Survival impact of pulmonary metastasectomy for patients with head and neck cancer

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1 ORIGINAL ARTICLE Survival impact of pulmonary metastasectomy for patients with head and neck cancer Takuya Miyazaki, MD, Yasuhisa Hasegawa, MD,* Nobuhiro Hanai, MD, Taijirou Ozawa, MD, Hitoshi Hirakawa, MD, Atsushi Suzuki, MD, Hiroki Okamoto, MD, Ikuma Harata, MD Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Chikusa-ku, Nagoya, Aichi, Japan. Accepted 26 November 2012 Published online 6 March 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to evaluate the survival impact and prognostic factors of pulmonary metastasectomy in patients with pulmonary metastasis from head and neck cancer. Methods. A retrospective study of 69 patients was analyzed. Twentyfour patients (35%) underwent pulmonary metastasectomy, and the remaining 45 patients (65%) were treated with chemotherapy or best supportive care. Results. The 1-year overall survival (OS) of 69 patients was 28%. Pulmonary metastasectomy (p ¼.01) and histology (p <.001) had a significant impact on the prognosis. One-year OS of patients who underwent metastasectomy and those who did not was 90% and 35%, respectively. In the metastasectomy group, recurrence of primary ahead of lung metastasis (p ¼.006) and disease-free interval (DFI; 21.4 months; p ¼.046) were significant negative prognostic factors. Conclusion. Pulmonary metastasectomy has an impact on survival in carefully selected patients, especially for those with a long DFI and with no recurrence of primary cancer ahead of lung metastasis. VC 2013 Wiley Periodicals, Inc. Head Neck 35: , 2013 KEY WORDS: head and neck cancer, pulmonary metastasis, surgical treatment prognostic factors INTRODUCTION As local and regional control of head and neck cancer has improved in chemotherapy, radiotherapy, and surgery, distant control has become increasingly important for patients with prolonged survival and follow-up. The lung is a major site of distant metastasis. The incidence of pulmonary metastases in these patients is reported to range from 6.5% to 16.8%. 1 5 The pulmonary metastases are generally treated with chemotherapy, which is toxic, and long-term results are poor. 6 8 One of the theoretical bases of local treatment, such as surgical resection, for metastatic malignancy is the "cascade-spreading process posited by Viadana et al. 9 Even with hematogenous metastasis, there may be a presystemic stage, that is, tumor spread is still limited to the "key-site organs (ie, lung). 10 Fair results after hepatic or pulmonary metastasectomy might be consistent with this cascade hypothesis. Although pulmonary resection has become the standard therapy for a variety of metastatic malignancies to the lungs, 11,12 few reports are available on the role of pulmonary metastasectomy for patients with head and neck cancer. The purpose of this study was to evaluate the survival impact of surgical resection of pulmonary metastases for patients with head and neck cancer. Furthermore, we *Corresponding author: Y. Hasegawa, 1-1 Kanokoden, Chikusa-ku Nagoya , Aichi, Japan. hasegawa@aichi-cc.jp attempted to characterize the prognostic factors for improved survival among patients with head and neck cancer treated with pulmonary metastasectomy. MATERIALS AND METHODS Patients From January 1999 through December 2009, 2100 patients with head and neck cancers were seen at the Aichi Cancer Center Hospital. Ninety-three of these patients (4.4%) were considered to have developed pulmonary metastases in the course of their follow-up. All the patients in this study had received treatment for the primary tumor in our hospital. The initial treatment for the patients in the hope of preserving the form and function of the organ was 2 cycles of induction chemotherapy consisting of cisplatin (80 mg/m 2 /day) on day 5 and 5-fluorouracil (800 mg/m 2 /day) on days 1 to 4 were performed, and then we evaluated the response. For patients who achieved a response to induction chemotherapy, definitive concurrent chemoradiotherapy (CRT) was then performed. CRT consisted of a radiation dose of 66 to 70 Gy plus cisplatin (30 mg/m 2 /day) given weekly for 5 to 7 cycles during radiotherapy. On the other hand, for patients who experienced no response to induction chemotherapy, surgery was performed. In either treatment group, adjuvant chemotherapy was not carried out. In the clinical course after initial treatment, patients who had resectable local recurrent disease underwent salvage surgery, and patients under control for recurrent lesions did HEAD & NECK DOI /HED DECEMBER

2 MIYAZAKI ET AL. TABLE 1. Characteristics of all 69 patients and results of univariate analysis. Characteristics No. of patients (%) 1-year survival rate, % 3-year survival rate, % p value Age, y.098 Median ¼ (48) > Median ¼ (52) Sex.264 Male 56 (81) Female 13 (19) Primary tumor site Hypopharynx 23 (33) 53 7 Oral cavity 16 (23) 25 8 Salivary gland 10 (16) Larynx 7 (10) 53 0 Oropharynx 7 (10) Maxillary sinus 4 (6) Nasopharynx 1 (1) External ear 1 (1) 0 0 Histology <.001 SCC 57 (83) Other 12 (17) Adenoid cystic carcinoma 6 (9) Salivary duct carcinoma 2 (3) Acinic cell carcinoma 1 (1) Adenocarcinoma 1 (1) Carcinoma expleomorphic adenoma 1 (1) Malignant fibrous histiocytoma 1 (1) T classification*.821 T1/2 19 (27) T3/4 50 (73) N classification*.041 N0 34 (49) N1/2/3 35 (51) Initial treatment Ope 31 (45) IC and ope 16 (23) CRT 16 (23) IC and CRT 6 (9) Pulmonary metastasectomy <.001 Yes 24 (35) No 45 (65) Location of metastases.065 Unilateral 36 (52) Bilateral 33 (48) No. of metastases.029 Solitary (n ¼ 1) 28 (40) Multiple (n 2) 41 (60) Abbreviations: SCC, squamous cell carcinoma; Ope, operation; IC, induction chemotherapy; CRT, chemoradiotherapy. * The TNM stage of head and neck primary tumor was determined using the Union Internationale Contre le Cancer 6th edition. not generally received adjuvant chemotherapy. There were a total of 69 patients who met the following inclusion criteria: (1) primary carcinoma of the head and neck; (2) initial stage of no distant metastases; (3) pulmonary metastasis; and (4) no sign of extrapulmonary metastases at the time of diagnosis of pulmonary metastasis. Treatment Patients who met the following criteria were considered to have undergone resection of their pulmonary metastases: (1) pulmonary lesions were deemed completely resectable; (2) metastatic disease was limited to the lungs; (3) locoregional control of their head and neck primary cancer was obtained; and (4) the patient s general condition was good enough to withstand surgery. The surgical method depends upon characteristics of the metastases including their location, number, and size on CT. Lymph node dissection was not routinely performed and depended on the clinical judgment of individual clinicians. On the other hand, patients who did not meet these criteria were treated with chemotherapy or best supportive care. We generally used platinum-based chemotherapy, cisplatin (80 mg/m 2 /day) on day 5 and 5- fluorouracil (800 mg/m 2 /day) on days 1 to 4. Patients who were refractory or not tolerant of platinum were treated with fluoropyrimidine drugs, S-1 (80 mg/m 2 /day) for a 2-week application followed by a 1-week rest regimen, or taxane-based drugs, docetaxel (60 mg/m 2 /day) on day HEAD & NECK DOI /HED DECEMBER 2013

3 PULMONARY METASTASIS IN HEAD AND NECK CANCER TABLE 2. Multivariate analysis of factors influencing survival of all 69 patients. Characteristics HR 95% CI p value Pulmonary metastasectomy No/yes <.001 Primary tumor histology SCC/other <.001 N classification N0/N1/2/ No. of metastases Solitary (n ¼ 1)/ multiple (n 2) Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval; SCC, squamous cell carcinoma. Data collection For every patient, we collected data on age, sex, primary tumor histopathology, primary site, clinical stage, treatment initiation date, modality of initial treatment, and the characteristics of metastases (number and location). Furthermore, for patients with metastasectomy, the following information was recorded: recurrence of primary tumors before detection of the lung metastasis, the interval between primary treatment and the diagnosis of pulmonary metastases (disease-free interval [DFI]), the interval between the time of locoregional control treatment and the diagnosis of pulmonary metastases, which we defined as the absolute DFI, and the size of pulmonary metastasis lesion. Details were also obtained on metastasectomy (surgical approach, extent of resection, hospital stay, and postoperative complication), and site of recurrence after initial thoracotomy. Statistical analysis Overall survival (OS) was calculated from the time of diagnosing pulmonary metastases to the time of death from any cause, or to time of last follow-up. Survival curves were constructed using the Kaplan Meier method. To evaluate the impact of each factor on OS, univariate and multivariate Cox proportional hazard modeling was applied. The multivariate analysis was used and we considered those variables that attained statistical significance in the univariate analysis. Therefore, the measure of association in this study was the hazard ratio along with the 95% confidence interval. Moreover, the categorical data between the metastasectomy and nonmetastasectomy group were analyzed by the chi-square test. Statistical analyses were performed using the SPSS statistical software package, version 11 (SPSS, Chicago, IL) and a p value <.05 was considered statistically significant. RESULTS Patients and characteristics Between January 1999 and December 2009, there were 93 consecutive patients with the diagnosis of pulmonary metastases. Twenty-four patients were excluded from this analysis for the following reasons: thyroid carcinoma (n ¼ 10), skin carcinoma (n ¼ 1), primary lung cancer (n ¼ 2), suspected for primary lung malignancy in the pathology results of patients who underwent surgery (n ¼ 2), initial stage M1 (n ¼ 3), and with extrapulmonary metastases at the time of diagnosis of metastases to the lung (n ¼ 6). Thus, a total of 69 patients were analyzed in this study. The patient characteristics are summarized in Table 1 and 2. In the above-mentioned criteria, 24 patients underwent resection of pulmonary metastases, 41 patients were treated with systemic chemotherapy, and 4 patients were treated with best supportive care. The patients background factors between the metastasectomy and nonmetastasectomy group are summarized in Table 3. Survival The median follow-up time from the diagnosis of pulmonary metastases to the time of death from any cause, or the time of last follow-up, was 12 months (range, months). The 1-year OS rate of 69 patients was 54%. Table 1 shows the univariate and multivariate analyses for each prognostic factor in all 69 patients. From multivariate analysis, surgical resection (p ¼.01) and histology (p <.001) were found to have a significant impact on prognosis. In the metastasectomy group, the 1-year and 3-year OS rate of 24 patients was 90% and 68%, respectively. Furthermore, the 1-year and 3-year progression-free survival rate was 85% and 63%, respectively (Fig 1.). In the nonmetastasectomy group, the 1-year and 3-year OS rate of 45 patients was 35% and 15%, respectively. Metastasectomy experience Twenty-four patients underwent resection of pulmonary metastases. The patient characteristics are summarized in Table 3. Eight patients (33%) had a locoregional recurrence before detection of the lung metastasis. All the recurrent lesions were resected completely and were well controlled until diagnosis of pulmonary metastases. Median DFI was 24.6 months and median absolute DFI was 21.4 months. Open thoracotomies were performed in 16 cases (64%), and video-assisted thoracoscopic surgery was performed in 9 cases (36%). Twenty-two patients (92%) with unilateral tumors underwent a unilateral thoracotomy for resection of their metastases, whereas the remaining 2 patients (8%) had a bilateral thoracotomy. One patient underwent simultaneous bilateral thoracotomy and the other patient had a staged bilateral thoracotomy for bilateral lesions. The extent of resection was wedge resection in 14 patients (56%), segmental resection in 3 patients (12%), and lobectomy in 8 patients (32%). Complete resection of metastatic tumor in the lung was achieved in 22 patients (22%). Lymph node dissection was not routinely performed and depended on the clinical judgment of individual clinicians. Table 4 shows the univariate and multivariate analyses for each prognostic factor. By univariate analysis, recurrence of primary ahead of lung metastasis (p ¼.006) and DFI (p ¼.046) had a significant impact on prognosis. By multivariate analysis, there was no significant prognostic factor. There was no postoperative mortality. Mean hospital stay was 11.2 days (range, 6 32 days). Complications occurred in 3 cases (12%); 1 patient had pulmonary atelectasis, another had marginal residual lung capacity, and HEAD & NECK DOI /HED DECEMBER

4 MIYAZAKI ET AL. TABLE 3. Background characteristics of patients between metastasectomy (n 5 24) and nonmetastasectomy group (n 5 45). No. of patients (%) Characteristics Metastasectomy Nonmetastasectomy p value Age, y.676 Median ¼ (85) 23 (51) > Median ¼ (15) 22 (49) Sex.325 Male 21 (88) 35 (78) Female 3 (12) 10 (22) Primary tumor site.150 Hypopharynx 6 (24) 17 (38) Oral cavity 4 (17) 12 (27) Salivary gland 2 (8) 8 (18) Larynx 3 (13) 4 (9) Oropharynx 4 (17) 3 (6) Maxillary 3 (13) 1 (2) Nasopharynx 1 (4) 0 (0) External ear 1 (4) 0 (0) Histology.907 SCC 20 (83) 37 (82) Other 4 (17) 8 (18) T classification.017 T1/2 10 (42) 9 (20) T3/4 14 (58) 36 (80) N classification.022 N0 16 (67) 17 (38) N1/2/3 8 (33) 28 (62) Initial treatment.031 Ope 8 (33) 23 (51) CRT 3 (13) 13 (29) IC þ ope 4 (17) 2 (4) IC þ CRT 9 (37) 7 (16) DFI, mo Median Range Location of metastases <.001 Unilateral 22 (92) 14 (31) Bilateral 2 (8) 31 (69) No. of metastases <.001 n ¼ 1 19 (79) 9 (20) n 2 5 (21) 36 (80) Abbreviations: SCC, squamous cell carcinoma; Ope, operation; CRT, chemoradiotherapy; IC, induction chemotherapy; DFI, disease-free interval. the third patient needed drainage for 2 weeks because of prolonged air leakage. The median time at follow-up examination was 19.9 months (range, months). Eleven patients (46%) are alive without evidence of disease after their first thoracic operation, and 12 patients developed recurrences, the majority of which were located in the lung (Table 5). The median time to recurrence after initial pulmonary resection was 9.8 months (range, months). Two of five patients with pulmonary recurrence could undergo resection. Because the remaining 3 patients had multiple pulmonary metastases and intrathoracic dissemination, they received palliative treatment. Eight patients (33%) died of disease and 1 patient (4%) died of other causes. DISCUSSION With the improved efficacy of local tumor management in head and neck carcinoma, pulmonary metastases have become an increasingly common problem. Chemotherapy was used to treat for patients with distant metastases, but the results are quite poor. 6 8 Pulmonary metastasectomy is thought to be the standard treatment for other malignant tumors, and a few retrospective studies have demonstrated that the pulmonary metastasectomy in properly selected patients with head and neck cancer with pulmonary metastasis was significantly associated with survival. 2,13 17 However, owing to the small number of previous studies, the prognostic impact of surgery for pulmonary metastasis has not been thoroughly examined in patients with head and neck cancer. Thus, this study was conducted to examine this issue. Furthermore, we clarified the prognostic factor for improved survival among patients with head and neck cancer treated with pulmonary metastasectomy. Histology In our study, for all 69 patients, the histology was significantly associated with survival by multivariate 1748 HEAD & NECK DOI /HED DECEMBER 2013

5 PULMONARY METASTASIS IN HEAD AND NECK CANCER Thus, if the patient had an intervening locoregional recurrence before pulmonary resection, careful assessment of the indication for surgical treatment is necessary. In addition, 6 of 8 patients (75%) who had local recurrence before their pulmonary metastasis was detected, most often had distant metastasis after pulmonary resection, so adjuvant systemic chemotherapy after pulmonary resection might help prolong survival. FIGURE 1. Overall and progression-free survival of patients after metastasectomy (n ¼ 24). analysis (p ¼.001) (Table 2.). These results coincided with the previous reports. However, small numbers in the nonsquamous cell group may affect this outcome, and so it is necessary to interpret these results with caution. For the patients treated with pulmonary metastasectomy, histology had a trend toward statistical significance predictor of survival in univariate analysis (p ¼.119). Pulmonary metastasectomy In the group of patients who underwent metastasectomy, our results are compatible with those of previous studies. 2,13 19 Pulmonary metastasectomy was one of the strong predictive factors of survival in our study (Table 2.). So far, the prognostic factors in patients who underwent surgical resection remain unclear. Because of this dominant difference, further analyses were performed. Recurrence of primary cancer ahead of lung metastasis Eight patients had intervening locoregional recurrence before pulmonary resection. All the recurrent lesions were resected completely and were well controlled at the time of diagnosis of pulmonary metastasis. Chen et al 17 reported that locoregional recurrence of the primary disease before lung metastasectomy did not affect survival, and no reports identified locoregional control of the head and neck primary tumor as an important prognostic factor. In our study, the recurrence of primary cancer ahead of lung metastasis was independently associated with survival (p ¼.006). The 1-year and 3-year survival rate of patients who had no recurrence of primary disease ahead of lung metastasis were 100% and 84%, respectively. Whereas the 1-year and 3-year survival rate of patients who had recurrence were 75% and 37%, respectively. To our knowledge, our study is the first to report factors significantly associated with a poor prognosis according to recurrence of primary cancer ahead of lung metastasis. It might reflect aggressive and invasive biological behavior. Disease-free interval and absolute disease-free interval In most studies, the DFI is defined as the interval between primary treatment and the diagnosis of pulmonary metastases. 2,13,14,18 However, DFI should decrease in patients who had a local recurrence before pulmonary metastasis. Therefore, for patients who had locoregional recurrence of the primary disease before lung metastasectomy, we measured the interval between the time of locoregional control treatment and the diagnosis of pulmonary metastases, which we defined as the absolute DFI and investigated it as a prognostic factor. With respect to DFI influencing the survival rate, the intervals differed among various studies, 2,13,14,18 after all, a short DFI is predictive of a negative outcome. In this study, the median DFI is the significant factor by the univariate analysis (p ¼.046) but not a significant difference by multivariable analysis (p ¼.318). The absolute median DFI tends to show a significant difference by univariate analysis (p ¼.056). We could not elucidate any causal relationship between DFI and poor prognosis, but this result implies that DFI has more significant influence on OS than absolute DFI. Number and location of pulmonary metastases According to most articles showing that the number of pulmonary metastases does not correlate with survival, 13 16,18,19 we also did not observe a statistically significant survival difference in patients with single or multiple pulmonary metastases. Also, we did not observe a significant relationship between patients with unilateral and bilateral metastases, in accord with previous reports. 13,19 However, the impact of the number and location of metastases is difficult to judge because, both in our study and in the previous reports, only a few patients with multiple and bilateral metastases underwent surgery. We recognize that our study has several limitations. First, it is possible that some of the solitary nodules in our study were in fact second primaries. Patients with head and neck cancer are at an increased risk for developing a second primary lung cancer with the reported incidence ranging from 4.5% to 6.9% Generally, the patient s clinical course, stage of primary sites, and radiologic findings, as well as pathological diagnosis were used to help the differential diagnosis of metastatic or the primary lung cancer. Especially with solitary lesions or squamous cell carcinoma, the differential diagnosis is often difficult. However, this does not change the clinical implication that a solitary lung lesion in a patient with a radically treated head and neck cancer is a potential candidate for resection therapy. 14,16 Second, there is a selection bias affecting pulmonary metastasectomy outcome HEAD & NECK DOI /HED DECEMBER

6 MIYAZAKI ET AL. TABLE 4. Characteristics of 24 patients with pulmonary metastasectomy and results of univariate and multivariate analyses. Characteristics No. of patients (%) 1-year survival rate, % 3-year survival rate, % Univariate p value Multivariate p value Age, y.182 Median ¼ (46) > Median ¼ (54) Sex.113 Male 21 (88) Female 3 (12) Primary tumor site Hypopharynx 6 (25) Oral cavity 4 (17) Oropharynx 4 (17) Larynx 3 (13) Maxillary sinus 3 (13) Salivary gland 2 (8) Nasopharynx 1 (4) External ear 1 (4) 0 0 Histology.119 SCC 20 (83) Other 4 (17) T classification.843 T1/2 10 (42) T3/4 14 (58) N classification.129 N0 16 (67) N1/2/3 8 (33) Initial treatment IC and ope 9 (37) Ope 8 (33) CRT 4 (17) IC and CRT 3 (13) Recurrence of primary cancer ahead of lung metastasis Yes 8 (33) No 16 (67) Lung metastases DFI, mo Median ¼ (47) > Median ¼ (53) Absolute DFI, mo.056 Median ¼ (53) > Median ¼ (47) Location of metastases.319 Unilateral 22 (92) Bilateral 2 (8) No. of metastases.461 Single (n ¼ 1) 19 (79) Multiple (n 2) 5 (21) Largest size, mm.220 Median ¼ (54) > Median ¼ (46) Surgical exposure Wedge 13 (54) Segmental 8 (33) Lobectomy 8 (33) Type of exposure.849 VATS 8 (33) Other 16 (67) Completeness of resection.452 Complete 22 (92) Incomplete 2 (8) Lymph dissection.257 Yes 16 (67) No 8 (33) Abbreviations: SCC, squamous cell carcinoma; IC, induction chemotherapy; Ope, operation; CRT, chemoradiotherapy; DFI, disease-free interval; VATS, video-assisted thoracotomy surgery HEAD & NECK DOI /HED DECEMBER 2013

7 PULMONARY METASTASIS IN HEAD AND NECK CANCER TABLE 5. The details of clinical courses of 24 patients after initial metastasectomy. Location No evidence of recurrence 12 Locoregional recurrence 1 Distant metastasis Lung 5 Bone 4 Liver 1 Skin 1 No. of patients with site involved results. Candidates for pulmonary metastasectomy are strictly selected based on the aforementioned criteria. In our study, there were significant differences between the metastasectomy and nonmetastasectomy group for T classification, N classification, initial treatment, location, and number of metastases (Table 3). In this manner, these 2 groups are different. Therefore, the present study may be presenting relatively good survival rates. However, selection bias is unavoidable and is a difficult problem to resolve. A prospective randomized trial for pulmonary metastasis treatment is ethically difficult, and is not practical. Third, this study includes several types of histology both in the whole group and metastasectomy group; therefore, we need to take into account seemingly different biological characteristics. For example, adenoid cystic carcinoma is a rare tumor, known to be slow, their high propensity to distant metastases, and protracted course with multiple recurrences. Locati et al 24 reported that resection did not cure patients with pulmonary metastasis. Fourth, this is a single-institution retrospective study with a relatively small number of patients. A greater number of cases are necessary to evaluate a prognostic factor properly and to determine the selection criteria for resection. A prospective randomized trial that compares metastasectomy with no metastasectomy could give a definitive answer, but such a trial is ethically difficult and not practical. In conclusion, pulmonary metastasectomy has an impact on survival in properly selected patients even if there are multiple pulmonary lesions. Recurrence of primary cancer ahead of lung metastasis and shorter DFI were poor prognostic factors for pulmonary metastasectomy. Further studies of a large series are warranted to determine the proper selection of candidates for pulmonary resection. Acknowledgement The authors thank Motoo Nomura for consultation in statistical analyses and critical reading of the manuscript. REFERENCES 1. de Bree R, Deurloo EE, Snow GB, Leemans CR. Screening for distant metastases in patients with head and neck cancer. Laryngoscope 2000;110(3 Pt 1): Liu D, Labow DM, Dang N, et al. Pulmonary metastasectomy for head and neck cancers. Ann Surg Oncol 1999;6: J ackel MC, Rausch H. Distant metastasis of squamous epithelial carcinomas of the upper aerodigestive tract. The effect of clinical tumor parameters and course of illness. 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