Radiotherapy Use and Incidence of Locoregional Recurrence in Patients With Favorable-Risk, Node-Positive Breast Cancer Enrolled in the SWOG S1007 Trial.

Importance: Little is known about regional nodal irradiation (RNI) practice patterns or rates of locoregional recurrence (LRR) with and without RNI in patients with limited nodal disease and favorable biology treated with modern surgical and systemic therapy, including approaches that de-escalate those latter treatments. Objective: To investigate how often patients with low-recurrence score breast cancer with 1 to 3 nodes involved receive RNI, incidence and predictors of LRR, and associations between locoregional therapy and disease-free survival. Design, Setting, and Participants: In this secondary analysis of the SWOG S1007 trial, patients with hormone receptor-positive, ERBB2-negative breast cancer, and a Oncotype DX 21-gene Breast Recurrence Score assay result of no more than 25, were randomized to endocrine therapy alone vs chemotherapy then endocrine therapy. Prospectively collected radiotherapy information was collected from 4871 patients treated in diverse settings. Data were analyzed June 2022 to April 2023. Exposure: Receipt of RNI (targeting at least the supraclavicular region). Main Outcome(s) and Measure(s): Cumulative incidence of LRR was calculated by locoregional treatment received. Analyses were assessed for associations between invasive disease-free survival (IDFS) and locoregional therapy, adjusted for menopausal status, treatment group, recurrence score, tumor size, nodes involved, and axillary surgery. Radiotherapy information was recorded in the first year after randomization, so survival analyses were landmarked as starting at 1 year among those still at risk. Results: Of 4871 female patients (median [range] age, 57 [18-87] years) with radiotherapy forms, 3947 (81.0%) reported radiotherapy receipt. Of 3852 patients who received radiotherapy and had complete information on targets, 2274 (59.0%) received RNI. With a median follow-up of 6.1 years, the cumulative incidence of LRR by 5 years was 0.85% among patients who received breast-conserving surgery and radiotherapy with RNI; 0.55% after breast-conserving surgery with radiotherapy without RNI; 0.11% after mastectomy with postmastectomy radiotherapy; and 1.7% after mastectomy without radiotherapy. Similarly low LRR was observed within the group assigned to endocrine therapy without chemotherapy. The rate of IDFS did not differ by RNI receipt (premenopausal: hazard ratio [HR], 1.03; 95% CI, 0.74-1.43; P = .87; postmenopausal: HR, 0.85; 95% CI, 0.68-1.07; P = .16). Conclusions and Relevance: In this secondary analysis of a clinical trial, RNI use was divided in the setting of biologically favorable N1 disease, and rates of LRR were low even in patients who did not receive RNI. Disease-free survival was not associated with RNI receipt; omission of chemotherapy among patients similar to those enrolled in the S1007 trial is not an independent indication for use of RNI.

Challenges and Opportunities With the Use of Hypofractionated Radiation Therapy in Cancer Care: Regional Perspectives From South Korea, Japan, Singapore, and Australia.

Hypofractionated radiotherapy schedules provide higher per-fraction radiation doses delivered in fewer fractions than conventional schedules. This novel delivery method is supported by a large body of clinical trial evidence across various cancer sites in both curative and palliative settings. Hypofractionation is associated with benefits such as lower costs, improved patient access and increased treatment precision, which has led to its inclusion in various treatment guidelines. Despite this, utilization is not uniform across cancer sites and geographic regions due to reasons such as reimbursement models, nuances in healthcare systems, and professional culture. Key factors to ensure patients benefit from access to high quality radiotherapy include publishing clinical evidence, cross-country collaboration to fill knowledge gaps, reviewing reimbursement models, and improving patient advocacy in treatment decision-making.

Radiation nephropathy: Mechanisms of injury and recovery in a murine model.

BACKGROUND: Radiation nephropathy (RN) can be a severe late complication for patients treated with radiotherapy (RT) targeting abdominal and paraspinal tumors. Recent studies investigating the mechanisms of RT-mediated injury in the kidney have demonstrated that RT disrupts the cellular integrity of renal podocytes leading to cell death and loss of renal function. AIM: To determine if RT-induced renal dysfunction is associated with alterations in podocyte and glomerular function, and whether RT-induced podocyte alterations were associated with changes in the glomerular basement membrane (GBM). METHODS: C57BL/6 mice were treated with focal bilateral X-irradiation using a single dose (SD) of 4 Gy, 10 Gy, or 14 Gy or fractionated dosing (FD) of 5x6Gy or 24x2Gy. Then, 10-40 weeks after RT parameters of renal function were measured, along with glomerular filtration rate (GFR) and glomerular histology, as well as ultrastructural changes in GBM by transmission electron microscopy. RESULTS: RT treatment resulted in persistent changes in renal function beginning at 10 weeks with little recovery up to 40 weeks post RT. Dose dependent changes were seen with increasing SD but no functional sparing was evident after FD. RT-induced loss of renal function was associated with expansion of the GBM and significant increases in foot process width, and associated with significant reduction in GFR, podocyte loss, and renal fibrosis. CONCLUSION: For the first time, these data show that expansion of the GBM is one consequence of radiation injury, and disarrangement of the GBM might be associated with the death of podocytes. These data shed new light on the role podocyte injury and GBM in RT-induced renal dysfunction.

Post-mastectomy radiation therapy in HER-2 positive breast cancer after primary systemic therapy: Pooled analysis of TRYPHAENA and NeoSphere trials.

PURPOSE: The role of post-mastectomy radiation therapy (PMRT) following primary systemic therapy (PST) in HER-2 positive breast cancer (Her2 + BC) remains poorly understood. The current study evaluates PMRT based on the pathological response to PST in Her2 + BC. METHODS AND MATERIALS: TRYPHAENA and NeoSphere are randomized phase II trials that investigated PST for Her2 + BC. Our study is a pooled analysis of both trials, including 312 node-positive patients treated with HER-2 targeted PST followed by mastectomy with or without PMRT. The primary endpoint is loco-regional recurrence-free survival (LRRFS). RESULTS: Our analysis included 172 (55%) patients who achieved complete nodal pathological response (ypN0) and 140 (45%) patients who did not. Patients with ypN0 had a 5-year LRRFS of 97% in both, the PMRT and no PMRT, groups (p = 0.94). Patients with ypN + had 5-year LRRFS of 89% in the PMRT group and 82% in the no PMRT group (p = 0.17). Patients with ypN1 (n = 62) disease who received PMRT (n = 40) had a 5-year LRRFS of 85% as compared to 89% in those who did not (n = 22); (p = 0.60). A significant LRRFS difference was noted in patients with ypN2-3 (n = 78) disease who received PMRT (n = 53) compared to those who did not (n = 25) (5-year LRRFS 92% vs. 75%; p = 0.019). On multivariate analysis, clinical nodal disease at diagnosis and ypN0 were significantly associated with loco-regional recurrence (LRR). CONCLUSIONS: Her2 + BC patients who achieve ypN0 after PST have excellent locoregional-control which supports de-escalation of PMRT. In contrast, patients with ypN2-3 disease derive significant benefit from PMRT. Clinical nodal stage at presentation and ypN0 status are significantly associated with LRR risk in Her2 + BC.

Urinary 20-HETE: A prospective Non-Invasive prognostic and diagnostic marker for diabetic kidney disease.

INTRODUCTION: The identification and validation of a non-invasive prognostic marker for early detection of diabetic kidney disease (DKD) can lead to substantial improvement in therapeutic decision-making. OBJECTIVES: The main objective of this study is to assess the potential role of the arachidonic acid (AA) metabolite 20-hydroxyeicosatetraenoic (20-HETE) in predicting the incidence and progression of DKD. METHODS: Healthy patients and patients with diabetes were recruited from the Hamad General Hospital in Qatar, and urinary 20-HETE levels were measured. Data analysis was done using the Statistical Package for Social Sciences (SPSS). RESULTS: Our results show that urinary 20-HETE-to-creatinine (20-HETE/Cr) ratios were significantly elevated in patients with DKD when compared to patients with diabetes who did not exhibit clinical signs of kidney injury (p < 0.001). This correlation was preserved in the multivariate linear regression accounting for age, diabetes, family history of kidney disease, hypertension, dyslipidemia, stroke and metabolic syndrome. Urinary 20-HETE/Cr ratios were also positively correlated with the severity of kidney injury as indicated by albuminuria levels (p < 0.001). A urinary 20-HETE/Cr ratio of 4.6 pmol/mg discriminated between the presence and absence of kidney disease with a sensitivity of 82.2 % and a specificity of 67.1%. More importantly, a 10-unit increase in urinary 20-HETE/Cr ratio was tied to a 10-fold increase in the risk of developing DKD, suggesting a 20-HETE prognostic efficiency. CONCLUSION: Taken together, our results suggest that urinary 20-HETE levels can potentially be used as non-invasive diagnostic and prognostic markers for DKD.

A phase II single arm study of Nivolumab with stereotactic Ablative radiation Therapy after induction chemotherapy in CHOlangiocarcinoma (NATCHO).

BACKGROUND: Intrahepatic cholangiocarcinoma (CCA) is amongst the most common primary liver tumors worldwide. CCA carries a bad prognosis prompting research to establish new treatment modalities other than surgery and the current chemotherapeutic regimens adopted. Hence, this trial explores a new therapeutic approach, to combine stereotactic body radiation therapy (SBRT) and immunotherapy (Nivolumab), and asses its clinical benefit and safety profile after induction chemotherapy in CCA. METHODOLOGY: This is a Phase II open-label, single-arm, multicenter study that investigates Nivolumab (PD-1 inhibitor) treatment at Day 1 followed by SBRT (30 Gy in 3 to 5 fractions) at Day 8, then monthly Nivolumab in 40 patients with non-resectable locally advanced, metastatic or recurrent intrahepatic or extrahepatic CCA. Eligible patients were those above 18 years of age with a pathologically and radiologically confirmed diagnosis of non-resectable locally advanced or metastatic or recurrent intrahepatic or extrahepatic CCA, following 4 cycles of cisplatin-based chemotherapy with an estimated life expectancy of more than 3 months, among other criteria. The primary endpoint is the progression free survival (PFS) rate at 8 months and disease control rate (DCR). The secondary endpoints are overall survival (OS), tumor response rate (TRR), duration of response, evaluation of biomarkers: CD3 + , CD4 + and CD8 + T cell infiltration, as well as any change in the PD-L1 expression through percutaneous core biopsy when compared with the baseline biopsy following 1 cycle of Nivolumab and SBRT. DISCUSSION: SRBT alone showed promising results in the literature by both inducing the immune system locally and having abscopal effects on distant metastases. Moreover, given the prevalence of PD-L1 in solid tumors, targeting it or its receptor has become the mainstay of novel immunotherapeutic drugs use. A combination of both has never been explored in the scope of CCA and that is the aim of this study. TRIAL REGISTRATION: ClinicalTrials.gov NCT04648319 , April 20, 2018.

SMPDL3b modulates radiation-induced DNA damage response in renal podocytes.

The kidneys are radiosensitive and dose-limiting organs for radiotherapy (RT) targeting abdominal and paraspinal tumors. Excessive radiation doses to the kidneys ultimately lead to radiation nephropathy. Our prior work unmasked a novel role for the lipid-modifying enzyme, sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), in regulating the response of renal podocytes to radiation injury. In this study, we investigated the role of SMPDL3b in DNA double-strand breaks (DSBs) repair in vitro and in vivo. We assessed the kinetics of DSBs recognition and repair along with the ATM pathway and nuclear sphingolipid metabolism in wild-type (WT) and SMPDL3b overexpressing (OE) human podocytes. We also assessed the extent of DNA damage repair in SMPDL3b knock-down (KD) human podocytes, and C57BL6 WT and podocyte-specific SMPDL3b-knock out (KO) mice after radiation injury. We found that SMPDL3b overexpression enhanced DSBs recognition and repair through modulating ATM nuclear shuttling. OE podocytes were protected against radiation-induced apoptosis by increasing the phosphorylation of p53 at serine 15 and attenuating subsequent caspase-3 cleavage. SMPDL3b overexpression prevented radiation-induced alterations in nuclear ceramide-1-phosphate (C1P) and ceramide levels. Interestingly, exogenous C1P pretreatment radiosensitized OE podocytes by delaying ATM nuclear foci formation and DSBs repair. On the other hand, SMPDL3b knock-down, in vitro and in vivo, induced a significant delay in DSBs repair. Additionally, increased activation of apoptosis was induced in podocytes of SMPDL3b-KO mice compared to WT mice at 24 h post-irradiation. Together, our results unravel a novel role for SMPDL3b in radiation-induced DNA damage response. The current work suggests that SMPDL3b modulates nuclear sphingolipid metabolism, ATM nuclear shuttling, and DSBs repair.

Is breast conservation superior to mastectomy in early stage triple negative breast cancer?

PURPOSE: Compare overall survival (OS) and breast cancer-specific survival (BCSS) outcomes of breast conservative therapy (BCT) and mastectomy in a large cohort of patients with early-stage triple negative breast cancer (TNBC), using a propensity score-based matching approach. METHODS: Surveillance, Epidemiology, and End Results (SEER) database was used to study the role of RT in early stage TNBC. Primary end points were OS and BCSS. Cox proportional hazard regression models and Kaplan-Meier plots were used to generate the desired outcomes. Propensity score matching was done to minimize bias. RESULTS: 12,761 patients with T1-2N0M0 TNBC as their first malignancy were retrieved. Of these 7237 had lumpectomy with RT, and 5524 had mastectomy only. Age, race, marital status, tumor laterality, grade and stage, and receipt of chemotherapy were prognostic variables for OS and BCSS. Among 4848 matched subjects, the 5-year OS was significantly higher in patients with lumpectomy and RT (89%) compared to mastectomy alone (84.5%) (p-value <0.001). Similarly, BCSS was significantly higher in patients with lumpectomy and RT (93%) compared to mastectomy alone (91%) (p-value <0.001). On subgroup analysis, patients who are younger than 40 had similar survival outcomes after either mastectomy alone or lumpectomy with RT. However, those who are older than 60, have any grade or T stage had better survival outcomes with lumpectomy and RT. CONCLUSIONS: Overall, lumpectomy followed by RT is associated with better OS and BCSS compared to mastectomy in T1-2N0M0 TNBC patients. Further research is needed to determine the optimal treatment strategy for specific patient subgroups.

Evaluation of Cardiotoxicity in HER-2-Positive Breast Cancer Patients Treated With Radiation Therapy and Trastuzumab.

PURPOSE: Trastuzumab is associated with cardiac dysfunction in patients with human epidermal growth factor receptor 2 (HER-2)-positive breast cancer. The current study examines the effect of radiation therapy (RT) on cardiotoxicity in this patient population. METHODS AND MATERIALS: The Herceptin Adjuvant (HERA) trial is a phase 3 prospective, randomized clinical trial that established the efficacy of trastuzumab in HER-2-positive breast cancer. The current study is a retrospective analysis of 3321 trial patients treated with trastuzumab, with or without RT. Cardiac function was closely monitored over a median follow-up period of 11 years. The primary endpoint of the current study was to determine the effect of RT on left ventricular ejection fraction (LVEF) and the occurrence of cardiovascular events. RESULTS: Patients were divided into 3 groups: 1270 patients received trastuzumab and left-sided RT (group 1); 1271 patients received trastuzumab and right-sided RT (group 2); and 780 patients received trastuzumab with no RT (group 3). The incidence of decline in LVEF documented by echocardiography was 9.18%, 8.99%, and 8.80%, respectively, with no significant differences among the 3 groups (P = .073). The incidence of cardiovascular events was low in all groups, with the lowest incidence noted in group 3 (0.62%) followed by group 2 (0.92%) and group 1 (1.08%) (P = .619). Univariate and multivariate competing-risks regression showed that left-sided and right-sided RT delivery did not significantly increase the risk of LVEF decline or cardiovascular events. CONCLUSIONS: Our analysis of the HERA trial suggests that RT does not significantly increase the risk of cardiotoxicity in HER-2-positive breast cancer patients treated with trastuzumab. Continued monitoring of patients is needed to investigate late effects of contemporary treatments for breast cancer patients.

Post-mastectomy Radiation Therapy in Triple-Negative Breast Cancer Patients: Analysis of the BEATRICE Trial.

PURPOSE: Post-mastectomy radiation therapy (PMRT) improves locoregional control and overall survival in patients with breast cancer. With the evolution of systemic therapy, the benefit of PMRT in patients with triple-negative disease requires further evaluation. PATIENTS AND METHODS: BEATRICE is a phase III randomized clinical trial that examined the efficacy of bevacizumab in patients with triple-negative breast cancer (TNBC). The current study is a retrospective analysis of data on patients enrolled and treated with mastectomy and systemic therapy. The primary endpoint was determining the effect of PMRT on locoregional recurrence rates (LRR). Hazard ratios were estimated using Cox regression, and LRR curves were generated by the Kaplan-Meier method. RESULTS: In total, 940 patients were included in our analysis, of whom 359 (38.2%) received PMRT while 581 (61.8%) did not. At median follow-up of 5 years, no significant difference in LRR was noted between the PMRT and no PMRT groups in node-negative patients (HR = 1.09). Patients with N1 disease had 5-year LRR-free survival of 96% for PMRT versus 91% for no PMRT (HR = 0.46). Most N2 patients received PMRT and had 5-year LRR-free survival of 76%. CONCLUSION: PMRT benefit in TNBC patients treated with modern systemic therapy is lower than historical reports. Delivery of PMRT in patients with N1 disease enrolled in the BEATRICE trial was not shown to improve local control. As this might be due to patient selection for PMRT, future randomized controlled trials are required to assess the role of PMRT in this patient population.

Glioblastoma multiforme metastasizing to the skin, a case report and literature review.

Glioblastoma Multiforme (GBM) is the most common primary central nervous system (CNS) malignancy in adults. It is very aggressive and is notorious for its fast and local invasion of nearby brain parenchyma. Consequently, the overall survival (OS) of patients with GBM is short despite resection, radiotherapy and chemotherapy regimens. The most common sites of metastasis of GBM are the lungs and pleura, cervical lymph nodes, and bone. Metastasis to the skin is a rare event and to our knowledge, there are less than 30 cases of GBM metastasizing to cutaneous or subcutaneous tissue described in the literature. None of these cases were diagnosed and/or treated in the Middle East region; and the majority of the metastases found were adjacent to the site of surgery undergone to remove the primary malignancy. We present the case of a 53-year-old male diagnosed with GBM and later showing signs of metastases at the anterio-auricular side of his face near-distant from the site of previous surgery done to remove the primary tumor.

Crosstalk Between SMPDL3b and NADPH Oxidases Mediates Radiation-Induced Damage of Renal Podocytes.

Patients undergoing radiotherapy (RT) for various tumors localized in the abdomen or pelvis often suffer from radiation nephrotoxicity as collateral damage. Renal podocytes are vulnerable targets for ionizing radiation and contribute to radiation-induced nephropathies. Our prior work previously highlighted the importance of the lipid-modifying enzyme sphingomyelinase acid phosphodiesterase like 3b (SMPDL3b) in modulating the radiation response in podocytes and glomerular endothelial cells. Hereby, we investigated the interplay between SMPDL3b and oxidative stress in mediating radiation injury in podocytes. We demonstrated that the overexpression of SMPDL3b in cultured podocytes (OE) reduced superoxide anion generation and NADPH oxidase activity compared to wild-type cells (WT) post-irradiation. Furthermore, OE podocytes showed downregulated levels of NOX1 and NOX4 after RT. On the other hand, treatment with the NOX inhibitor GKT improved WTs' survival post-RT and restored SMPDL3b to basal levels. in vivo, the administration of GKT restored glomerular morphology and decreased proteinuria in 26-weeks irradiated mice. Taken together, these results suggest a novel role for NOX-derived reactive oxygen species (ROS) upstream of SMPDL3b in modulating the response of renal podocytes to radiation.

Oligometastatic breast cancer: Are we there yet?

Patients with metastatic breast cancer are usually considered incurable. Recent advances have resulted in significant improvements in survival for patients with metastatic breast cancer. Due to the lack of randomised trials and heterogeneous disease biology, treatment decisions for patients with oligometastatic breast cancer vary widely. Some patients are treated similar to those with widespread disease while others are treated more aggressively. We conducted a review of the evidence for treatment options in oligometastatic breast cancer and consulted ClinicalTrials.gov to explore currently accruing or studies in development aimed at investigating oligometastatic disease in breast cancer. Surgery to the primary tumour in patients with metastatic breast cancer has failed to show any advantage over systemic therapy. However, there may be a benefit in women with controlled systemic disease who are hormone receptor positive with bone-predominant metastasis. Stereotactic radiotherapy has gained increased interest in this setting due to its excellent efficacy and lower rates of associated toxicity. A significant challenge remains in identifying the patient population who would benefit from such an approach, and to do so, we need to understand the distinct biology of oligometastatic breast cancer. Unique miRNA expression and low levels of tumour infiltrating lymphocytes in the immune micro-environment have been described in tumour tissues in patients with oligometastatic breast cancer. There is ongoing research aimed to better characterise these tumours, thus, allowing the selection of patients who would truly benefit from multi-modality treatment in an attempt for long-term survival and cure.

Post-lumpectomy radiation therapy boost in breast cancer patients: evidence revisited.

PURPOSE: Radiation therapy is an integral part in the management of breast cancer after breast conservative surgery. In selected patients at high risk for local recurrence (LR), a boost radiation dose is commonly applied to the tumour bed. METHODS: We performed a review of the English literature using PubMed, Medline and Google Scholar for published manuscripts addressing the effect of boost radiation in breast cancer patients, focusing mainly on LR and overall survival (OS). RESULTS: A total of seven studies were included in our review. Most studies (6/7, 85.7%) showed a significant improvement in local control independent of age (hazard ratios ranging between 0.34 and 0.73), with the largest absolute benefit in younger patients. None of the studies, however, was able to demonstrate an improvement in OS. CONCLUSIONS: With lack of sufficient studies addressing the role of boost radiation, individualised treatment decisions are recommended, taking into account the risk factors for LR, including tumour biology. Real-life data are sorely needed to better assess the role of tumour bed boost in the contemporary era.

Noninvasive assessment of radiation-induced renal injury in mice.

PURPOSE: The kidney is a radiosensitive late-responding normal tissue. Injury is characterized by radiation nephropathy and decline of glomerular filtration rate (GFR). The current study aimed to compare two rapid and cost-effective methodologies of assessing GFR against more conventional biomarker measurements. METHODS: C57BL/6 mice were treated with bilateral focal X-irradiation (1x14Gy or 5x6Gy). Functional measurements of kidney injury were assessed 20 weeks post-treatment. GFR was estimated using a transcutaneous measurement of fluorescein-isothiocyanate conjugated (FITC)-sinistrin renal excretion and also dynamic contrast-enhanced CT imaging with a contrast agent (ISOVUE-300 Iopamidol). RESULTS: Hematoxylin and eosin (H&E) and Periodic acid-Schiff staining identified comparable radiation-induced glomerular atrophy and mesangial matrix accumulation after both radiation schedules, respectively, although the fractionated regimen resulted in less diffuse tubulointerstitial fibrosis. Albumin-to-creatinine ratios (ACR) increased after irradiation (1x14Gy: 100.4 ± 12.2 µg/mg; 6x5Gy: 80.4 ± 3.02 µg/mg) and were double that of nontreated controls (44.9 ± 3.64 µg/mg). GFR defined by both techniques was negatively correlated with BUN, mesangial expansion score, and serum creatinine. The FITC-sinistrin transcutaneous method was more rapid and can be used to assess GFR in conscious animals, dynamic contrast-enhanced CT imaging technique was equally safe and effective. CONCLUSION: This study demonstrated that GFR measured by dynamic contrast-enhanced CT imaging is safe and effective compared to transcutaneous methodology to estimate kidney function.

Radiation-induced neuropathies in head and neck cancer: prevention and treatment modalities.

Head and neck cancer (HNC) is the sixth most common human malignancy with a global incidence of 650,000 cases per year. Radiotherapy (RT) is commonly used as an effective therapy to treat tumours as a definitive or adjuvant treatment. Despite the substantial advances in RT contouring and dosage delivery, patients suffer from various radiation-induced complications, among which are toxicities to the nervous tissues in the head and neck area. Radiation-mediated neuropathies manifest as a result of increased oxidative stress-mediated apoptosis, neuroinflammation and altered cellular function in the nervous tissues. Eventually, molecular damage results in the formation of fibrotic tissues leading to susceptible loss of function of numerous neuronal substructures. Neuropathic sequelae following irradiation in the head and neck area include sensorineural hearing loss, alterations in taste and smell functions along with brachial plexopathy, and cranial nerves palsies. Numerous management options are available to relieve radiation-associated neurotoxicities notwithstanding treatment alternatives that remain restricted with limited benefits. In the scope of this review, we discuss the use of variable management and therapeutic modalities to palliate common radiation-induced neuropathies in head and neck cancers.