The Diminishing Impact of Margin Definitions and Width on Local Recurrence Rates following Breast-Conserving Therapy for Early-Stage Invasive Cancer: A Meta-Analysis.

BACKGROUND: The optimal tumor-free margin definition and width following breast-conserving therapy (BCT) for early-stage invasive cancers has been evaluated in previous meta-analyses and guidelines. We performed an updated meta-analysis to assess how improvements in treatment over time have affected the impact of margins on local recurrence (LR) rates over time. METHODS: A systematic literature review identified 38 eligible studies comprising 54,502 patients treated between 1968 and 2010. Inclusion criteria included patients treated with BCT and minimum follow-up of 50 months, pathologic definitions of margin status explicitly stated, and LR data in relation to margin status. Data were pooled using a Bayesian logistic regression model to evaluate the risk of LR in relation to both margin status and study enrollment periods. RESULTS: Median follow-up was 7.25 years. Absolute LR rates decreased over time for each margin width cohort, with maximum differences between negative margin groups of less than 1% for the most recent enrollment period. However, relative rates of LR between different margin groups remained stable over time. CONCLUSIONS: With an additional 22,000 patients compared with the previous meta-analysis, this updated meta-analysis supports the consensus guideline of "no tumor on ink" for the majority of patients. Additionally, while concerns exist regarding a benefit with wider margins from previous studies, the analysis demonstrates the impact of margin width on LR rates has declined substantially over time, with very small differences between the narrowest and widest margin groups in the most recent cohort. Hence, older studies appear to have limited value to inform current management guidelines.

Validation of RTOG 0813 Proximal Bronchial Tree Constraints for Pulmonary Toxicity With Stereotactic Body Radiation Therapy for Central Non-small Cell Lung Cancer.

PURPOSE: Clinical validation of protocol-specified dosimetric constraints for the proximal bronchial tree (PBT) is limited for central non-small cell lung cancer treated with stereotactic body radiation therapy. We sought to validate Radiation Therapy Oncology Group (RTOG) PBT constraints with a large institutional data set. METHODS AND MATERIALS: Lesions ≤2 cm from the PBT treated with definitive stereotactic body radiation therapy from 2009 to 2016 were identified from a prospective registry of 1462 patients. Every PBT dose and volume combination, ranging from 0 cGy to 8000 cGy in increments of 10 cGy and volumes ranging from 0.03 cm3 to 50 cm3 in increments of 0.03 cm3, was analyzed. The sensitivity and specificity of these endpoints for identifying pulmonary toxicity were calculated. Pulmonary toxicity was classified as pneumonitis or nonpneumonitis toxicity (NPT) (fistula, stenosis, necrosis, hemoptysis, clinically significant pleural effusion). The optimal dosimetric predictor was chosen by calculation of F-score (highest sensitivity and specificity). RESULTS: The study included 132 patients, with 26.0-month median follow-up. Eight grade ≥2 NPT (2 grade 5) and 8 grade 2 pneumonitis toxicities were observed. The PBT dosimetric endpoint with the highest F-score for identification of grade 2 to 5 NPT was D0.03cc ≤5000 cGy and that for grade 3 to 5 NPT was D0.33cc ≤4710 cGy, with sensitivity and specificity of 87.5% and 76.6% and 100.0% and 85.7%, respectively. Applying the RTOG 0813 PBT constraints to our data set achieved a sensitivity and specificity of 33.3% and 92.1% for D4cc ≤1800 cGy and 37.5% and 92.7% for D0.03cc ≤5250 cGy for identification of grade 2 to 5 NPT. A PBT dosimetric correlation for pneumonitis toxicity could not be identified. CONCLUSIONS: This novel dosimetric analysis validates current RTOG constraints and emphasizes high-dose, small-volume constraints as better predictors for NPT. We demonstrated that a slightly lower maximum point dose PBT constraint may be optimal for identification of NPT. Validation of these findings in a larger cohort of patients with longer follow-up is necessary.

Outcomes with intraoperative radiation therapy for early-stage breast cancer.

Adjuvant radiation therapy has been associated with improved local control following breast-conserving surgery. Traditionally, treatment has been delivered with whole breast irradiation over 3-6 weeks or partial breast irradiation over 1-3 weeks. However, intraoperative radiation therapy (IORT) has emerged as a technique that delivers a single dose of radiotherapy at the time of surgery for early-stage breast cancers. We report initial outcomes and acute toxicities with intraoperative radiation from a single institution. Patients with DCIS or Stage I-II breast cancer who underwent lumpectomy and sentinel lymph node biopsy (nodal sampling excluded in some cases) were included. All patients in this analysis were treated with IORT as at the time of surgery, 20 Gy in 1 fraction with 50 kV x-ray. Patients were treated at a single institution between 2011 and 2019. Follow-up was per standard institutional protocol. Two hundred and one patients were included in the analysis, with a median follow-up of 23 months (range: 0-73 months). Median age was 71 years old. Overall, 4 (2.0%) patients had DCIS, 186 (92.5%) patients had Stage 1 disease, and 11 patients had (5.5%) Stage 2 disease. All patients were estrogen receptor-positive, 175 (87.9%) progesterone receptor-positive, and 1 (0.5%) HER2 amplified. The crude rate of local recurrence was 2.0% (n = 4) and distant metastasis rate was 0.5% (n = 1). The rate of arm lymphedema was 0.5% (n = 1) and chronic telangiectasia rate was 1.1% (n = 2). Intraoperative radiation therapy, in a cohort of low-risk patients, demonstrated low rates of recurrence and reproducibility in a multi-disciplinary setting. Further follow-up, analysis of patient satisfaction and cosmesis, and comparison to whole breast irradiation and partial breast techniques is necessary in order to further validate these findings.

Initial outcomes with image-guided partial breast irradiation delivered with intensity-modulated radiation therapy.

Patients were treated at a single institution to a dose of 30 Gy in five fractions delivered every other day using image-guided intensity modulated radiation therapy (IMRT) partial breast irradiation. A total of 34 patients were treated with a median follow-up of 4.6 months. The rate of acute Grade 1 dermatitis was 23.5% (n = 8), and Grade 1 fatigue was 17.6% (n = 6), with no Grade 2 or higher acute toxicities. The rate of chronic Grade 1 dermatitis was 25.0% (n = 6), Grade 1 fat necrosis 4.2% (n=1), with no patients demonstrating other chronic toxicities. Image-guided APBI delivered with IMRT is associated with low rates of acute and chronic toxicity though additional follow-up is warranted.

Long-term complications and reconstruction failures in previously radiated breast cancer patients receiving salvage mastectomy with autologous reconstruction or tissue expander/implant-based reconstruction.

Salvage mastectomy (SM) is the standard of care for patients with local recurrence (LR) after breast conservation therapy (BCT), often with immediate reconstruction. Complications of reconstruction are a concern for these patients, and long-term data are limited. We sought to compare rates of complications requiring re-operation (CRR) and reconstruction failure (RF) between autologous reconstruction (AR) and tissue expander/implant reconstruction (TE/I). Patients with locally recurrent breast cancer after BCT, treated with SM and immediate AR or TE/I between 2000 and 2008, were identified. CRR was defined as unplanned return to operating room for wound infection, dehiscence, necrosis (including flap, skin, or fat), hematoma, or hernia (for AR) and extrusion, leak, or capsular contracture (for TE/I). RF was defined as conversion to another reconstruction technique or to flat chest wall. This study included 103 patients with 107 reconstructions. Median follow-up was 6.6 years. CRR and RF were significantly higher with TE/I (n = 34) compared to AR (n = 73) at 5 years (50.9% vs 25.5%; P = 0.02) and (42.1% vs 5.8%; P < 0.001). On univariate analysis (UVA), TE/I (HR = 2.14; P = 0.02) and diabetes (HR = 5.10; P = 0.007) were significant predictors for CRR. On UVA, TE/I (HR = 7.30; P < 0.001) and older age at reconstruction (HR = 1.03; P = 0.003) were significant predictors for RF. In this population of previously irradiated patients, TE/I was associated with significantly higher CRR and RF. Complications continue to occur up to 10 years after TE/I. AR should be considered in appropriately selected patients, though TE/I may remain a reasonable option in patients without high-risk factors for surgical complications.

Long-Term Outcomes After Autologous or Tissue Expander/Implant-Based Breast Reconstruction and Postmastectomy Radiation for Breast Cancer.

PURPOSE: The toxicity profile of breast reconstruction with postmastectomy radiation therapy (PMRT) varies by technique and timing, and long-term data are limited. We compared rates of complications requiring reoperation (CRR) and reconstruction failure (RF) between immediate autologous reconstruction (I-AR), immediate tissue expander/implant reconstruction (I-TE/I), delayed autologous reconstruction (D-AR), and delayed tissue expander/implant reconstruction (D-TE/I) in patients receiving PMRT. METHODS AND MATERIALS: Patients who received autologous reconstruction (AR) or tissue expander/implant reconstruction (TE/I) and PMRT between 2000 to 2008 were included. Reconstruction was immediate if performed on the same day as mastectomy followed by PMRT (I-AR or I-TE/I) or delayed if after PMRT (D-AR and D-TE/I). CRR was defined as an unplanned return to the operating room for infection, dehiscence, necrosis, hematoma, or hernia (with AR) and extrusion, leak, or contracture (with TE/I). RF was defined as unplanned conversion to another reconstruction technique or to flat chest wall. Cumulative incidence of CRR and RF was calculated using Kaplan-Meier and compared using the log-rank test. Logistic regression was used to identify variables associated with CRR and RF. RESULTS: Two hundred four patients were included. Median follow-up was 8 years. There were 127 AR cases (63%) and 77 TE/I cases (38%). At 5 years, CRR was 18%, 38%, 34%, and 70% (P = .010) and RF was 4%, 22%, 7%, and 56% (P < .0001) for I-AR, I-TE/I, D-AR, and D-TE/I, respectively. On multivariate analysis, TE/I (hazard ratio [HR] 2.0; P = .011), body mass index ≥30 (HR 3.9; P = .002), and smoking (HR 2.7; P = .001) were significant predictors for CRR, and TE/I (HR 6.6; P < .0001), diabetes (HR 4.1; P = .044), and hypertension (HR 3.5; P = .005) were significant for RF. When excluding RF because of infection, the rate of RF was not significantly different among the 4 groups (P = .23). CONCLUSIONS: With PMRT, TE/I reconstruction in the immediate and delayed setting is associated with higher CRR and RF compared with AR. Patient factors should guide selection of technique. Efforts to reduce rates of RF with TE/I should focus on minimizing risks for infection.

Association of Disease Recurrence With Survival Outcomes in Patients With Cutaneous Squamous Cell Carcinoma of the Head and Neck Treated With Multimodality Therapy.

Importance: It has previously been demonstrated that immunosuppressed patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) treated with surgery and postoperative radiotherapy have significantly inferior disease-related outcomes compared with immunocompetent patients, but data on outcomes after disease recurrence are limited. Objectives: To report survival outcomes in patients with cSCC-HN after disease recurrence after surgery and postoperative radiotherapy and to investigate the association of immune status with disease-related outcomes. Design, Setting, and Participants: A multi-institutional study of 205 patients treated at the Cleveland Clinic, Washington University in St Louis, and the University of California, San Francisco, in which patients who underwent surgical resection and postoperative radiotherapy for primary or recurrent stage I to IV (nonmetastatic) cSCC-HN between January 1, 1995, and December 31, 2014, were identified. Patients with any disease recurrence, defined as local, regional, and/or distant failure, were included. Patients were categorized as immunosuppressed if they received a diagnosis of chronic hematologic malignant neoplasm or HIV or AIDS, or were treated with immunosuppressive therapy for organ transplantation 6 months or more before diagnosis. Statistical analysis was conducted from January 1, 1995, to December 31, 2015. Main Outcomes and Measures: Overall survival calculated using the Kaplan-Meier method and compared using the log-rank test. Results: Of the 205 patients in the original cohort, 72 patients (63 men and 9 women; median age, 71 years [range, 43-91 years]) developed disease recurrence after surgery and postoperative radiotherapy. Forty patients (55.6%) were immunosuppressed, and 32 patients (44.4%) were immunocompetent. Locoregional recurrence was the most common first pattern of failure for both groups (31 immunosuppressed patients [77.5%]; 21 immunocompetent patients [65.6%]). After any recurrence, 1-year overall survival was 43.2% (95% CI, 30.9%-55.4%), and median survival was 8.4 months. For patients for whom information on salvage treatment was available (n = 45), those not amenable to surgical salvage had significantly poorer median cumulative incidence of survival compared with those who were amenable to surgical salvage (4.7 months; 95% CI, 3.7-7.0 months vs 26.1 months; 95% CI, 6.6 months to not reached; P = .01), regardless of their immune status. Conclusions and Relevance: Results of this study suggest that patients with cSCC-HN who experience disease recurrence after definitive treatment with surgery and postoperative radiotherapy have poor survival, irrespective of immune status. Survival rates are low for patients with recurrent disease that is not amenable to surgical salvage. The low rate of successful salvage underscores the importance of intensifying upfront treatment to prevent recurrence.

Investigation of brachial plexus dose that exceeds RTOG constraints for apical lung tumors treated with four- or five-fraction stereotactic body radiation therapy.

PURPOSE/OBJECTIVESS: We sought to determine the rate of brachial plexopathy (BPX) in patients exceeding RTOG dose constraints for treatment of apical lung tumors. MATERIALS/METHODS: Patients with apical lung tumors treated with four- or five-fraction SBRT were identified from a prospective registry. Dosimetric data were obtained for ipsilateral subclavian vein (SCV) and anatomic BP (ABP) contours. Cumulative equivalent dose in 2 Gy equivalents (EQD2) was calculated for the SCV contour in patients with a history of prior ipsilateral RT. Five-fraction SBRT RTOG constraints of D0.03cc ≤32.0 Gy and D3cc ≤30.0 Gy were used. BPX was graded according to Common Terminology Criteria for Adverse Events 3.0. RESULTS: A total of 64 patients met inclusion criteria. Median follow-up was 21 months. Six patients (9.4%) had prior ipsilateral conventional fractionated RT with varying degrees of overlap with subsequent SBRT field. Eleven patients without prior ipsilateral RT exceeded D0.03cc ≤32.0 Gy to SCV (mean 43.8 Gy ± 5.8). No BPX was observed in these patients. Out of the six patients who had prior ipsilateral RT, three patients exceeded D0.03cc ≤32.0 Gy to SCV (44.2 Gy ± 11.3), with two of these patients developing Grade 2 BPX within one year of SBRT. The EQD2 cumulative maximum point dose to BP was 122.6 Gy and 184.7 Gy for the two patients who developed Grade 2 BPX. The D0.03cc was >10 Gy higher to the ABP contour than the SCV contour in 14 patients. CONCLUSION: Without a history of prior ipsilateral RT, no BPX was observed at 21 month follow-up in 11 patients who exceeded the RTOG five-fraction BP constraint. This observation is hypothesis generating and more experience with longer follow-up is necessary to validate these findings. For tumors located in close proximity to apical structures, there was substantial variation in dose between the ABP and SCV contours.

Effect of Tumor Location and Dosimetric Predictors for Chest Wall Toxicity in Single-Fraction Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer.

PURPOSE: Dosimetric parameters to limit chest wall toxicity (CWT) are not well defined in single-fraction (SF) stereotactic body radiation therapy (SBRT) phase 2 trials. We sought to determine the relationship of tumor location and dosimetric parameters with CWT for SF-SBRT. METHODS AND MATERIALS: From a prospective registry of 1462 patients, we identified patients treated with 30 Gy or 34 Gy. Gross tumor volume was measured as abutting, ≤1 cm, 1 to 2 cm, or >2 cm from the chest wall. CWT was prospectively graded according to Common Terminology Criteria for Adverse Events version 3.0, with grade 2 requiring medical therapy, grade 3 requiring procedural intervention, and grade 4 being disabling pain. Grade 1 CWT or radiographic rib fracture was not included. Logistic regression analysis was used to identify the parameters associated with CWT and calculate the probability of CWT with dose. RESULTS: This study included 146 lesions. The median follow-up time was 23.8 months. The 5-year local control, distant metastasis, and overall survival rates were 91.8%, 19.2%, and 28.7%, respectively. Grade 2 to 4 CWT was 30.6% for lesions abutting the chest wall, 8.2% for ≤1 cm from the chest wall, 3.8% for 1 to 2 cm from the chest wall, and 5.7% for >2 cm from the chest wall. Grade ≥3 CWT was 1.4%. Tumor abutment (odds ratio [OR]: 6.5; P = .0005), body mass index (OR: 1.1; P = .02), rib D1cc (OR: 1.01/Gy; P = .03), chest wall D1cc (OR: 1.08/Gy; P = .03), and chest wall D5cc (OR: 1.10/Gy; P = .01) were significant predictors for CWT on univariate analysis. Tumor abutment was significant for CWT (OR: 7.5; P = .007) on multivariate analysis. The probability of CWT was 15% with chest wall D5cc at 27.2 Gy and rib D1cc at 30.2 Gy. CONCLUSIONS: The rate of CWT with SF-SBRT is similar to the rates published for fractionated SBRT, with most CWT being low grade. Tumor location relative to the chest wall is not a contraindication to SF-SBRT, but the rates increase significantly with abutment. Rib D1cc and chest wall D1cc and D5cc may be used as predictors of CWT.

Suboptimal Outcomes in Cutaneous Squamous Cell Cancer of the Head and Neck with Nodal Metastases.

BACKGROUND/AIM: There are limited data regarding survival, failure patterns, and factors associated with disease recurrence in patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) with nodal metastases. PATIENTS AND METHODS: A retrospective analysis of patients with cSCC-HN metastatic to cervical and/or parotid lymph nodes treated with surgery and post-operative radiation therapy was performed. RESULTS: This study included 76 patients (57 immunocompetent and 18 immunosuppressed) with a median follow-up of 18 months. Overall survival, disease-free survival (DFS), and disease recurrence (DR) at 2 years was 60%, 49%, and 40%, respectively. Immunosuppressed patients had significantly lower 2-year DFS (28% vs. 55%; p=0.003) and higher DR (61% vs. 34%; p=0.04) compared to immunocompetent patients. Analysis of immunocompetent patients demonstrated extracapsular extension (ECE) as the only factor associated with DR (p<0.0001). CONCLUSION: Patients with nodal metastases from cSCC-HN have suboptimal outcomes. ECE and immunosuppression were significantly associated with DR.

Most patients are eligible for an alternative to conventional whole breast irradiation for early-stage breast cancer: A National Cancer Database Analysis.

We evaluated the proportion of patients eligible for alternatives to standard whole breast irradiation (WBI) following breast-conserving surgery using the National Cancer Database (NCDB). Using the 2016 dataset, Stage I-III patients were identified. Eligibility for hypofractionated WBI (HFRT), accelerated partial breast irradiation (APBI) and endocrine therapy (ET-alone) was defined using eligibility from large clinical trials as well as consensus guidelines. For patients with pN0 breast cancer, 20.6% and 37.0% were eligible for ET-alone based on the CALGB 9343/PRIME-II trials, respectively. In terms of HFRT, 72.5% and 50.4% were eligible based on IMPORT LOW/ASTRO HFRT guidelines, respectively. Based on IMPORT LOW/GEC-ESTRO trial/ASTRO guidelines/ABS guidelines/GEC-ESTRO guidelines, 72.5%, 86.1%, 39.0%, 72.5%, 45.7%, respectively, were eligible for APBI. Of those who qualify for HFRT per ASTRO guidelines, approximately 90% were eligible for APBI and 50% for ET-alone. This analysis shows that a large proportion of patients with node-negative breast cancer are eligible for HFRT, APBI and/or ET-alone after breast-conserving surgery.

Evaluating Candidacy for Hypofractionated Radiation Therapy, Accelerated Partial Breast Irradiation, and Endocrine Therapy After Breast Conserving Surgery: A Surveillance Epidemiology and End Results (SEER) Analysis.

PURPOSE/OBJECTIVE(S): After breast conserving surgery, adjuvant radiation therapy represents the standard of care for most patients. However, multiple options exist beyond standard fractionated whole breast irradiation including hypofractionated whole breast irradiation (HFRT), accelerated partial breast irradiation (APBI), and endocrine therapy (ET) alone, which can limit treatment duration, and potentially reduce morbidity and cost. Limited data are available on the percentage of patients eligible for these alternatives; therefore, a Surveillance Epidemiology and End Results (SEER) analysis was performed to assess candidacy for these alternative options in women with early stage breast cancer. MATERIALS AND METHODS: Women treated for breast cancer between the years of 2010 and 2012 were identified in the SEER database. Patients with unknown staging, metastatic disease, T3/T4 disease, and ≥N1 disease were excluded. Patients were defined as eligible for HFRT based on the American Society for Radiation Oncology (ASTRO) consensus guidelines and randomised trial testing intensity modulated and partial organ radiotherapy following breast conservation surgery for early breast cancer (IMPORT LOW) trial criteria, APBI based on the ASTRO, American Brachytherapy Society and the Groupe Européen de Curiethérapie of European Society for Therapeutic Radiotherapy and Oncology (GEC-ESTRO) consensus guidelines, and GEC-ESTRO APBI and IMPORT LOW trial criteria, and ET alone based on the Cancer and Leukemia Group B 9343 and Post-operative Radiotherapy in Minimum Risk Elderly II inclusion criteria. RESULTS: A total of 108,484 women with early stage breast cancer who met the aforementioned inclusion criteria were identified. Of these patients, 86,896 (80.1%) were eligible for HFRT based on ASTRO consensus guidelines and 81,459 (75.0%) based on IMPORT LOW trial criteria. Regarding APBI, 44,797 (41.2%), 81,020 (74.6%), 81,020 (74.6%) were eligible according to ASTRO, ABS, GEC-ESTRO consensus guidelines, respectively, 97,301 (89.7%) patients according to the GEC-ESTRO trial criteria, and 81,459 (75.0%) patients according to the IMPORT LOW trial criteria. For ET alone, 23,006 (21.2%) were eligible according to Cancer and Leukemia Group B 9343 criteria and 42,104 (38.8%) according to Post-operative Radiotherapy in Minimum Risk Elderly II criteria. CONCLUSIONS: This SEER analysis demonstrates that a substantial proportion of women with early stage breast cancer are eligible for HFRT, APBI, or ET alone after breast conserving surgery according to consensus guidelines and prospective trial criteria. With incorporation of additional pathologic, dosimetric, and chemotherapy data, quality assurance pathways may use such data to help ensure patients are receiving appropriate risk stratified treatment recommendations.

A multi-institutional comparison of outcomes of immunosuppressed and immunocompetent patients treated with surgery and radiation therapy for cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Patients who are chronically immunosuppressed have higher rates of cutaneous squamous cell carcinoma of the head and neck (cSCC-HN). This is the largest multi-institutional study to date investigating the effect of immune status on disease outcomes in patients with cSCC-HN who underwent surgery and received postoperative radiation therapy (RT). METHODS: Patients from 3 institutions who underwent surgery and also received postoperative RT for primary or recurrent, stage I through IV cSCC-HN between 1995 and 2015 were included in this institutional review board-approved study. Patients categorized as immunosuppressed had chronic hematologic malignancy, human immunodeficiency/acquired immunodeficiency syndrome, or had received immunosuppressive therapy for organ transplantation ≥6 months before diagnosis. Overall survival, locoregional recurrence-free survival, and progression-free survival were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox proportional-hazards regression. RESULTS: Of 205 patients, 138 (67.3%) were immunocompetent, and 67 (32.7%) were immunosuppressed. Locoregional recurrence-free survival (47.3% vs 86.1%; P < .0001) and progression-free survival (38.7% vs 71.6%; P = .002) were significantly lower in immunosuppressed patients at 2 years. The 2-year OS rate in immunosuppressed patients demonstrated a similar trend (60.9% vs 78.1%; P = .135) but did not meet significance. On multivariate analysis, immunosuppressed status (hazard ratio [HR], 3.79; P < .0001), recurrent disease (HR, 2.67; P = .001), poor differentiation (HR, 2.08; P = .006), and perineural invasion (HR, 2.05; P = .009) were significantly associated with locoregional recurrence. CONCLUSIONS: Immunosuppressed patients with cSCC-HN had dramatically lower outcomes compared with immunocompetent patients, despite receiving bimodality therapy. Immune status is a strong prognostic factor that should be accounted for in prognostic systems, treatment algorithms, and clinical trial design. Cancer 2017;123:2054-2060. © 2017 American Cancer Society.

Early and Severe Radiation Toxicity Associated with Concurrent Sirolimus in an Organ Transplant Recipient with Head and Neck Cutaneous Squamous Cell Carcinoma: A Case Report.

We present a case of a 71-year-old man with a history of liver transplantation who was treated with adjuvant radiotherapy with concurrent cisplatin for recurrent cutaneous squamous cell carcinoma of the head and neck. The patient was transitioned from tacrolimus to sirolimus for immunosuppression immediately prior to the start of radiation therapy, with the goal of reducing the risk for further skin cancer recurrence. The patient developed severe normal tissue toxicity, disproportionate to the dose delivered. He was diagnosed with Grade 4 esophagitis and mucositis after just 2,400 cGy in 12 fractions (planned 6,400 cGy in 32 fractions), requiring cessation of therapy. Six months later, the patient was diagnosed with local recurrence and distant metastases in the lung, and unfortunately passed away one month later. Randomized data have demonstrated the anti-neoplastic benefit of sirolimus. Pre-clinical studies and animal models have suggested that sirolimus may be a radiation sensitizer; however, the literature is limited regarding the clinical translation of these biologic findings. The case we presented reflects that concurrent radiation therapy with sirolimus may enhance the cytotoxic effects of radiation therapy and contribute to dose-limiting toxicity. Certainly, further study is necessary to explore this observation.

Inferior outcomes in immunosuppressed patients with high-risk cutaneous squamous cell carcinoma of the head and neck treated with surgery and radiation therapy.

BACKGROUND: Immunosuppressed patients have higher rates of cutaneous squamous cell carcinoma of the head and neck. OBJECTIVE: This study reviews the effect of immune status on disease characteristics and treatment outcomes. METHODS: Patients with cutaneous squamous cell carcinoma of the head and neck treated with surgery and postoperative radiotherapy between 2000 and 2011 were included. Immunosuppressed patients underwent prior organ transplantation or chemotherapy. Baseline variables were compared using χ(2) and unpaired t tests. Overall survival and disease-free survival were calculated using the Kaplan-Meier method. RESULTS: In this study of 59 patients, 38 (64%) were immunocompetent and 21 (36%) were immunosuppressed. Most patients had recurrent tumors (63%) and node-positive disease (61%), which were well balanced between the groups. Poorly differentiated tumors (62% vs 21%; P = .009), lymphovascular invasion (29% vs 11%; P = .08), and extracapsular extension (57% vs 41%; P = .09) were more frequent in the immunosuppressed group. Two-year disease-free survival (45% vs 62%) and 2-year overall survival (36% vs 67%) were inferior for immunosuppressed patients. LIMITATIONS: Limitations include single institution, retrospective study with small sample size, and potential referral bias. CONCLUSIONS: Immunosuppressed patients with cutaneous squamous cell carcinoma of the head and neck more frequently present with high-risk pathologic features and inferior outcomes. Early multidisciplinary assessment and alternate management strategies merit prospective investigation.

The Impact of Preoperative Radiation Therapy on Locoregional Recurrence in Patients with Stage IV Rectal Cancer Treated with Definitive Surgical Resection and Contemporary Chemotherapy.

PURPOSE: Definitive resection of primary rectal cancers is frequently incorporated, with or without preoperative radiotherapy and perioperative chemotherapy, in the management of selected patients with metastatic rectal adenocarcinoma. This study reviews the impact of preoperative radiotherapy and perioperative chemotherapy on locoregional recurrence and overall survival in these patients. METHODS AND MATERIALS: This retrospective study with an Institutional Review Board (IRB) waiver included 109 patients with metastatic rectal adenocarcinoma who underwent definitive primary resection between 1998 and 2011. In addition to resection, 64 patients were treated with preoperative radiotherapy and perioperative chemotherapy and 45 patients were treated with perioperative chemotherapy alone. Radiotherapy dose was typically 50.4 Gy. Baseline variables were compared using chi-square and unpaired t tests. Overall survival was calculated using Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox proportional hazards regression. RESULTS: There were no significant baseline differences between the two groups. There was no significant difference in locoregional recurrence (10.9 vs. 11.1%; p = 0.90) or overall survival (34.5 vs. 34.8 months; p = 0.89) for patients treated with preoperative radiotherapy compared to those treated with perioperative chemotherapy alone, respectively. Patients who underwent radiotherapy were less likely to have a positive margin (10.9 vs. 20.0%; p = 0.19), lymphovascular invasion (32.8 vs. 53.3%; p = 0.03), and pathologic stage N2 disease (25.0 vs. 42.2%; p = 0.02). Grade 2 postoperative complications were more common in the preoperative radiotherapy group (32.8 vs. 15.6%; p = 0.04). Multivariate analysis demonstrated that patients with poorly differentiated tumors (HR 2.19; p = 0.009) and those that did not undergo liver-directed therapy (HR 2.20; p = 0.005) had inferior survival. CONCLUSIONS: Locoregional recurrence is modest in patients with metastatic rectal adenocarcinoma receiving definitive primary resection, irrespective of the use of radiotherapy. Preoperative radiotherapy may enhance pathologic downstaging at the expense of increased grade 2 postoperative complications. Its use should be reserved for patients at high risk for locoregional recurrence.