C. Jillian Tsai

The prevalence and risk factors associated with osteoradionecrosis of the jaw in oral and oropharyngeal cancer patients treated with intensity-modulated radiation therapy (IMRT): The Memorial Sloan Kettering Cancer Center experience

OBJECTIVE To determine the prevalence and correlation of various risk factors [radiation dose, periodontal status, alcohol and smoking] to the development of osteoradionecrosis (ORN). PATIENTS AND METHODS The records of 1023 patients treated with IMRT for oral cavity cancer (OCC) and oropharyngeal cancer (OPC) between 2004 and 2013 were retrospectively reviewed to identify patients who developed ORN. Fisher exact tests were used to analyze patient characteristics between ORN patients with OCC and OPC. Paired Wilcoxon tests were used to compare the dose volumes to the ORN and contralateral non-ORN sites. To evaluate an association between ORN and risk factors, a case-control comparison was performed. One to 2 ORN-free patients were selected to match each ORN patient by gender, tumor site and size. General estimation equations models were used to compare the risk factors in ORN cases and matched controls. RESULTS 44 (4.3%) patients developed ORN during a median follow-up time of 52.5months. In 82% of patients, ORN occurred spontaneously. Patients with OPC are prone to develop ORN earlier compared to patients with OCC (P=0.03). OPC patients received a higher Dmax compared to OCC patients (P=0.01). In the matched case-control analysis the significant risk factors on univariate analysis were poor periodontal status, history of alcohol use and radiation dose (P=0.03, 0.002 and 0.009, respectively) and on multivariate analysis were alcohol use and radiation dose (P=0.004 and 0.026, respectively). CONCLUSION In our study, higher radiation dose, poor periodontal status and alcohol use are significantly related to the risk of developing ORN.

Long-term patterns of relapse and survival following definitive intensity-modulated radiotherapy for non-endemic nasopharyngeal carcinoma.

BACKGROUND We report treatment outcomes for a large non-endemic cohort of patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) and chemotherapy. METHODS We identified 177 consecutive patients with newly diagnosed, non-metastatic nasopharyngeal cancer treated with definitive IMRT between 1998 and 2011. Endpoints included local, regional, distant control, and overall survival. RESULTS Median follow-up was 52months. The 3-/5-year actuarial rates of local control, regional control, distant control, and overall survival were 92%/83%, 93%/91%, 86%/83%, and 87%/74%, respectively. The median time to local recurrence was 30months; the annual hazard of local recurrence did not diminish until the 6th year of follow-up. CONCLUSIONS Overall, we observed excellent rates of disease control and survival consistent with initially reported results from our institution. Attaining locoregional control in patients with extensive primary tumors remains a significant clinical challenge. With mature follow-up we observed that more than half of observed local relapses occurred after 2years, a pattern distinct from that of carcinomas arising from other head and neck sites. These findings raise the possibility that patients with NPC may benefit from close follow-up during post-treatment years 3-5.

Radiographic osteoradionecrosis of the jaw with intact mucosa: Proposal of clinical guidelines for early identification of this condition

Osteoradionecrosis (ORN) remains an unintended debilitating complication of radiation therapy despite the advent of intensity-modulated radiation therapy (IMRT) which aims to deliver doses of radiation to the tumor site while minimizing doses to healthy tissues [[1], [2], [3], [4]. The etiopathogenesis of ORN has been attributed to the avascular effect of radiation to the bone resulting in hypoxia, hypovascularity, and hypocellularity [5], [6]. Radiation-induced fibrosis has also been implicated in the pathophysiology of ORN [7. Recent studies have placed reported incidences of ORN at 1–30% [2], [8], [9], [10], [11]. ORN of the jaw was defined as an area of exposed necrotic bone greater than 1 cm in an area of previous irradiation that failed to heal after 6 months [5]. This definition of ORN has been used for years and still remains the most widely used clinical criterion for the diagnosis of ORN though it fails to incorporate cases with radiologic evidence of necrosis with intact mucosa [5], [12], [13], [14], [15]. Although a report by Van Merkesteyn et al. described a case of ORN of the jaw with intact mucosa [16], subsequently only two series have likewise reported this condition. In 2000, Store and Boysen reported 17 patients with radiographic osteoradionecrosis of the jaw (rORN) with intact mucosa at initial diagnosis as did He et al. in a recent article where they described 16 patients presenting with rORN with intact mucosa [17], [18]Thus, it appears that rORN with intact mucosa is underdiagnosed. The objectives of this article are to: 1. Describe new cases of rORN with intact mucosa. 2. Correlate the dosimetric analyses of the involved area with the radiographic presentation and to determine the best predictor of rORN with intact mucosa. 3. Propose modification of Store and Boysen’s staging system of ORN. 4. Propose clinical guidelines for early identification of rORN with intact mucosa.

Sparing of high retropharyngeal nodal basins in patients with unilateral oropharyngeal carcinoma treated with intensity modulated radiation therapy

PURPOSE The introduction of intensity modulated radiotherapy (IMRT) has facilitated dose painting and sparing of uninvolved/low-risk nodal basins in head and neck cancers. In oropharynx cancer (OPC), the need for elective coverage of uninvolved high contralateral retropharyngeal (RP) nodes and the risk associated with sparing this region remain unclear. We examined outcomes of OPC patients treated with IMRT and omission of contralateral high RP coverage. METHODS AND MATERIALS We identified 102 OPC patients with cN0-N2b disease treated with definitive IMRT with or without concurrent chemotherapy between 2010 and 2013. The contralateral RP nodal basins superior to the vertebral level of C1 were omitted from the elective IMRT field for all patients. Of the 67 patients (66%) with p16 status available, 63 (94%) were p16+. We used the Kaplan-Meier method to estimate overall survival, as well as freedom from local failure, regional failure, distant failure, and retropharyngeal failure. RESULTS The median follow-up was 26.9 months (range, 3.0-59.9 months). There were no failures in the treated ipsilateral RP nodes or the spared contralateral high RP nodes in the entire cohort. In the p16+ cohort and the entire cohort, the 2-year rates of overall survival and freedom from local, regional, distant, and retropharyngeal failure were 98.0% and 95.1%, 98.1% and 97.7%, 96.4% and 96.7%, 98.1% and 95.1%, and 100% and 100%, respectively. CONCLUSIONS Omission of contralateral high RP nodes in patients with p16+ OPC with unilateral disease is safe.

Cervical nodal level V can safely be omitted in the treatment of locally advanced oropharyngeal squamous cell carcinoma with definitive IMRT.

OBJECTIVES Patients treated with definitive chemoradiation for oropharyngeal squamous cell carcinoma (OPC) experience excellent outcomes but treatment toxicities remain significant. The adoption of intensity modulated radiation therapy (IMRT) reduced morbidity by allowing targeting of at risk areas while sparing uninvolved regions. We explored whether level V lymphatics (LVN) can be omitted from elective volumes in OPC. MATERIALS AND METHODS This analysis included 408 patients treated for stage III/IV OPC with IMRT at our institution. For 295 (72.3%) patients, bilateral LVN were covered, while LVN were omitted in 113 (27.7%). Nodal staging was N2a or greater in 324 patients (79.4%). All but one received concurrent chemotherapy. Actuarial regional recurrence was calculated using the KM method with the event of interest defined as any regional recurrence; all others were censored. Univariate and multivariate analyses were performed on variables significantly associated with both the inclusion of elective LVN and regional recurrence. RESULTS After a median follow-up of 63.6months (range, 1.3-125months), there were no level V failures in either group. The 2-year cumulative rate of regional failure (RF) was 4.5% (95% CI=2.9-6.6) in the overall cohort, 2.2% (95% CI=0.1-5.9) in the LVN untreated group, and 5.4% (95% CI=3.4-8.1) in the LVN treated group. After adjusting for Stage and tobacco status, there was no significant difference between the two groups in RF (HR=1.75 95% CI=(0.61-5.07), p=0.30). CONCLUSION LVN can be safely omitted from the clinical target volume in locally advanced OPC without gross LVN involvement.

Intensity-Modulated Radiation Therapy With or Without Concurrent Chemotherapy in Nonanaplastic Thyroid Cancer with Unresectable or Gross Residual Disease

BACKGROUND Differentiated thyroid cancer typically has an indolent clinical course but can cause significant morbidity by local progression. Oncologic surgical resection can be technically difficult due to the proximity to critical normal structures in the neck. Our objective was to review the safety, feasibility, and outcomes of definitive-intent intensity-modulated radiation therapy (IMRT) and to analyze whether patients receiving concurrent chemotherapy (CC-IMRT) had higher rates of disease control and survival over IMRT alone in patients with unresectable or gross residual disease (GRD). METHODS Eighty-eight patients with GRD or unresectable nonanaplastic, nonmedullary thyroid cancer treated with definitive-intent IMRT between 2000 and 2015 were identified. Local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and overall survival (OS) were evaluated using the Kaplan-Meier method. Univariate and multivariate analyses using cox regression were used to determine the impact of clinical conditions and treatment on LPFS, DMFS, and OS. RESULTS Of the 88 patients identified, 45 (51.1%) were treated CC-IMRT and 43 (48.9%) were treated with IMRT alone. All patients treated with CC-IMRT received weekly doxorubicin (10 mg/m2). The median follow-up among surviving patients was 40.3 months and 29.2 months for all patients. The LPFS at 4 years was 77.3%. Patients receiving CC-IMRT had higher LPFS compared with IMRT alone (CC-IMRT 85.8% vs. IMRT 68.8%, p = 0.036). The 4-year OS was 56.3% for all patients. Patients treated with CC-IMRT had higher OS compared to patients treated with IMRT alone (CC-IMRT 68.0% vs. IMRT 47.0%, p = 0.043). On multivariate analysis, receipt of concurrent chemotherapy was associated with a lower risk of death (HR 0.395, p = 0.019) and lower risk of local failure (HR 0.306, p = 0.042). Grade 3+ acute toxicities occurred in 23.9% of patients, the most frequent being dermatitis (18.2%) and mucositis (9.1%). 17.1% of patients required a percutaneous endoscopic gastrostomy (PEG) tube during or shortly after completion of RT, with 10.1% of patients needing a PEG more than 12 months after therapy. The rates of acute and late toxicities were not statistically higher in the CC-IMRT cohort, although trends towards higher toxicity in the CC-IMRT were present for dermatitis and PEG requirement. CONCLUSIONS IMRT is a safe and effective means to achieve local control in patients with unresectable or incompletely resected nonanaplastic, nonmedullary thyroid cancer. Concurrent doxorubicin was not associated with worse toxicity and should be considered in these patients given its potential to improve local control and overall survival.

Impact of Insurance Coverage on Outcomes in Primary Breast Sarcoma

Private insurance is associated with better outcomes in multiple common cancers. We hypothesized that insurance status would significantly impact outcomes in primary breast sarcoma (PBS) due to the additional challenges of diagnosing and coordinating specialized care for a rare cancer. Using the National Cancer Database, we identified adult females diagnosed with PBS between 2004 and 2013. The influence of insurance status on overall survival (OS) was evaluated using the Kaplan–Meier estimator with log-rank tests and Cox proportional hazard models. Among a cohort of 607 patients, 67 (11.0%) had Medicaid, 217 (35.7%) had Medicare, and 323 (53.2%) had private insurance. Compared to privately insured patients, Medicaid patients were more likely to present with larger tumors and have their first surgical procedure further after diagnosis. Treatment was similar between patients with comparable disease stage. In multivariate analysis, Medicaid (hazard ratio (HR), 2.47; 95% confidence interval (CI), 1.62–3.77; p < 0.001) and Medicare (HR, 1.68; 95% CI, 1.10–2.57; p=0.017) were independently associated with worse OS. Medicaid insurance coverage negatively impacted survival compared to private insurance more in breast sarcoma than in breast carcinoma (interaction p < 0.001). In conclusion, patients with Medicaid insurance present with later stage disease and have worse overall survival than privately insured patients with PBS. Worse outcomes for Medicaid patients are exacerbated in this rare cancer.

Rising rates of bilateral mastectomy with reconstruction following neoadjuvant chemotherapy: Breast surgery after neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NAC) is used to allow more limited breast surgery without compromising local control. We sought to evaluate nationwide surgical trends in patients with operable breast cancer treated with NAC and factors associated with surgical type. We used the National Cancer Database to identify 235,339 women with unilateral T1‐3 N0‐3 M0 breast cancer diagnosed between 2010 and 2014 and treated with surgery and chemotherapy. Of these, 59,568 patients (25.3%) were treated with NAC. Rates of pathological complete response (pCR) to NAC increased from 33.3% at the start of the study period in 2010 to 46.3% at the end of the period in 2014 (p = 0.02). Rates of breast‐conserving surgery (BSC) changed little, from 37.0 to 40.8% (p = 0.22). Although rates of unilateral mastectomy decreased from 43.3 to 34.7% (p = 0.02) and rates of bilateral mastectomy without immediate reconstruction remained similar (11.7–11.5%; p = 0.82), rates of bilateral mastectomy with immediate reconstruction rose from 8.0 to 13.1% (p = 0.02). Patients who were younger, with private/managed care insurance, and diagnosed in more recent years were more likely to achieve pCR; however, these same characteristics were associated with receipt of bilateral mastectomy (vs. BCS). In addition, non‐Hispanic white ethnic and higher area education attainment were both associated with bilateral mastectomy. These findings did not differ by age or molecular subtype. Further study of nonclinical factors that influence selection of more extensive surgery despite excellent response to NAC is warranted.