Concurrent chemoradiation for adenoid cystic carcinoma of the head and neck

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1 ORIGINAL ARTICLE Concurrent chemoradiation for adenoid cystic carcinoma of the head and neck Sandeep Samant, MS, FRCS, 1 * Michiel W. van den Brekel, MD, 2 Merrill S. Kies, MD, 3 Jim Wan, PhD, 4 K. Thomas Robbins, MD, 5 David I. Rosenthal, MD, 6 Coen Rasch, MD, 7 Randal S. Weber, MD 8 1 Department of Otolaryngology Head and Neck Surgery, University of Tennessee Health Science Center, Memphis, Tennessee, 2 Department of Head and Neck Surgery and Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands, 3 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 4 Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, 5 Department of Otolaryngology Head and Neck Surgery, Southern Illinois University, Springfield, Illinois, 6 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 7 Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands, 8 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. Accepted 5 July 2011 Published online 15 November 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. We performed a retrospective review of patients with nonresected head and neck adenoid cystic carcinoma (ACC) treated with concurrent chemoradiation. Methods. Sixteen patients (nasopharynx 7, oropharynx 4, trachea 3, oral and nasal cavity 1 each) were treated at 3 tertiary care centers. Six patients received intraarterial cisplatin and 10 received intravenous cisplatin or carboplatin concurrently with radiation. Results. Thirteen patients are alive, 7 without signs of disease with a median follow-up of 61 months. Tumor progression was noted in 8 patients (50%) (distant metastasis in 5 patients and local tumor progression in 3 patients) with a median time to progression of 25 months (range, 4 52 months). Overall survival (OS), progression-free survival (PFS), and local progression free survival (LPFS) rates at 5 years were 87%, 39%, and 61%, respectively. Conclusion. Concurrent chemoradiation is a feasible treatment option and may lead to sustained locoregional tumor control in patients with nonresected ACC of the head and neck. VC 2011 Wiley Periodicals, Inc. Head Neck 34: , 2012 KEY WORDS: adenoid cystic carcinoma, salivary neoplasms, chemoradiation, drug therapy, radiation therapy Adenoid cystic carcinoma (ACC) is an uncommon malignancy constituting 10% of salivary neoplasms, but is the most frequent malignant tumor of the submandibular and minor salivary glands. 1 ACC may have an indolent clinical course, but there tends to be moderate to high risk of systemic recurrences, which may develop in the absence of locoregional failure. There is a propensity for discreet regions of tumor infiltration along cranial nerves, but lymph node metastases are uncommon. Surgical resection followed by radiotherapy yields favorable local and regional tumor control results that are superior to radiation as a single modality and, hence, is the mainstay of therapy for many patients. 2 4 The role of chemotherapy has largely been directed to palliation for recurrent or metastatic disease. 5 Experience with the combined use of chemotherapy and radiation as primary treatment for ACC is limited. 6 9 While surgery remains the principal treatment modality for this cancer at each of the 3 participating institutions in this study, concurrent chemoradiation has been used in highly selected patients for the treatment of ACC not considered to be amenable for resection or in instances where *Corresponding author: S. Samant, Department of Otolaryngology Head and Neck Surgery, University of Tennessee Health Science Center, Memphis, Tennessee. ssamant@uthsc.edu patients have refused surgery. The purpose of this review was to evaluate our experience with concurrent chemoradiation in the management of patients with inoperable ACC of the head and neck. MATERIALS AND METHODS We reviewed the clinical records of patients with ACC of the head and neck region who received primary care with definitive concurrent chemoradiation at the University of Tennessee Health Science Center (UTHSC), The University of Texas MD Anderson Cancer Center (MD Anderson), and The Netherlands Cancer Institute (NKI). At the UTHSC, patients were identified from a preexisting database for patients receiving intraarterial cisplatinbased chemoradiation (RADPLAT). MD Anderson patients were culled from treatment records identifying the administration of chemoradiotherapy. NKI patients were selected from a chemoradiation database maintained for patients with head and neck cancer. In each case, patients had been presented for multidisciplinary evaluation before making recommendations for definitive therapy. Table 1 lists the reasons for the final choice of nonsurgical treatment for each patient. Permission was obtained from respective institutional review boards for the study. Information regarding age, sex, location and extent of disease, staging, radiologic findings, histology, details of chemotherapy and radiation, toxicity, response HEAD & NECK DOI /HED SEPTEMBER

2 SAMANT ET AL. TABLE 1. Patient details. Follow-up, mo Current status Recurrence time to progression (treatment) No of infusions Response Reason for nonsurgical therapy Treatment Treatment details Patient no./institution Age sex Tumor Stage 1/UTHSC 57 F Palate T3N0 Refused surgery RADPLAT DDP 150 mg/m2/wk 4 CR Neck, lungs 23 months DOD 62 2/UTHSC 28 M NP T3N0 Unresectable RADPLAT DDP 150 mg/m2/wk 4 CR NED 93 3/UTHSC 71 F BOT T4aN0 Refused 2/3rd glossectomy RADPLAT DDP 150 mg/m2/wk 2 CR NED 46 IV CRT DDP 100 mg/m2q3wks 3 CR NED 60 4/NKI 33 M Trachea Refused laryngectomy, esophagectomy 5/NKI 62 F OPH T3N0 Refused total glossectomy RADPLAT DDP 150 mg/m2/wk 4 CR Lung 27 months AWD 75 6/NKI 56 F NCV T4bN0 Unresectable RADPLAT DDP 150 mg/m2/wk 4 CR NED 67 7/NKI 51 F OPH T2N0 Refused total glossectomy RADPLAT DDP 150 mg/m2/wk 3 CR NED 41 8/MDACC 47 M NP T4N0 Unresectable IV CRT DDP 100 mg/m2q3wks 3 SD Lung 4 months DOD 39 9/MDACC 79 M BOT T3NoM1 Refused total glossectomy IV CRT DDP 30 mg/m2/wk 7 PR AWD 58 10/MDACC 45 F Trachea Unresectable IV CRT DDP 30 mg/m2/wk 7 PR Lung 22 months AWD 37 11/MDACC 28 F NP T4N2 Unresectable IV CRT DDP 80 mg/m2q3wks 3 PR NED 82 12/MDACC 58 F NP T4N0 Unresectable IV CRT CBDCA AUC 2/wk 2 PR Local 51 months (systemic therapy) AWD 76 13/MDACC 37 F Trachea Unresectable IV CRT DDP 30 mg/m2/wk 7 SD DOD 23 14/MDACC 60 F NP T4N0 Unresectable IV CRT DDP 30 mg/m2/wk 6 PR Local 47 months (resected) NED 65 15/MDACC 49 F NP T4N0 Unresectable IV CRT CBDCA AUC 2/wk 7 PR Local 53 months (resected partially) AWD 77 16/MDACC 38 M NP T4N0 Unresectable IV CRT DDP 30 mg/m 2/wk 6 PR Bone 12 months (systemic therapy) AWD 36 Abbreviations: UTHSC, University of Tennessee Health Science Center; DDP, cisplatinum; CR, complete response; DOD, died of disease; NP, nasopharynx; NED, no evidence of disease; BOT, base of tongue; NKI, Netherlands Cancer Institute; IV CRT, intravenous chemoradiation; OPH, oropharynx; AWD, alive with disease; NCV, nasal cavity; MDACC, MD Anderson Cancer Center; SD, stable disease; PR, partial response; AUC, area under curve; CBDCA, carboplatinum. to treatment, recurrences, and cause and time of death was abstracted from these records. Response assessments, per the Response Evaluation Criteria in Solid Tumors, were performed based upon clinical and radiographic findings obtained 8 to 12 weeks after completing radiotherapy. Progressive disease was designated if there was 25% or greater enlargement of the greatest tumor dimension or the appearance of new lesions. A partial response (PR) indicated a 30% or greater reduction in the largest tumor dimension. Stable disease reflected tumor control but without achieving PR status. Complete response (CR) indicated that there was no remaining clinical or radiographic evidence of tumor for at least 2 assessments, at minimum of 3 months duration. Biopsy was not routinely performed. Overall survival (OS) was defined as the time from diagnosis until death. Progression-free survival (PFS) was defined as the time from diagnosis until disease progression at any site or death. Local progression free survival (LPFS) was defined as the time from diagnosis until local tumor progression or death. Five-year point estimates for survival were calculated using the Kaplan Meier method. RESULTS Patient and tumor characteristics Sixteen patients, presenting at the initial diagnosis between December 1996 and April 2007, were identified. These patients underwent concurrent chemoradiation as primary therapy for previously untreated ACC of the head and neck: 3 from UTHSC, 4 from NKI, and 9 from MD Anderson. Median follow-up was 61 months (range, months; Table 1). Age at diagnosis ranged from 28 through 71 years old. The primary cancer was located in the nasopharynx in 7 patients, base of tongue in 4 patients, trachea in 3 patients, the oral cavity in 1 patient, and the nasal cavity in 1 patient. T classification was T2 in 1 patient, T3 in 4 patients, and T4 in 8 patients; no T classification was assigned to those with tracheal primaries. One patient had cervical lymph node metastases and 1 patient had lung metastases at the time of presentation. Treatment All 3 patients from UTHSC and 3 of the 4 patients from NKI received intraarterial cisplatin concurrently with radiation as per the RADPLAT protocol (150 mg/ m2 of body surface area intraarterially along with intravenous sodium thiosulfate at 9 mg/m2 administered weekly for up to 4 infusions). 10 The number of weekly cisplatin infusions administered was 4 in 4 patients, 3 in 1 patient, and 2 in 1 patient. The other 10 patients received single-agent cisplatin (30 mg/m 2 weekly at MD Anderson or 100 mg/m 2 q 3 weeks 3 doses at NKI) or carboplatin (area under the curve [AUC] ¼ 2/week at MD Anderson) intravenously during the course of radiation (Table 1). All patients were treated with definitive doses of radiation (median dose 70 Gray [Gy] typically administered in 35 fractions) to the primary tumor plus adequate margins. Patients with named cranial nerve involvement near the skull base underwent therapy directed to the ganglia. N HEAD & NECK DOI /HED SEPTEMBER 2012

3 CHEMORADIATION FOR ADENOID CYSTIC CARCINOMA patients received elective nodal irradiation. Intensitymodulated radiation therapy was used in 12 patients, 3- dimensional conformal radiation was used in 3 patients, and 1 patient was treated with proton irradiation for a tracheal tumor. Treatment toxicity, tumor responses patterns of failure, and survival Grade 3 mucosal toxicity was noted in 8 patients, and grade 3 hematologic toxicity and grade 3 nausea was noted in 1 patient each. No grade 4 toxicity was observed, and there were no associated deaths or lifethreatening effects. Mild to moderate fatigue and blood count suppression were consistent with expected risks based upon the general medical and radiation oncology literature. Tumor responses to treatment were assessed 8 to 12 weeks after completion of therapy by clinical examination and imaging with CT or MRI scans. Eventual CR of tumor was noted at the primary site in 7 patients even though, in many cases, tumor was clinically appreciable at the time of completion of therapy. PR was observed in 7 patients and stable disease at the primary site in 2 patients. One patient had metastasis to the lungs at presentation. This patient received intravenous cisplatin concurrently with radiation to the primary tumor in the tongue base. He is living on systemic therapy with erlotinib, with stable disease in the lungs and no evidence of cancer at the primary site at the time of last follow-up at 58 months. All 6 patients treated with intraarterial chemotherapy achieved CR of disease at the primary site. Among the 10 patients treated with intravenous chemotherapy, 1 achieved CR, 7 achieved PR, and 2 achieved stable disease. However, this may be reflective of how responses were categorized at different institutions based on clinical assessment only as histologic assessment of response was not performed (Table 1). Median follow-up at the time of analysis was 61 months (range, months). In the 7 patients achieving CR at the primary site, there has been no observed recurrence of disease locally. Progression of disease obtained in 8 of 16 patients with a median time-to-progression of 25 months (range, 4 52 months). Development of distant metastasis was the most common site for progression (5 patients) appearing in the lung in 3 patients, in the neck and lungs in 1 patient, and in bone in another patient; 2 of these patients had been treated with RADPLAT and 3 with intravenous chemoradiation. Local progression of disease was noted in 3 patients all of whom had a nasopharyngeal primary and all of whom had been deemed to have a PR. One of these 3 patients underwent salvage surgery (even though her tumor at presentation was deemed unresectable) and remains without any evidence of disease now 18 months after her recurrence was detected. No local disease progression was noted in the 4 other patients judged clinically to have had a PR. Lymph node recurrence in the neck was seen in 1 patient who also developed lung metastasis. At the time of last follow-up, 6 patients were alive with disease, 7 remained free of any evidence of cancer, and 3 had died due to advanced cancer. OS, PFS, and LPFS rates at 5 years were 87%, 39%, and 61%, respectively (Figure 1). DISCUSSION In a 35-year review of patients with salivary neoplasms treated at the Memorial Sloan-Kettering Cancer Center, Spiro 1 reported minor salivary gland origin in 65% of 287 cases of ACC, while parotid and submandibular glands were the location of origin in 19% and 16% of the cases, respectively. All 16 patients in our study had tumors arising from minor salivary glands. Minor salivary gland tumors occur in sites where surgical resection is often not feasible due to proximity to vital structures or the subsequent functional loss attendant to surgery; this may be particularly true for more extensive cancers of the nasopharynx, tongue base, and trachea, which make up 88% of our cases. Recommendations for chemoradiation as primary treatment followed an assessment that the FIGURE 1. (A) Overall survival. (B) Progression-free survival. (C) Local progression free survival. HEAD & NECK DOI /HED SEPTEMBER

4 SAMANT ET AL. primary malignancy was either not amenable to adequate gross total surgical resection or patient refusal of surgery due to perceived functional or cosmetic deficits (Table 1). For tumors that are operable, surgery remains the mainstay of therapy. Postoperative radiation has been reported to improve locoregional control and is, therefore, commonly used for most cases excepting the very early lesions resected with clearly adequate margins and absence of perineural invasion However, beneficial effect of postoperative treatment on survival is less clear, partly because successful surgical salvage is frequently possible after locoregional failure and also because survival is related to the high risk for development of distant metastasis, which may be unrelated to locoregional control. 14 Table 2 summarizes the results of therapy from some of the recent reports in literature on this disease. 2,4 6,13,15 21 Local control rates for standard therapy with surgery and postoperative radiation in the head and neck vary between 60% and 94% with a majority of reports noting an 85% or greater local control at 5 years. Results with radiation as a single modality are inferior, with local control varying between 6.5% and 56% at 5 years, although a selection bias of more advanced or unresectable disease being treated with definitive radiotherapy is likely. For patients who have nonresected tumors, or who are left with a macroscopic residual after subtotal surgical resection, the use of higher-dose conformal proton irradiation or high-linear energy transfer radiation with neutrons or carbon ions has been promising. The rationale for the use of such therapy is related not TABLE 2. Treatment results of adenoid cystic carcinoma. Author, year Patients Treatment Local control DM Survival (OS, unless DFS specifically mentioned) Surgery or combined therapy Chummun, Sx or Sx þ RT 87% absolute 36% absolute 71% and 65% at 3 and 5 y Chen, Sx or Sx þ RT 88% and 77% at 33, 44% at 5, 10 y 85% and 64% at Silverman, Sx or Sx þ RT 85% and 74% at 11% and 25% 80% and 63% at 5, 10 y Sung, Sx or Sx þ RT 60% absolute 39% and 62% at Mendenhall, Sx þ RT or RT 77% and 69% at 5 and 10 y overall. 94% and 91% for Sx þ RT Conventional radiation Mendenhall, Sx þ RT or RT 56% and 43% at 5 and 10 y for RT Vikram, RT or Sx þ RT 6.5% for RT only Neutron therapy Krull, (systematic review) Neutrons 67% Laramore, Neutron vs photons 56% with neutrons and 17% with photons Photon RT with carbon ion boost Schultz Ertner, Group A: photon RT with carbon ion boost; Group B: photon RT 78% at 4 y in group A; 25% at 4 y in group B 20% and 27% at 20% and 27% at 5 and 10y 14% in group A and 68% in Group B at 90% and 58% DFS at 5 and 10 y. OS after DM was 69% and 35% at 2 and 5 y 68% and 49% at overall. 77% and 55% for Sx þ RT 57% and 42% at 5 and 10 y for RT 76% in group A and 78% in group B at 4 y Proton therapy Pommier, Protons 93% at 5 y 38% at 5 y 77% at 5 y Chemoradiation Our series 16 IA or IV cisplatin/ carboplatin chemoradiation Local tumor progression in 3/16 (19%) Abbreviations: DM, distant metastasis; OS, overall survival; DFS, disease-free survival; Sx, surgery; RT, radiation therapy; IA, intraarterial; IV, intravenous. 6/16 (37.5%), 1 had DM at presentation 87% at 5 y 1266 HEAD & NECK DOI /HED SEPTEMBER 2012

5 CHEMORADIATION FOR ADENOID CYSTIC CARCINOMA only to the higher radiobiologic effectiveness relative to photon therapy but also to the greater precision in radiation delivery such that higher tumor volume dose intensity may be obtained without an enhancement of normal tissue effects in the immediate neighborhood of the tumor. This is particularly of value in the skull-base region. Carbon ions, administered as a boost to photon-based therapy, and protons are both superior to neutrons in regard to conformality of the treatment plan and, thus, can be given in higher aggregate doses with lesser normal-tissue injury. Local control rates of 78% and 93%, respectively, have been reported with carbon ions and protons 18,19 that seem to be superior to those noted with neutrons (67% in a review of results from multiple European centers). 16 The largest series consisting of 151 patients with ACC treated with neutron radiotherapy for gross disease showed only a modest 57% local control at 5 years, 22 although an improvement in local control (88% at 40 months) has been recently demonstrated with the use of a gamma knife boost at the skull base to supplement neutron-based treatment. 23 However, both protons and high-linear energy transfer radiation suffer from the limitations of restricted availability and significantly higher cost. By contrast, the combination of chemotherapy with conventional radiation is widely available and is commonly used in the management of locally advanced squamous cell cancers of the head and neck. It has been shown to improve both locoregional control and survival when used for treating unresectable disease or for organ preservation However, little has been published regarding the application of chemoradiation for management of ACC, an uncommon cancer, most often amenable to surgical resection. This is because conventional cytotoxic chemotherapy is considered to have only modest activity in adenoid cystic carcinoma. 5 This case series suggests that concurrent singleagent platins may be effectively administered to selected patients. We have observed marked tumor responses in 14 of 16 patients (7 CRs and 7 PRs); with lasting local control in our patient population such that all of the 7 patients deemed to have had CR and 4 of the 7 with PR experienced no local progression of tumor. We must point out that the lack of data on histologic assessment of response is a weakness of the study introducing subjectivity that likely accounts for the difference in the observed rates of response among institutions (Table 1). Hence, we believe that subsequent observation of tumor progression at the primary site, which occurred in only 3 of 16 patients, may be a more reliable measure of the effectiveness of platinum-based chemoradiation in achieving locoregional control for this cancer. The RADPLAT format with intraarterial high-dose cisplatin chemoradiation seemed to be quite active with 6 of 6 patients achieving lasting local disease control, and this approach deserves further study. Although scant, there is some evidence in the literature that concurrent chemoradiation may have efficacy in ACC. Haddad et al 6 reported their experience of treating 5 patients over a 4-year period with carboplatin, AUC 1.5, and paclitaxel, 45 mg/m2 of body-surface area, administered weekly concurrently with radiation therapy, which was given in standard daily fractions of 1.8 Gy in 4 patients and 2 Gy in 1 patient to a total dose ranging between 64 and 75.6 Gy. The tumor arose in the paranasal sinuses in 4 patients and the larynx in 1 patient. With a median follow-up of 36 months, locoregional tumor control was obtained in all 5 patients. Distant metastases developed in 1 patient, but the entire cohort was alive at the time of reporting. There are also isolated case reports of successful treatment of ACC with concurrent chemoradiation 7,8 as well as a report of tumor control after intraarterial cisplatin when added to conventional therapy (orbital exenteration and radiation) in the management ACC of the lacrimal gland. 9 Our results corroborate the findings of these earlier reports that there is the potential for long-term locoregional control after concurrent chemoradiation. The observed rate of systemic metastasis (37.5%) in our review is comparable to that reported in other series (Table 2), and is the predominant tumor failure pattern in our small, retrospective case series. As the growth rate of ACC may be indolent, many patients survive with metastatic disease for extended periods. 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