Response to oxaliplatin with cetuximab in minor salivary gland ...

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May 26, 2008 - Esophageal localization of adenoid cystic carcinoma of minor salivary ... In the majority of cases, it arises from subepithelial glands of the.
Tumori, 95: 378-381, 2009

Response to oxaliplatin with cetuximab in minor salivary gland adenoid cystic carcinoma Sara De Dosso1 , Luca Mazzucchelli2, Michele Ghielmini1, and Piercarlo Saletti1 1

Division of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona; Istituto Cantonale di Patologia, Locarno, Switzerland

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ABSTRACT

Esophageal localization of adenoid cystic carcinoma of minor salivary glands is rare; it may occur in the early to mid-sixties’ age group and is more frequently encountered in men than women. In the majority of cases, it arises from subepithelial glands of the middle to lower third of the esophagus, a similar distribution as squamous cell carcinoma. Prognosis depends mostly on tumor staging and resectability, which represents the only chance of cure. Due to the extreme rarity of this condition, there is limited experience with systemic therapy for advanced disease. We report a case of a patient with metastatic primary esophageal adenoid cystic carcinoma progressing on platinum- and irinotecan-based regimens, who achieved an objective response with oxaliplatin-based chemotherapy in combination with cetuximab. Case report In April 1999, a 52-year-old man complained of a 3-month history of progressive dysphagia. Upper endoscopy revealed an ulcerated mass in the middle third of the esophagus, and the biopsy was consistent with adenocarcinoma. Endoscopic ultrasound showed limited tumor stage (usT2N0) and no distant metastases were found on thoracic and abdominal computed tomography (CT). The patient underwent transthoracic en bloc resection of the esophagus, without evidence of direct invasion into the neighboring structures or macroscopic lymphatic involvement. On definitive histology of the surgical specimen, the presence of clear cells with S-100 protein expression on immunohistochemistry suggested a myoepithelial component, as can be observed in the solid type of adenoid cystic carcinoma (ACC) (2005 WHO Classification of salivary gland tumors, Figure 1A, B). The lack of both heterotopic gastric and Barrett’s mucosa was also suggestive of an origin from the submucosal esophageal glands. The tumor invaded the muscularis propria, without evidence of metastatic spread to the regional lymph nodes (pT2N0). The surgical procedure was radical. In February 2004 a chest X-ray revealed multiple lung lesions, which were confirmed at CT examination. No abnormal findings were seen at clinical examination (including head and neck) and in laboratory tests. Biopsy was consistent with metastases of the ACC, not suitable for resection. We decided to administer cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (5FU) by continuous infusion (750 mg/m2 daily day 1-5) repeated every 3 weeks. Six courses were delivered from March to August 2004, and a partial remission was achieved. In March 2005, a first progression was documented. Because of residual platinum-induced peripheral sensory neuropathy, a second line according to the simplified FOLFIRI schedule (irinotecan 180 mg/m2, folinic acid 200 mg/m2, 5FU bolus 400 mg/m2 given on day 1, followed by 5FU continuous infusion 2400 mg/m2 for 46 hours every 2 weeks) was chosen. Chemotherapy was interrupted in July 2005 after completion of 8 courses, the best response having been disease stabilization. Six months later the disease progressed (Figure 2A), while the patient’s performance status was still conserved. Immunohistochemical expression of epidermal growth factor receptor (EGFR) in the esophageal tumor specimen was examined and

Key words: adenoid cystic carcinoma, esophagus, cetuximab, oxaliplatin. Correspondence to: Sara De Dosso, Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland. Tel +41-91-8117900; fax +41-91-8117916; e-mail [email protected] Received May 26, 2008; accepted July 27, 2008.

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A

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Figure 1 - Esophageal adenoid cystic carcinoma: (A) hematoxylin-eosin coloration, (B) S-100 protein staining, (C) EGFR expression.

proved positive (Figure 1C). After giving his informed consent, in January 2006 the patient received cetuximab (loading dose of 400 mg/m2, then weekly maintenance of 250 mg/m2) with an oxaliplatin-based regimen (FOLFOX6: oxaliplatin 85 mg/m2, folinic acid 200 mg/m2, 5FU bolus 400 mg/m2 on day 1, followed by 5FU continuous infusion 2400 mg/m2 for 46 hours every 2 weeks), as the peripheral sensory neuropathy had completely resolved. After 8 weeks of therapy, chest X-ray revealed an encouraging partial regression of the lung metastases (Figure 2B). The treatment was relatively well tolerated, although a typical grade 2 cutaneous rash developed and peripheral sensory neuropathy grade 2 reappeared. For the latter limiting toxicity, the FOLFIRI schedule was resumed in combination with cetuximab,

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and in August 2006 the disease remained stable. In January 2007 progression was observed and the patient was treated with an anthracycline-based regimen (CAV: cyclophosphamide, doxorubicin, vincristine) until May 2007, without any response. He was then referred to best supportive care and died in September 2007 due to progressive disease complicated by fatal lung embolism.

Discussion ACC commonly originates in the major salivary glands; it is a slowly growing but extremely invasive cancer with high local recurrence rates, while distant

B

Figure 2 - Chest X-ray showing progressive disease in January 2006 (A) and response to treatment, with partial regression of lung metastases (B).

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metastases rarely influence the outcome. On the other hand, esophageal ACC shows a more aggressive behavior and distant failure characterizes the clinical course of this rare condition. In fact, unlike the favorable 5-year survival rate of ACC of the major salivary glands (6070%), the esophageal location correlates with a survival rate of 5-10%, and the median survival time is approximately 9 months1-3. Distant metastases can develop several years after primary treatment; the lungs are the most frequent site of tumor relapse. In advanced disease, objective responses to cytotoxic agents are infrequent, whereas disease stabilization is often observed; however, the rates of “no change” need to be interpreted in light of the indolent behavior of this uncommon neoplasm4. Due to its rarity, the experience with antiblastic agents in esophageal ACC is extremely limited, including sporadic reports of combinations of etoposide with tegafur5, adriamycin, cisplatin and bleomycin6, and cisplatin, cyclophosphamide, vincristine and doxorubicin7. Our case illustrates a patient with previously treated metastatic disease in whom the use of oxaliplatin might have impacted the clinical outcome, as it led to sustained disease control with partial regression of lung metastases. On the basis of the EGFR overexpression of neoplastic cells, our patient was given oxaliplatin with cetuximab, a drug that has been extensively evaluated in chemotherapy-resistant metastatic colorectal cancer as a single agent, in combination with irinotecan in irinotecan-refractory patients and, more recently, in combination with chemotherapy in first-line treatment8. Moreover, the addition of cetuximab to either FOLFIRI or FOLFOX was shown to significantly increase the response rates compared with either regimen alone9. EGFR is highly expressed in patients with squamous cell carcinoma and adenocarcinoma of the esophagus10, and cetuximab combined with FOLFIRI was investigated as first-line treatment of advanced gastric or gastroesophageal junction adenocarcinoma in a phase II trial, showing that this combination is active and well tolerated11. In esophageal adenoid cystic subtypes, there is – to the best of our knowledge – no report on the expression of EGFR, which was shown to be present in almost 90% of ACC of the salivary glands12. Despite the high reported levels of EGFR overexpression, the anti-EGFR gefitinib does not appear to have single-agent activity4. Cetuximab was recently evaluated in a phase II study in patients with advanced salivary gland carcinomas (for the most part ACC, 43%, previously treated with chemotherapy) and EGFR overexpression13: no objective responses were observed, suggesting a lack of activity of cetuximab in these neoplasms as a single agent. On the other hand, it has been established that oxaliplatin lacks cross-resistance with cisplatin and seems to be useful for the treatment of some cisplatin-resistant

S DE DOSSO , L MAZZUCCHELLI, M GHIELMINI, P SALETTI

cancers14, although confirmatory clinical evidence in upper gastrointestinal tract tumors is weak and controversial, arising from small phase II trials15,16. Therefore, the additive effect of the monoclonal antibody to chemotherapy can be only speculative in our patient, as chemotherapy might have been active by itself. As no standard options are available and the role of oxaliplatin in this very rare condition is still unknown, its use might be of interest and possibly merits further investigation.

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