (Table IV), the only significant predictive factor was the depth of esophageal tumor invasion (P ⫽ 0.0019).
COMMENTS In this study only patients who underwent potentially curative treatment for both cancers were studied. Longterm survival was similar in the synchronous cancers group and the solitary esophageal carcinoma group. Squamous cell carcinoma of the esophagus and head and neck cancers are associated in 12% to 17% of cases.9,10 The risk varies with the anatomic location of the neck cancer, with an increased incidence in patients with cancer of the oral cavity and hypopharynx.11,12 The concept of “field cancerization,” originally forwarded by Slaughter et al13 to explain the high local recurrence rate of oral cancers, also seems to explain the high rate of multiple synchronous and metachronous carcinomas of the upper aerodigestive digestive tract.14,15 There may be a panmucosal disease of the aerodigestive tract in which heavy use of tobacco and alcohol have a regional carcinogenic effect.3
THE AMERICAN JOURNAL OF SURGERY® VOLUME 178 SEPTEMBER 1999
253
LONG-TERM RESULTS AFTER ESOPHAGECTOMY/WIND ET AL
TABLE IV Univariate and Multivariate Overall Survival Analysis of 75 Patients with an Esophageal Carcinoma Prognosis Factors Group Depth invasion ⬍pT3 Depth invasion pT3 N stage: pN⫺ N stage: pN⫹
Group
5-Year Survival (%)
Univariate Analysis P
Multivariate Analysis P
Solitary Synchronous Solitary Synchronous Solitary Synchronous Solitary Synchronous Solitary Synchronous
14.3 ⫾ 5.7 17.5 ⫾ 7.9 32 ⫾ 11.5 27.5 ⫾ 11.6 0 0 20.9 ⫾ 8 31.2 ⫾ 14.8 0 7.1 ⫾ 6.9
0.8660
0.4375
0.0002
0.0019
0.0373
0.3408
In the current study, patients with synchronous cancers were younger than those with solitary esophageal carcinoma. The explanation could be a particular genetic susceptibility to multiple cancers,16 increased exposure to carcinogenic factors, or earlier diagnosis of the esophageal carcinoma owing to routine panendoscopy in patients with head and neck cancer.5 The location of the esophageal cancer in patients with multiple carcinomas was similar to that in patients with solitary esophageal carcinoma, confirming the findings of other studies.12,17 As report by others,17,18 patients with synchronous multiple cancers were more likely to have esophageal cancer limited to the esophageal wall, but the difference was not statistically significant in our study. The rate of lymph node involvement in the two groups must be analyzed cautiously, as different surgical procedures were used for esophagectomy. Moreover, some patients in the synchronous group underwent cervical lymph node dissection at the time of head and neck cancer surgery. As a result, cervical lymph node metastases could not be accurately attributed to the esophageal or head and neck cancer. The grim prognosis of double primary esophageal and head and neck carcinomas and their anatomic proximity19 –21 often limit the therapeutic possibilities for both cancers.22 As a result, esophageal resection is probably considered less often than for solitary tumors. In this study, except for total esopharyngolaryngectomy when required, we aimed to use the same therapeutic approach for each lesion as that used for single distinctive primary lesions. Esophagectomy was delayed to avoid an extensive surgical procedure for two cancers in adjacent sites. Theoretically, the radical therapy previously applied to the head and neck cancer may also obviate further treatment. Cervical dissection is rendered difficult after previous cervical incision or cervical radiation therapy. Anastomotic leakage and recurrent nerve paralysis rates are potentially increased. Precarious phonation or swallowing function after conservative laryngeal surgery may be worsened by esophageal surgery involving recurrent cervical incision. All these factors increase pulmonary complications, which in turn increase mortality and morbidity after oesophagectomy.23 In addition, the esophageal tumor may progress during head and neck cancer therapy. In the interval, neoadjuvant chemoradiation therapy can be undertaken, but a recent study24 suggested that it did not improve overall survival, while 254
increasing mortality after esophagectomy. Esophageal resection as first-step therapy carries similar disadvantages, because esophagectomy has its own complications25 that can also compromise or delay the treatment of the head and neck cancer. Moreover, esophagectomy is impossible when the head and neck cancer causes airway obstruction. In this study the initial head and neck cancer treatment allowed us to conduct esophagectomy in selected patients who had potentially been cured, and to reduce the influence of the head and neck cancer treatment on esophagectomy. The interval between the treatment of each cancer depended on the modalities of the head and neck cancer therapy. This interval also allowed for an improvement in the patient’s general condition (including tobacco and alcohol withdrawal) before esophagectomy. The mortality and pulmonary morbidity rates after esophagectomy in patients with synchronous tumors were similar to those in patients with solitary esophageal carcinoma. The only complication that occurred more frequently was cervical anastomotic leakage in the synchronous group, probably resulting from recent cervical incision or cervical radiation therapy. This complication delayed oral feeding but did not affect the length of the hospital stay. For tumors arising in the middle or lower thoracic esophagus, intrathoracic anastomosis avoids repeated cervical incision and reduces the interval between the treatment of the two cancers. Esophagectomy for squamous cell carcinoma of the esophagus gives a 15% to 25% 5-year survival rate,1,26 the main prognostic factors being tumor penetration in the esophageal wall and lymph node involvement.27,28 In this study, 5-year survival rates were similar in the two groups. Nevertheless, two restrictions must be taken into account. First, all patients in the synchronous group received neoadjuvant chemotherapy for their head and neck cancer, although this is known to have no impact on survival after esophageal cancer resection.29,30 Secondly, although the difference was not statistically significant, the synchronous group comprised more patients with tumors limited to the esophageal wall. However, among the prognostic factors studied in multivariate analysis, the simultaneous presence of a head and neck tumor did not affect survival. Therefore, despite the high rate of cervical anastomotic leakage, esophagectomy is feasible in patients with synchronous tumors, with acceptable mortality and long-term outcome.
THE AMERICAN JOURNAL OF SURGERY® VOLUME 178 SEPTEMBER 1999
LONG-TERM RESULTS AFTER ESOPHAGECTOMY/WIND ET AL
REFERENCES 1. Mu¨ller JM, Erasmi H, Stelzner M, et al. Surgical therapy of esophageal carcinoma. Br J Surg. 1990;77:845– 857. 2. Munoz N. Epidemiological aspects of oesophageal cancer. Endoscopy. 1993;25:609 – 612. 3. Wynder E, Mushinski M, Spivak J. Tobacco and alcohol consumption in relation to development of multiple primary cancers. Cancer. 1977;40:1872–1878. 4. Choy A, Hasselt CAV, Chisholm EM, et al. Multiple primary cancers in Hong Kong chinese patients with squamous cell cancer of the head or neck. Cancer. 1992;70:815– 820. 5. Ina H, Shibuya H, Ohashi I, Kitagawa M. The frequency of a concomitant early esophageal cancer in male patients with oral or oropharyngeal cancer. Cancer. 1994;73:2038 –2041. 6. Day GL, Blot WJ. Second primary tumors in patients with oral cancer. Cancer. 1992;70:14 –19. 7. Tachimori Y, Watanabe H, Kato H, et al. Treatment for synchronous and metachronous carcinomas of the head and neck and esophagus. J Surg Oncol. 1990;45:43– 45. 8. Gluckman JL, Crissman JD. Survival rates in 548 patients with multiple neoplasms of the upper aerodigestive tract. Laryngoscope. 1983;93:71–74. 9. Fogel T, Harrison L, Son Y. Subsequent upper aerodigestive malignancies following treatement of esophageal cancer. Cancer. 1985;55:1882–1885. 10. Hoar S, Wilson J, Blot W, et al. Second cancer following cancer of the digestive system in Connecticut, 1935–1982. Natl Cancer Inst Monograph. 1985;68:49 – 82. 11. Tepperman B, Fitzpatrick P. Second respiratory and upper digestive tract cancers after oral cancer. Lancet. 1981;12:547–549. 12. Shibuya H, Wakita T, Nakagawa T, et al. The relation between an esophageal cancer and associated cancers in adjacent organs. Cancer. 1995;76:101–105. 13. Slaughter D, Southwick H, Smejkal W. “Field cancerization” in oral stratified squamous epithelium. Cancer. 1953;6:963–968. 14. Shibuya H, Hisamitsu S, Shioiri S, et al. Multiple primary cancer risk in patients with squamous cell carcinoma of the oral cavity. Cancer. 1987;60:3083–3086. 15. Guirt FM, Matthews B, Koufman J. Multiple simultaneous tumors in patients with head and neck cancer. Cancer. 1982;50: 1195–1199. 16. Yokoyama A, Muramatsu T, Ohmori T, et al. Multiple primary esophageal and concurrent upper aerodigestive tract cancer and the
aldehyde dehydrogenase-2 of Japanese alcoholics. Cancer. 1996;77: 1986 –1990. 17. Takiyama W, Moriwaki S, Mandai K, Takashima S. Relationship of esophageal dysplasia to associated head and neck cancer in patients with esophageal carcinoma. Jpn J Oncol. 1996;26:12–17. 18. Shiozaki H, Tahara H, Kobayaschi K, et al. Endoscopic screening of early esophageal cancer with the lugol dye method in patients with head and neck cancers. Cancer. 1990;66:2068 –2071. 19. Asamura H, Kato H, Watanabe H, et al. Combined gastric pull-up and microvascular jejunal transfer procedure after pharyngolaryngoesophagectomy. Ann Thorac Surg. 1989;48:423– 425. 20. Sun K, Matsubara T, Ueda M. Surgical treatment for primary esophageal cancer developing after pharyngolaryngectomy for head and neck cancer. Surgery. 1997;122:15–19. 21. Yoshino K, Endo M, Nara S, Ishikawa N. Surgery for synchronous double cancer in the hypopharynx and thoracic esophagus. Hepato-gastroenterology. 1995;42:275–278. 22. Panosetti E, Luboinski B, Mamelle G, Richard JM. Multiple synchronous and metachronous cancers of the upper aerodigestive tract: a nine year study. Laryngoscope. 1989;99:1267–1273. 23. Tsutsui S, Moriguchi S, Morita M, et al. Multivariate analysis of postoperative complications after esophageal resection. Ann Thorac Surg. 1992;53:1052–1056. 24. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous cell cancer of the esophagus. NEJM. 1997;337:161–167. 25. Law S, Fok M, Wong J. Risk analysis in resection of squamous cell carcinoma of the esophagus. World J Surg. 1994;18:339 –346. 26. Watson A. Operable esophageal cancer: current results from the west. World J Surg. 1994;18:361–366. 27. Killinger WA, Rice TW, Adelstein DJ, et al. Stage II esophageal carcinoma: the significance of T and N. J Thorac Cardiovasc Surg. 1996;111:935–940. 28. Ide H, Nakamura T, Hayashi K, et al. Esophageal squamous cell carcinoma: pathology and prognosis. World J Surg. 1994;18:321– 330. 29. Roth JA, Pass HI, Flanagan MM, et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg. 1988;96:242–248. 30. Schlag P. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. Arch Surg. 1992;127: 1446 –1450.
THE AMERICAN JOURNAL OF SURGERY® VOLUME 178 SEPTEMBER 1999
255