ORIGINAL ARTICLE

Concomitant chemoradiotherapy for advanced squamous cell carcinoma of the temporal bone Hirotaka Shinomiya, MD,1* Shingo Hasegawa, MD,1 Daisuke Yamashita, MD,1 Yasuo Ejima, MD,2 Yoshida Kenji, MD,2 Naoki Otsuki, MD,1 Naomi Kiyota, MD,3 Shunsuke Sakakibara, MD,4 Tadashi Nomura, MD,4 Kazunobu Hashikawa, MD,4 Eiji Kohmura, MD,5 Ryohei Sasaki, MD,2 Ken-ichi Nibu, MD1 1

Department of Otolaryngology–Head and Neck Surgery, Kobe University Graduate School of Medicine, Chuo-Ku, Kobe, Hyogo, Japan, 2Department of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-Ku, Kobe, Hyogo, Japan, 3Department of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Chuo-Ku, Kobe, Hyogo, Japan, 4Department of Plastic Surgery, Kobe University Graduate School of Medicine, Chuo-Ku, Kobe, Hyogo, Japan, 5Department of Neurosurgery, Kobe University Graduate School of Medicine, Chuo-Ku, Kobe, Hyogo, Japan.

Accepted 14 May 2015 Published online 18 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24133

ABSTRACT: Background. The purpose of this study was to analyze outcomes for the treatment of locally advanced temporal bone cancer by means of concomitant chemoradiotherapy (CCRT) with a combination of cisplatin (CDDP), 5-fluorouracil (5-FU), and docetaxel (TPF). Methods. Between 2006 and 2011, 34 patients with squamous cell carcinoma of the temporal bone were treated at Kobe University Hospital. Medical records were retrospectively reviewed to obtain information concerning patient characteristics, extent of disease, treatment, adverse events, and oncologic results.

Results. Ten patients were treated with CCRT using TPF regimen. The 5year overall survival rate and disease-free survival rate were both 60%. Of special interest is that even for patients with unresectable T4 disease, the 5-year overall survival rate was 56%. Conclusion. The results of our study indicate that CCRT with TPF for locally advanced temporal bone cancer is an effective and promising regimen. C 2015 Wiley Periodicals, Inc. Head Neck 38: E949–E953, 2016 V

INTRODUCTION

ease ranged from 17% to 40%2,4–6 and are accompanied by an unfavorable quality of life for survivors because of facial palsy, hearing loss, and balance disorder. Surgical treatment for advanced disease can also lead to serious complications, such as meningitis, cerebral infarction, or brain edema. Moreover, the prognosis for patients with T4 temporal bone cancer treated with conventional radiotherapy (RT) is similarly poor. As a result, the optimal treatment for advanced temporal bone cancer has yet to be established. To address these issues, in 2006, we initiated treatment of locally far advanced temporal bone cancers by means of concomitant chemoradiotherapy (CCRT) using a combination of combination of cisplatin (CDDP), 5fluorouracil (5-FU), and docetaxel (TPF). This report deals with our experience with CCRT for advanced temporal bone cancers in terms of oncologic results and adverse effects. Although the number of patients and follow-up periods were limited, long-time survival with satisfactory quality of life was obtained even for patients with unresectable T4 diseases.

Squamous cell carcinoma of the temporal bone is extremely rare with an annual incidence estimated between 1 to 6 cases per million of the populations.1 Because of its rarity and the complex anatomy of the temporal bone involving critical organs, such as the internal carotid artery and cranial nerves, considerable experience and advanced techniques are required for surgical treatment. However, radiotherapy and/or chemotherapy are even less desirable options because they have been found to be less effective at treating cancer in this location than they are for treating other types of mucosal head and neck cancer. For early stages of T1 and T2, as defined by the Pittsburgh staging system,2 sleeve resection of the external canal or en bloc lateral temporal bone resection, have yielded favorable oncologic and functional results and are the treatment of choice at most institutions.3–5 On the other hand, oncologic and functional results obtained with these treatment modalities for locally advanced temporal bone cancers have not been satisfactory.6 The 5-year survival rates for surgically treated patients with unresectable T4 dis-

KEY WORDS: ear cancer, temporal bone, concomitant chemoradiotherapy, cisplatin, docetaxel

PATIENTS AND METHODS *Corresponding author: H. Shinomiya, Department of Otolaryngology–Head and Neck Surgery, Kobe University Graduate School of Medicine, 7-5-1 KusunokiCho, Chuo-Ku, Kobe, Hyogo 650-0017, Japan. E-mail: [email protected]

Approval for this study was obtained from our institution’s Internal Review Board. Between 2006 and 2011, 34 patients with squamous cell carcinoma of the temporal bone were treated at Kobe University Hospital.

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TABLE 1. Patient characteristics. Extent of disease Patient no.

1 2 3 4 5 6 7 8 9 10

Age, y

Sex

T classification

N classification

Facial paralysis

61 58 45 58 45 63 70 48 54 57

F F M M F F F F F F

3 3 4 4 4 4 4 4 4 4

0 0 0 0 0 0 0 0 2a 2a

– – – 1 – 1 – – 1 1

ICA

IJV/SS

Dura

Brain

1* 1* 1

1†

1 1 1 1 1

1 1

Abbreviations: ICA, internal carotid artery; IJV, internal jugular vein; SS, sigmoid sinus; Dura, invasion into the dura mater; Brain, invasion into the temporal lobe. T classification: size and/or extent of the primary tumor; N classification: involvement of regional lymph nodes. * Extensive invasion. † Associated with brain edema.

All patients were pathologically diagnosed as having squamous cell carcinoma of either the external auditory canal or the middle ear cavity. At the initial diagnosis, extent of disease was assessed with the aid of contrast CT, MRI, and 18-fluoro-2-deoxyglucose positron emission tomography. Tumors were staged according to the most recent version of the Pittsburgh classification system (2000).2 During this period, T1 and T2 cases were mostly treated with lateral temporal bone resection and patients who refused surgical treatment were treated with radiation alone. T3 and resectable T4 cases were treated with subtotal temporal bone resection. CCRT was recommended for patients who refused surgical treatment or had unresectable T4 disease. Finally, patients who could not tolerate surgical treatment or chemotherapy because of poor general condition underwent conventional radiotherapy or proton beam therapy. Postoperative RT or CCRT was recommended for surgically treated patients if the surgical margin was positive or close. For lateral temporal bone resection, the bony external auditory canal, tympanic membrane, malleus, and incus were resected with extended mastoidectomy in an en bloc manner. The superficial lobe of the parotid gland was resected in most cases and the facial nerve was preserved in all cases. For subtotal temporal bone resection, the temporal bone, except the petrous apex, was resected in an en bloc manner by means of temporal and occipital craniotomies. The internal carotid artery was drilled out from the carotid canal and preserved. The jugular bulb and/or dura matter were resected in case of tumor invasion. The parotid gland and condyle of the mandible were resected simultaneously. Prophylactic selective neck dissection was performed for the clinically negative necks and modified radical neck dissection was performed for the clinically positive necks. Invasion of tumors into the internal carotid artery or petrous apex was considered to constitute a surgical contraindication. Cases with extensive invasion into the jugular bulb, temporal lobe, or dura mater were considered inoperable. For CCRT, a TPF regimen was used, which consisted of intravenous administration of 600 mg/m2 5-FU on days E950

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1 to 5, and bolus injection of 50 mg/m2 docetaxel and 60 mg/m2 cisplatin on day 1. Conventionally fractionated RT was performed with a standard radiation dose of 66 to 70 Gy/33 to 35 fractions (2 Gy/fraction, once a day, 5 times a week). Morphine was prescribed for control of pain because of mucositis, and oral care was provided routinely by dental hygienists. Antiemetic therapy with aprepitant, palonosetron, and dexamethasone was prescribed for all cases to control chemotherapy-induced nausea and vomiting. This protocol was approved by the institutional review board of Kobe University Hospital. Titanium silicate-1, a biochemical modulation of 5-FU, which contains tegafur, gimeracil, and oteracil potassium, was prescribed for 1 year if the patients requested adjuvant chemotherapy. Medical records were retrospectively reviewed to obtain information concerning patient characteristics, extent of disease, treatment, adverse events, and oncologic results. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Kaplan–Meier plots were used to summarize time to event measured from the start of the first treatment. The log-rank test was used for all statistical analyses. R software (version 3.0.2 2013, the R foundation for Statistical Computing, Vienna, Austria) was used for the statistical analysis.

RESULTS The age of the patients ranged from 43 to 88 years with a median age of 63.3 years and the follow-up period ranged from 9 to 104 months (median, 41 months). Three of the primary tumors were classified as T1, 6 as T2, 9 as T3, and 16 as T4. Of the patients with T3 disease, 2 were treated with CCRT, 4 with subtotal temporal bone resection, 2 with RT alone, and 1 with proton beam therapy alone. Of the patients with T4 disease, 8 were treated with CCRT, 2 with subtotal temporal bone resection, 4 with RT alone, and 2 with proton beam therapy alone. Of the 25 patients with T3 and T4 tumors, 6 underwent surgery. One patient with a T4 tumor had a positive

CONCOMITANT

CHEMORADIOTHERAPY FOR EAR CANCER

TABLE 2. Treatment and outcomes. Patient no.

RT, Gy

CTX

Response

Follow-up

Outcome

Recurrence

Adjuvant CTX

66 70 70 68 70 66 66 66 64 70

FP!TPF FP!TPF TPF 33 TPF 32 TPF 32 TPF 32 TPF 32 TPF 32 TPF 32 TPF 32

Complete response Complete response PR Complete response Complete response Complete response PR PR Complete response Complete response

86 mo 87 mo 21 mo 88 mo 60 mo 39 mo 9 mo 9 mo 104 mo 41 mo

NED NED DOD NED NED NED DOD DOD NED DOD

– – Local – – – Local 1 lung Local – Local

S–1 S–1 S–1 – – S–1 S–1 S–1 S–1 S–1

1 2 3 4 5 6 7 8 9 10

Abbreviations: RT, radiotherapy; Gy, Gray; CTX, chemotherapy; FP, 5-fluorouracil 1 cisplatin; TPF, docetaxel 1 cisplatin 1 5-fluorouracil; NED, no evidence of disease; PR, partial response; DOD, died of disease.

margin, and the other 5 had negative margins. The patient with the positive margin received adjuvant CCRT, and 2 others received adjuvant RT. All of these patients started adjuvant therapy within 4 weeks after surgery. Characteristics of the 10 patients, 8 women and 2 men, who were treated with CCRT using TPF, are summarized in Table 1. Their age range was from 45 to 70 years and the follow-up period was 9 to 104 months (median, 51 months). There were 2 T3 cases and 8 T4 cases, and clinical lymph node metastases were detected in 2 of them. Seven cases with far-advanced disease were classified as unresectable for the following reasons: invasion into the carotid artery; apparent invasion into the internal jugular vein or sigmoid sinus; or widespread invasion into dura mater and/or temporal lobe. Four cases showed facial paralysis. Treatment modalities and oncologic outcomes for these patients are summarized in Table 2. RT was performed in all cases with a total dose of 64 to 70 Gy, whereas almost all the patients underwent CCRT using the TPF regimen with the exception of 2 patients for whom the 5FU 1 CDDP regimen was used as the first course. Eight patients received adjuvant chemotherapy with titanium silicate-1, and all of them started the treatment within 4 weeks after CCRT.

Complete response and partial response (PR) were attained for 7 and 3 patients, respectively. Local recurrence was detected in 4 patients and lung metastasis in 1 of them. These 4 patients died of the disease but the other 6 have survived with no evidence of disease. The 5year overall survival rates and disease-free survival rates were 60% and 60%, respectively. It is of special interest that the 5-year overall survival rate even for patients with unresectable T4 disease was 56%. All the patients who attained complete response have survived >3 years, whereas all 3 patients with PR died of disease within 2 years. Of the 6 patients without lymph node metastasis or dural invasion, 5 have survived without disease for >3 years. The survival rate for the patients with T4 disease treated with CCRT was better than that for the patients treated with the other modalities. Characteristics and oncologic outcomes for patients treated with other modalities are summarized in Table 3, whereas Kaplan–Meier survival curves are shown in Figure 1. Statistically, the difference between the 2 groups was significant (p 5 .028). Acute adverse events are summarized in Table 4. Grade 4 leukocytopenia and grade 3 febrile neutropenia occurred in only 1 patient who was treated with granulocyte colony-stimulating factor for 3 days, but the scheduled

TABLE 3. Patient treated with other modalities. Patient no.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Age, y

Sex

T classification

N classification

Treatment

89 74 39 57 61 66 45 79 84 88 78 60 60 61 63

F F F F F F M M M M F M F F M

3 3 3 3 3 3 3 4 4 4 4 4 4 4 4

0 0 0 0 0 2 0 0 0 0 0 0 0 0 0

RT RT Proton Surgery Surgery Surgery Surgery RT RT RT RT Proton Proton Surgery Surgery

Surgical margins

Negative Negative Negative Negative

Negative Positive

Follow-up

Outcome

Recurrence

Adjuvant therapy

33 mo 72 mo 57 mo 34 mo 54 mo 72 mo 9 mo 6 mo 6 mo 20 mo 30 mo 12 mo 17 mo 48 mo 19 mo

DOD NED DOD NED NED NED DOD DOD DOD NED DOD DOD DOD NED DOD

– Local Lung – – – Local Local Local – Local Local Local – Local

– – – – – RT – – – – – – – RT CCRT

Abbreviations: RT, radiotherapy; Proton, proton beam therapy; DOD, died of disease; NED, no evidence of disease; CCRT, concomitant chemoradiotherapy.

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FIGURE 1. Patient survival curves (with Kaplan–Meier estimates of overall survival for patients with T4 disease treated with concomitant chemoradiotherapy (CCRT) and other modalities. Fiveyear survival rates for the patients with T4 disease treated with CCRT using with docetaxel, cisplatin, and 5-fluorouracil (TPF; dotted line) were significantly better than those for the patients treated with other modalities (solid line; p 5 .028).

treatment plan could be completed without delay. For this patient only, the dose of docetaxel for the second course of chemotherapy was reduced to 80%, and for 1 patient treatment had been delayed for 5 days because of fever of unknown origin. Grade 3 non-hematotoxicity occurred in 3 cases, that is, mucositis, vomiting, and vomiting and anorexia in 1 patient each, but all 3 also successfully completed the treatment with the aid of fluid replacement. As for late toxicity, grade 1 central nervous system necrosis was detected in 1 case 90 months after the treatment. Of the 7 patients with complete response, 4 suffered complete hearing loss on the ipsilateral side, and 3 had moderate hearing impairment. However, none of these patients complained of equilibrium dysfunction. Of the 4 patients with facial paralysis at presentation, 1 patient had significant improvement in facial movement, whereas the remaining 3 patients showed no change. No other late adverse events were observed during the follow-up period.

DISCUSSION Because of its rarity and aggressive oncologic behavior, standard treatment for temporal bone cancer has not been established yet. For most reported cases, treatment consisting of surgical resection and postoperative RT has been selected.7 However, oncologic results for surgically treated patients with advanced temporal cancer have not been satisfactory.7 Essig et al8 reported that margin status is a significant predictor of outcome for resection of temporal cancer. However, resection with an adequate safety margin of malignancies involving the temporal bone is challenging because of the anatomic complexity of the temporal bone. Furthermore, extensive surgical resection may lower the quality of life because of hearing impairment, facial nerve palsy, and disequilibrium, or complicaE952

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tions induced by surgery, such as meningitis, cerebral infarction, or brain edema. Thus, a new treatment strategy for locally far-advanced cancer of the temporal bone is urgently needed. CCRT with tri-weekly CDDP has found wide acceptance for advanced head and neck squamous cell carcinomas. To improve the locoregional control of CCRT, Tsukuda et al9 developed CCRT using TPF. In the phase I trial, CCRT with TPF was well tolerated and efficacious for patients with locally advanced squamous cell carcinoma of the head and neck, but was associated with a high incidence(79%) of severe mucositis (grade 3 and 4),10,11 which prevented this protocol from being accepted as standard therapy for advanced head and neck cancers. Irradiation of temporal bone cancer, however, involves only a limited part of the pharyngeal mucosa. We started using this advantage in 2006 to use this protocol of CCRT with TPF as a standard therapeutic regimen for advanced temporal bone cancers on the assumption that radiation-induced mucositis would not be a serious problem in the case of temporal bone cancer. In fact, grade 3 mucositis occurred in only 1 of our cases reported here (10%) and grade 4 in none. In terms of adverse events, CCRT with TPF thus seems to be suitable for the treatment of cancers of the temporal bone. Reported 5-year overall survival rates for surgically treated patients with T4 tumors range from 17% to 40%.2,4–6,12–14 A meta-analysis of 752 patients with advanced (T3, T4) cancers of the temporal bone15 reported that 5-year overall survival rates for patients who underwent surgery 6 RT, preoperative chemoradiotherapy (CRT) followed by surgery, definitive CRT, and surgery followed by postoperative CRT were 53.5%, 85.7%, 43.6%, and 0%, respectively. These results suggest that preoperative CRT may lead to improved survival of surgically treated patients and that the effectiveness of definitive CRT may be equivalent to that of surgical

TABLE 4. Adverse events. Adverse event

Leukocytes Neutrophils Platelets Hemoglobin GOT GPT Creatinine Albumin Fever Febrile neutropenia Mucositis Dermatitis Anorexia Nausea/vomiting Taste disturbance Dizziness

Grade 1

Grade 2

Grade 3

Grade 4

1 1 4 3 4 4 1 3 2

2 3

6 5

1* 1

7 8 6 5 3 1

2 2 2 2

5 1 1 3 1 1 1 2

1

Abbreviations: GOT, glutamic oxaloacetic transaminase; transaminase. * Granulocyte colony-stimulating factor was used for 3 days.

GPT, glutamic pyruvate

CONCOMITANT

resection. However, a different chemotherapeutic protocol was used for each of these studies and the sample size was too small for meaningful evaluation. Similarly, because only 8 patients treated with preoperative CRT were included in this study, it is difficult to draw any definitive conclusions. Before the study reported here, Shiga et al11 were the first to publish their findings for the safety and efficacy of CCRT with TPF for temporal bone cancer. On the basis of favorable oncologic results for T4 diseases obtained with this procedure, they recommended CCRT with TPF as a standard treatment for locally advanced squamous cell carcinoma. The overall survival rate for patients with unresectable T4 tumors in our study was 56%, which agrees with the rate reported by Shiga et al.11 Although the sample size for both studies was small, the prognosis for patients treated with CCRT tended to be better than for those treated with the other modalities. Especially noteworthy is that 80% of the patients with T3 or T4 disease without lymph node metastasis or expansive dural invasion in our study have survived without disease for >3 years. Although further study comprising a large number of patients is required to validate the efficacy of this protocol, our results so far suggest that CCRT with TPF is a promising regimen for advanced temporal bone cancer.

CONCLUSION The results of our study suggest that CCRT with TPF for locally advanced temporal bone cancer is an effective and safe regimen. We therefore believe that CCRT with TPF can become an important treatment option for patients who have unresectable T4 disease or refuse surgical treatment. Our ongoing clinical trial is expected to validate the efficacy and safety, including very few late toxicities of this regimen for advanced temporal bone cancers.

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