Efficacy of Neutron Radiotherapy for Primary Tracheal Adenoid Cystic Carcinoma: A Single Institution Retrospective Analysis

Primary tracheal neoplasms are rare, occurring in less than 2 persons per 1,000,000 annually and thus very little data is available to guide health care practioners. Adenoid Cystic Carcinoma (ACC) is one of the most common primary tracheal neoplasms, second only to Squamous Cell Carcinoma (SCC) [1,2]. Historically, surgical resection has been the preferred method of curative treatment for ACC of the trachea [3-5]. However, due to the tumor’s indolent nature and a low index of clinical suspicion by physicians, patients often present with locally advanced neoplasms which is unresectable at the time of diagnosis. Patients presenting with ACC are sometimes less than ideal surgical candidates and even when they undergo Abstract

Citation: Patel  surgery, they are occasionally left with an incomplete surgical resection [6][7][8]. In the setting of inoperable, recurrent or incompletely resected ACC of the head and neck, neutron radiotherapy as primary treatment has been shown to be superior to photon radiotherapy [9,10]. Moreover, external beam neutron radiotherapy post-surgical resection has been suggested to improve locoregional control and overall survival [11,12].
Despite advances in treatment, ACC remains a therapeutic challenge due to its slow yet aggressive local behavior and frequent distant spread after long-term, apparent diseasefree intervals. About 30% of patients eventually develop distant metastases, which have been reported as late as 25 years after diagnosis [13]. For this reason, accumulation of complete patient data requires long follow-up and few centers have accumulated signifi cant patient numbers to report on the management of primary tracheal tumors. The benefi ts of neutron radiotherapy as a primary or adjuvant treatment remain unclear as do the benefi ts of HDR endobronchial brachytherapy. More data is needed to achieve better survival and disease-free outcome rates for treated patients [14,15]. This report updates our institutional experience treating primary adenoid cystic carcinoma of the trachea with neutron radiotherapy and reports the outcomes of treatment with and without HDR endobronchial brachytherapy.

Materials and methods
After approval by the Institutional Review Board, patients with adenoid cystic tracheal cancer were identifi ed using the multi-center cancer institution tumor database for all neoplasms of the trachea from 1993 to 2012. Thirty nine patients were identifi ed who had tumors that clearly originated from the trachea and had histologic proof of ACC.
Among the 39 ACC patients, 33 patients were treated with curative intent. Of the 33 patients, 32 received neutron beam radiotherapy as their only form of radiotherapy. One patient was treated with both neutron and photon therapy, receiving 10.7 neutron Gy with 14 photon Gy post surgical resection. Survival analysis of the 33 patients included two patients treated with surgical resection alone, 11 patients who received adjuvant neutron radiotherapy post surgical resection, and 18 patients who received neutron radiotherapy as their primary treatment. Two patients who received initial treatment of surgery and adjuvant neutron radiotherapy and 9 patients, who were treated with neutron radiotherapy alone, without surgery, were additionally treated with endobronchial brachytherapy using HDR 192 Ir source (Table 1).
Charts were reviewed for demographic features, tumor histology, tumor staging at diagnosis, treatments used and patient outcomes ( Table 2). The staging system suggested by Bhattacharyya et al was used as this has been previously used in tracheal malignancies.

Description of treatments
All patients were treated with a high-energy, Scanditronix (Uppsala, Sweden) MC 50 cyclotron. Fields were individualized according to the location and extent of the primary tumor. A margin of 2 to 3 cm was used between gross tumor volume and block edge. The median total dose was 19.2 nGy (range,14-28.8 nGy). The most commonly used fractionation schema consisted of 1.2 Gy given 4 times per week to a total dose of 19.2 nGy. Radiobiologic studies suggest an relative biological effectiveness (RBE) of 8 for ACC and 3-3.5 for normal latereacting tissues [16]. As such, a neutron dose of 19.2 Gy is estimated to be biologically equivalent to a photon dose of 154 Gy to ACC tumor and 67 Gy to normal late-reacting tissues.
To allow for acute tissue recovery, the endobronchial boost was delivered within 1 to 2 months of completing neutron radiotherapy. Endobronchial catheters were placed under general anesthesia, and treatments were delivered with a MicroSelectron 192Ir HDR unit (Nucletron, Veenendaal, The Netherlands). The longitudinal tumor extent was treated to a dose 3.5 Gy, to a median depth of 0.75 cm (range, 0.5-1 cm). A total of two treatments were delivered, for a cumulative dose of 7 Gy. The two treatments were separated by 1 week.  If death data was not available from patient fi les or from the social security registries, patients were censored based on the last date seen

Overall survival, disease-free survival, and locoregional control
Disease-free and overall survival, the follow-up time was from the date of fi rst treatment to date of recurrence. Patients with unknown recurrence status after their last appointment were censored based on the last date seen.
The fi ve-year actuarial overall survival rate and the median overall survival for the entire cohort were 77% and 89.5 months.  Figure 5a. Similarly, the disease-free survival for this same cohort was 39% vs 40% (p=0.216) as shown in Figure 5b. Patients in our cohort treated with adjuvant neutron radiotherapy post surgical resection and  Univariate analysis was performed to assess the parameters predictive of overall survival in this patient population ( Table   1). The parameters examined included age, tobacco use, sex, tumor grade, tumor size, treatment type, dose of radiation and  HDR endobronchial brachytherapy. In our cohort, increased age, tobacco use, the female sex and a tumor size greater than four centimeters were all associated with increased hazard ratio but were not statistically signifi cant (p=0.06, 0.27, 0.72, 0.24 respectively). Regarding treatment modalities, patients who underwent neutron radiotherapy alone appeared to have lower hazard ratio as compared to patients treated with surgery alone or with neutron radiotherapy adjuvantly post surgical resection (p=0.68 and p=0.37, respectively). Those who did not receive HDR endobronchial brachytherapy appear to have a somewhat higher hazard ratio, that like the other univariate analyses was not statistically signifi cant (p=0.76).        or increase in radiation dosage ( Table 3). None of the patient who received radiation had greater than grade 3 toxicity.

Discussion
Primary tracheal tumors are exceedingly rare, and little information is available on effi cacious treatments. Randomized trials do not exist for primary ACC of the trachea. Therefore we must rely on case reports and small retrospective studies to determine treatment options that will provide the greatest believed to increase the overall fi ve-year survival [17][18][19] .
In this discussion, we address the trends observed from the data analysis of 33 patients with ACC in our study. This report updates our institutional experience with neutron radiotherapy as primary treatment for locally advanced ACC of the trachea and the effi cacy of HDR endobronchial brachytherapy.
There is little data to support any single treatment modality for tracheal ACC. However, the largest published experiences are with surgical resection and thus surgery remains the standard treatment against which all other treatment modalities are compared [20][21][22]. While surgical resection has been the preferred method of curative treatment for ACC, it historically is only performed on less advanced tumors that tend to have an inherently better prognosis [23]. The classifi cation of tumors as not surgically resectable is based on extensive regional disease or airway compromise [24]. Unfortunately, due to the invasive nature of ACC approximately 25% of all patients will present with locally advanced disease and are consequently ineligible for complete surgical resection In a recent study by Chen et al. that looked at the treatment modalities for 52 patients with ACC of the trachea, no signifi cant disease free survival and overall survival were seen between patients with unresectable tumors who received radiation therapy alone versus those who received complete resection without adjuvant radiation therapy.
Additionally, this study found improved disease free survival and overall survival in patients who received postoperative radiation therapy after incomplete resection [25].
Up until recently, photon radiotherapy has been the treatment of choice for these patients for whom surgery is not an option. However, previous studies have now shown a higher RBE of neutron radiotherapy on slowly progressing ACC tumors over photon radiotherapy [26]. Batterman, et al.  should therefore be interpreted with this in mind. It makes it diffi cult to compare to this dataset as ACC patients can live many years with disease.
This data supports the Bittner, et al. conclusion that neutron radiotherapy is an effective treatment for locally advanced tracheal ACC. The data demonstrates a survival benefi t for patients with unresectable ACC tracheal tumors receiving neutron radiotherapy as a primary treatment with a fi ve-year overall survival of 93% and a fi ve-year disease-free survival of 38%. In terms of disease-free survival, patients receiving surgery had improved fi ve-year outcomes over those receiving neutron radiotherapy only. This is likely due to patients in the surgical treatment group having less advanced disease state at diagnosis.
These numbers are encouraging in the search for a defi nitive treatment for tracheal ACC. However, it is important to note that the data presented in this review is not statistically signifi cant due to the small sample size. This mirrors the low incidence of tracheal ACC in the population.
Beginning in November 2000 HDR endobronchial brachytherapy was offered to eligible patients with ACC of the trachea in attempts to address suboptimal local control rates [27]. HDR endobronchial brachytherapy was chosen as an adjuvant therapy because it was believed to be the safest and most direct way of increasing the dose at the site of the tumor while avoiding late tissue toxicity. HDR was performed on eleven ACC patients in our cohort. Consistent with Bittner, et al., our data analysis did not detect a statistically signifi cant difference between patients who did and did not receive HDR endobronchial brachytherapy in locoregional control (63% vs. 87%, p=0.469), fi ve-year disease-free survival (46% vs. 44%, p=0.251) or fi ve-year overall survival (89% vs. 72%, p=0.489).

Conclusion
In our cohort the failure sites were evenly distributed between local and distant, highlighting the need for both better local and systemic therapies. Local control continues to be a challenge, but data with respect to primary neutron radiotherapy and HDR endobronchial brachytherapy are certainly encouraging, especially when considering a patient population with locally advanced disease. The data supports the conclusion that ACC of the trachea can be treated with a combination of neutron radiation and HDR boost with favorable outcomes.