Japanese Journal of Clinical Oncology Advance Access originally published online on November 7, 2005
Japanese Journal of Clinical Oncology 2005 35(11):633-638; doi:10.1093/jjco/hyi178
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© 2005 Foundation for Promotion of Cancer Research
Preoperative Chemotherapy and Radiation Therapy for Squamous Cell Carcinoma of the Maxillary Sinus
1 Department of Radiology and 2 Department of Head and Neck Surgery, Chiba University Hospital, Chiba, Japan
For reprints and all correspondence: Koichi Isobe, Department of Radiology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan. E-mail: isobeko{at}ho.chiba-u.ac.jp
Received July 10, 2005; accepted August 28, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: This study was undertaken to assess the prognostic factors for the management of squamous cell carcinoma (SCC) of the maxillary sinus, who received preoperative chemotherapy and radiation therapy (RT). We also elucidated the appropriate sequence of chemotherapy.
Methods: A total of 124 patients (median age 62 years) with SCC of the maxillary sinus were analysed retrospectively. T3 or T4 disease was found in 93% of the patients. Thirty-nine patients received neoadjuvant chemotherapy (NA), 38 patients received concurrent chemoradiotherapy (CRT) and 47 patients received NA followed by CRT. The median dose of RT was 60 Gy. Maxillectomy was undertaken in 98 patients.
Results: The 5 year overall survival (OAS) and local control probability (LCP) were 56.6 and 73.7%, respectively. On univariate analysis, surgery (P < 0.0001) and T classification (P < 0.04) were significant prognostic factors for OAS and LCP. Histological grade and nodal status were also related to OAS. However, any chemotherapy sequence was not associated with the treatment outcome. On multivariate analysis, surgery (P < 0.0005) and T classification (P < 0.05) were identified as significant prognostic factors for LCP and OAS.
Conclusions: This study suggests that both surgery and T stage are important prognostic factors for LCP and OAS in the management of SCC of the maxillary sinus. The appropriate sequence of chemotherapy remains to be elucidated in the future study.
Key Words: maxillary sinus carcinoma • SCC • chemotherapy • radiation therapy • prognostic factor
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Malignancies of the maxillary sinus are relatively rare neoplasms, which are often reported along with nasal sinus and other paranasal sinus carcinomas. In 2001, 249 patients succumbed to paranasal sinus carcinomas, which accounted for 0.08% of all cancer deaths in Japan (1). This small incidence and the variety of histological subtypes have obstructed the confirmation of optimal treatment strategies in randomized controlled trials.
Surgery alone can produce a high local control rate in a limited number of patients with early stage disease. However, few patients have benefited from this procedure, because most patients are usually diagnosed at advanced stages. The combination of surgery and post-operative radiation therapy (RT) is the treatment of choice for patients with more advanced but resectable disease. Definitive RT is recommended only for patients who are medically unfit for surgery, refuse radical operation or have unresectable advanced disease (2).
In 1970, Sato and co-workers (3) reported a promising treatment outcome with a combination of necrotomy and RT concurrent with intra-arterial chemotherapy, for preventing cosmetic and functional loss. This treatment strategy with some modifications has been widely accepted since then in Japan (4–8). However, some investigators have advocated more aggressive strategies with a combination of partial or total maxillectomy, RT and chemotherapy by the introduction of new chemotherapeutic agents and the advances in surgical and radiotherapeutic techniques (9–11).
We have administered neoadjuvant chemotherapy (NA) and/or concurrent chemoradiotherapy (CRT) in combination with preoperative RT for patients with maxillary sinus carcinoma since 1983. Several groups have reported the effect of NA in small pilot studies with promising outcome (12–16). Thus, we herein report the efficacy of preoperative chemotherapy and RT in a large number of patients with squamous cell carcinoma (SCC) of the maxillary sinus. We also attempt to identify possible prognostic factors in the management of SCC of the maxillary sinus.
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PATIENTS AND METHODS |
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PATIENT CHARACTERISTICS
Between May 1983 and December 2002, 167 patients with maxillary sinus carcinoma received RT at our institution. Of these 167 patients, 36 were excluded from the present analysis for the following reasons: recurrent case (n = 8), palliative intent or patient refusal for curative treatment (n = 12), histological type other than SCC (n = 10), previous or concurrent history of other malignancies (n = 4), and distant metastasis at presentation (n = 2). Seven patients who received neither NA nor CRT were also excluded from the study to make the analysis clearly. The remaining 124 patients were the subjects of this retrospective analysis. The median follow-up was 46.4 months (range 1.6 months to 19.6 years), and that of the surviving patients was 8.3 years.
There were 96 males and 28 females, of ages ranging from 30 to 82 years, with a median of 62 years. All patients had a histopathological diagnosis of SCC. Although the histological grade was not recorded in 26 patients (21%), 36 had well differentiated (29%), 37 had moderately differentiated (30%) and 25 had poorly or undifferentiated (20%) histological subtypes. All patients were reclassified according to the 1997 American Joint Committee on Cancer (AJCC) staging system (17). Using these criteria, no patients had T1 disease, and 9, 53 and 62 patients had T2, T3 and T4 lesions, respectively. Of the 62 patients with T4 disease, 49 (79%) showed tumor invasion into orbital contents, which was the most common T4 factor. Twenty-one patients (17%) showed cervical lymph node involvement at presentation (Table 1).
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TREATMENT
During the study period, the institutional treatment strategy was combined modality therapy that consisted of NA, and preoperative CRT followed by partial or total maxillectomy with or without orbital exenteration. Those who refused surgery, had unresectable disease with intracranial invasion, or were medically unfit for surgery were scheduled to receive curative RT. Twenty-six patients did not receive maxillectomy, and the remaining 98 subjects underwent surgery following RT. Partial maxillectomy was performed in 11 patients, total maxillectomy in 56 and extended maxillectomy in 31. Total maxillectomy implied en bloc resection of entire maxilla and ethmoid sinus. Extended maxillectomy further expanded extent of resection to include eye ball, pterygoid plates and musculature, the mandibular condyle, the coronoid process, or facial muscles as required. Partial maxillectomy was less aggressive surgery than total maxillectomy. Of 62 patients with T4 disease, 46 (74%) received surgery, and 52 (84%) of 62 patients with less advanced disease underwent surgery. Seventeen patients received orbital exenteration. Surgical intervention for cervical nodes was performed in 16 patients. Surgical margin was positive or close in eight patients.
NA was administered in 39 patients and CRT in 38. Both NA and CRT were delivered in 47 patients. NA consisted of a combination of 75–100 mg of cisplatin (CDDP) and 5 days bolus injection of 5 mg/day of peplomycin (PEP) was administered in 46 patients. Forty patients received a same dose of CDDP and 5 days continuous infusion of 1000–1500 mg/day of 5-fluorouracil (5-FU). Patients received NA with a median of two cycles. All but two patients received 250 mg of daily 5-FU in a concurrent setting. The cumulative median dose of each agent was as follows: 175 mg of CDDP (range 60–450 mg), 7500 mg of 5-FU (range 750–30 000 mg) and 50 mg of PEP (range 7.5–110 mg). The decision regarding whether chemotherapy would be administered solely depended on the discretion of treating physician.
All patients received RT with a combination of 4 and 10 MV photons to achieve dose homogeneity. An appropriate energy of electron field was also applied to treat tumor behind the lens block in the photon field. With the intention to preserve normal tissue structure to the utmost, an anterior and ipsilateral wedge-pair technique was used in 89 patients (72%), and an anterior and tilted ipsilateral wedge-pair technique in 27. In this series, 119 patients received RT with a daily dose of 2 Gy, and a median tumor dose was 60 Gy (range 26–76 Gy). Accelerated hyperfractionation with a fraction size of 1.6 Gy was applied in the remaining five patients (Table 2).
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Overall survival (OAS), disease-free survival (DFS) and local control probability (LCP) were calculated from the day when we initiated treatment using the method of Kaplan and Meier (18). The log-rank test was used to assess the significance in univariate analysis. The Cox proportional hazards model was used to assess the significance in multivariate analysis (19).
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RESULTS |
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PATTERNS OF FAILURE AND SURVIVAL RATES
The 2 year OAS, DFS and LCP for all patients were 66.2, 56.3 and 73.7%, respectively. The corresponding figures at 5 years were 56.6, 52.0 and 73.7%, respectively (Fig. 1). At the time of analysis, 59 patients were alive without evidence of disease, and 56 relapses were observed in 54 patients. Of these 56 relapses, 30 were local persistent or recurrent disease, 9 were regional recurrence and 17 were distant metastasis. The median time to recurrence was 8.6 months. The metastatic sites included the lung, bone, liver, contralateral maxillary sinus, brain and skin. Three patients who experienced recurrence were successfully salvaged by a second operation. There were 65 deaths during the study period, 46 as a result of persistent or recurrent tumor. Six patients died of treatment related complications (post-operative problems in three patients, RT induced brain necrosis in two patients and adverse event of non-steroidal anti-inflammatory drug for acute radiation stomatitis in one patient). Of the remaining 13 patients, 10 were deceased from intercurrent disease, 2 from second malignancies (lung cancer and gastric cancer) and the cause of death was unknown in 1 patient.
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EFFECT OF SEQUENCE OF CHEMOTHERAPY AND PROGNOSTIC FACTORS
We divided 124 patients into three groups to explore the effect of sequence of chemotherapy and possible prognostic factors. The three groups consisted of 39 patients who received NA, 38 patients who received CRT and 47 patients who received both NA and CRT (NA + CRT). The patient characteristics and treatment factors associated with sequence of chemotherapy were shown in Table 3. The age distribution and total dose of RT was different between groups. The OAS, DFS and LCP as a function of sequence of chemotherapy were shown in Fig. 2. The OAS was not different between groups, however, DFS and LCP showed favorable trend in NA + CRT (P = 0.08). Furthermore, both DFS and LCP in NA + CRT were better than those in NA with statistical significance (P = 0.047 and 0.036). There was no difference in DFS and LCP between CRT and NA + CRT, and between NA and CRT.
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Then, we performed univariate analysis using the log-rank test to identify other potential prognostic factors for OAS, DFS and LCP. The variables examined for significance included patient age (<60 versus
60 years), gender, T classification (T2 and T3 versus T4), N classification (N0 versus others), histological grade (well differentiated versus others), use of surgery, cumulative dose of 5-FU (<4500 versus 4500 mg), total dose of RT (<60 versus 60 Gy) and treatment groups (NA versus CRT versus NA + CRT). Surgery was the most powerful statistically significant prognosticator for all three end points (P < 0.0001), followed by T classification. Histological grade and nodal status were also statistically significant factors for OAS and DFS. Age was marginally significant for OAS (P = 0.06), however, treatment group, total dose of RT and cumulative dose of 5-FU did not show any impact on outcomes (Table 4).
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Next, we used the Cox proportional hazards model to identify statistically significant prognostic factors in multivariate analysis. Surgery (P = 0.0004) and T classification (P = 0.0012) were significant predictors for OAS. Surgery (P < 0.0001), T classification (P = 0.0088) and nodal status (P = 0.0051) influenced DFS. Also again, surgery (P < 0.0001) and T classification (P = 0.044) were identified as prognostic factors for LCP (Table 5). The sequence of chemotherapy did not demonstrate any significant effect on all three end points again.
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TREATMENT SEQUELAE
The acute hematological toxicities were mild and well tolerated, however, more acute skin reaction and mucositis were seen in patients who received CRT than those who did not (data not shown). With regard to late sequelae, two patients developed Grade 4 brain necrosis. Grade 3 keratitis, retinopathy and optic neuropathy were observed in one patient each.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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As most maxillary sinus carcinomas do not develop regional or distant metastasis, appropriate treatment for controlling the primary tumor is crucial. However, the management of locally advanced disease is challenging despite the introduction of new chemotherapeutic agents and advances in RT and surgical technique. The survival after single modality treatment is generally disappointing. Amendola et al. (20) did not find a significant difference among patients who received definitive RT and those who were treated by surgery, with a 5 year survival rate of
30%. Two groups reported that a combination of surgery and RT yielded an 50% 5 year survival rate (21,22), one of which demonstrated a difference in DFS and LCP in favor of combined modality treatment over RT alone (22). In an attempt to improve LCP, the addition of chemotherapy to surgery and RT has been employed for several decades. CRT with intra-arterial 5-FU infusion is one of the most common schedules in Japan, and has obtained 5 year local control rates of between 58 and 74% (5–9,11), which are comparable to that of our current study. However, the finding that the irradiation dose, 5-FU dosages and extent of surgical resections were not uniform among these studies made it difficult to interpret these results.
Another strategy for improving treatment outcome is the incorporation of adjuvant and/or NA. Several groups have evaluated the efficacy of NA in the management of paranasal sinus carcinoma. These small pilot studies showed promising response rates, LCP and survival rates (12–16). However, the impact of NA in the management of SCC of the maxillary sinus remains to be determined, because these groups included only 29 patients with untreated or recurrent SCC of the maxillary sinus, and did not provide detailed individual patient data. This is the first and the largest study assessing the effect of sequence of chemotherapy in the management of SCC of the maxillary sinus, however, we could not find any significant effect of chemotherapy sequence for maxillary sinus cancers. A recent meta-analysis also had difficulty in establishing the best sequence of chemotherapy in the management of oropharyngeal, oral cavity, larynx and hypopharyngeal tumors (23).
In the current study, we found that patients with non-T4 tumor, and those who received surgery, had significantly favorable outcome by univariate analysis. We also identified that histological grade and nodal status were significant prognostic factors for OAS and DFS. In the multivariate analysis, we found that surgery and T classification were the powerful prognostic factors for all end points. Several investigators have also identified treatment modality, T classification and nodal status as significant prognostic factors (8,9,11,22). Many researchers would agree that a combination of surgery and RT is superior to either modality alone for patients with locoregionally advanced disease. However, there has been no study examining whether the addition of chemotherapy to surgery and RT would improve treatment outcome. Yoshimura et al. (8) found that patients who received >3500 mg of 5-FU had a better local control rate in a subgroup analysis. We also assessed the impact of a cumulative dose of chemotherapeutic agents including CDDP, PEP and 5-FU, but failed to demonstrate its significance. Two groups have found that intracranial or dural invasion, and extension to the pterygomaxillary fossa were poor prognostic factors for survival (11,24). We did not assess the significance of intracranial or dural invasion, because we were able to identify only a small number of patients with these findings (four and six patients each, respectively). However, of these 10 patients, 5 had unresectable disease, and 3 of the 4 subjects who received surgery experienced local recurrence, and we are confident that patients with these findings would have a very dismal outcome. We found that histological grade had prognostic significance for DFS and OAS, but another group demonstrated that histological subtype was statistically significant prognostic factor for survival (24). They reported that patients with adenocarcinoma or adenoid cystic carcinoma fared more favorably than those with SCC.
In this study, irreversible severe late adverse events occurred in 4% of the 124 patients, including two deaths from brain necrosis. Other investigators have reported that 9–40% of patients suffered from some form of late complications, mostly ocular damage and brain necrosis (5,7–11,15,21,22). In light of such high incidences of late sequelae, we have to attempt to deliver RT without jeopardizing the therapeutic outcome. Recent technical advances including intensity modulated RT (25) or three-dimensional conformal RT (2) would seem to be reasonable alternatives to conventional RT. These techniques would enable not only a decrease in the radiation dose to normal structures, but the delivery of higher doses to tumors.
This retrospective single institutional study is the largest series examining the effect of sequence of chemotherapy in the management of SCC of the maxillary sinus. We demonstrated that any sequence of chemotherapy in combination with preoperative RT did not have an impact upon DFS, LCP and OAS. Our strategies have produced comparable treatment outcome, however, persisting or recurrent locoregional tumor remains a dominant pattern of failure. This study suggested that both surgery and T classification might be important prognostic factors, and we have to make some attempt to improve LCP. It should also be kept in mind that the incidence of late complications is not so satisfactory, so we have to strive to deliver RT without compromising treatment outcome.
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