Improved Pathologic response to chemoradiation in MGMT methylated locally advanced rectal cancer.

Background and Purpose: With the growing interest in total neoadjuvant treatment for locally advanced rectal adenocarcinoma (LARC) there is an urgent unmet need to identify predictive markers of response to long-course neoadjuvant concurrent chemoradiotherapy (LCRT). O6-Methylguanine (O6-MG)-DNA-methyltransferase (MGMT) gene methylation has been associated in some malignancies with response to concurrent chemoradiotherapy. We attempted to find if pathologic response to LCRT was associated with MGMT promoter hypermethylation (MGMTh). Materials and Methods: Patients were identified with LARC, available pre-treatment biopsy specimens, and at least 1 year of follow-up who received LCRT followed by surgical resection within 6 months. Biopsies were tested for MGMTh using a Qiagen pyrosequencing kit (Catalog number 970061). The primary outcome of LCRT responsiveness was based on tumor regression grade (TRG), with grades of 0-1 considered to have excellent response and grades of 2-3 considered to be non-responders. Secondary outcomes included overall survival (OS) and recurrence free survival (RFS). Results: Of 96 patients who met inclusion criteria, 76 had samples which produced reliable assay results. MGMTh corresponded with higher grade and age of the biopsy specimen. The percentage of responders to LCRT was higher amongst the MGMTh patients than the MGMTn patients (60.0% vs 27.5%, p value = 0.0061). MGMTh was not significantly associated with improved OS (2-year OS of 96.0% vs 98.0%, p = 0.8102) but there was a trend for improved RFS (2-year RFS of 87.6% vs 74.2%, p = 0.0903). Conclusion: Significantly greater tumor regression following LCRT was seen in MGMTh LARC. Methylation status may help identify good candidates for close observation without surgery following LCRT.

Dose escalated simultaneous integrated boost of gross nodal disease in gynecologic cancers: a multi-institutional retrospective analysis and review of the literature.

PURPOSE: Typical doses of 45-50.4 Gy used to treat regional nodes have demonstrated inadequate control of gross nodal disease (GND) in gynecologic cancer, and accelerated repopulation may limit the efficacy of a sequential boost. We reviewed outcomes of patients treated with a simultaneous integrated boost (SIB) at 2.25 Gy per fraction to positron emission tomography (PET) avid GND to evaluate toxicity and tumor control using this dose-escalated regimen. MATERIALS AND METHODS: A total of 83 patients with gynecologic cancer and PET avid inguinal, pelvic, or para-aortic lymphadenopathy were treated using intensity-modulated radiation therapy (IMRT) with SIB. Primary cancers were mostly cervical (51%) and endometrial (34%), and included patients who received concurrent chemotherapy (59%) and/or brachytherapy boost (78%). RESULTS: Median follow-up from radiation completion was 12.6 months (range, 2.7 to 92.9 months). Median dose to elective lymphatics was 50.4 Gy (range, 45 to 50.4 Gy) at 1.8 Gy/fraction. Median SIB dose and volume were 63 Gy (range, 56.3 to 63 Gy) and 72.8 mL (range, 6.8 to 1,134 mL) at 2-2.25 Gy/fraction. Nodal control was 97.6% in the SIB area while 90.4% in the low dose area (p = 0.013). SIB radiotherapy (RT) field failure-free, non-SIB RT field failure-free, and out of RT field failure-free survival at 4 years were 98%, 86%, and 51%, respectively. Acute and late grade ≥3 genitourinary toxicity rates were 0%. Acute and late grade ≥3 gastrointestinal toxicity rates were 7.2% and 12.0%, respectively. CONCLUSION: Dose escalated SIB to PET avid adenopathy results in excellent local control with acceptable toxicity.

Vaginal cuff brachytherapy: do we need to treat to more than a two-centimeter active length?

PURPOSE: American Brachytherapy Society (ABS) guidelines recommend using a 3-5 cm active length (AL) when treating vaginal cuff (VC) in adjuvant setting of endometrial cancer (EC). The purpose of this study was to evaluate local control and toxicity, using an AL of 1 or 2 cm and immobilization with a traditional table-mounted (stand) or patient-mounted (suspenders) device. MATERIAL AND METHODS: Between 2005 and 2019, 247 patients with EC were treated with adjuvant high-dose-rate vaginal cuff (HDR-VC) brachytherapy with or without external beam radiation (EBRT). Treatment was prescribed to a 0.5 cm depth, with an AL of 1 or 2 cm, using stand or suspenders. VC boost after EBRT was typically administered with 2 fractions of 5.5 Gy, while VC brachytherapy alone was typically applied with 3 fractions of 7 Gy or 5 fractions of 5.5 Gy. RESULTS: The combination of suspender immobilization and an AL of 2 cm (n = 126, 51%) resulted in 5-year local control of 100%. An AL of 2 cm compared to 1 cm correlated with better local control (99.1% vs. 88.5%, p = 0.0479). Regarding immobilization, suspenders correlated with improved local control compared to stand (100% vs. 86.7%, p = 0.0038). Immobilization technique was significantly correlated with AL (p < 0.0001). Only 5 (2.0%) patients experienced grade ≥ 3 toxicity, all of whom received EBRT. CONCLUSIONS: In the present series, an AL of 2 cm provided excellent local control, while 1 cm was inadequate. Suspender immobilization was a practical alternative to stand immobilization in HDR brachytherapy of the vaginal cuff.

Custom mold applicator high-dose-rate brachytherapy for nonmelanoma skin cancer-An analysis of 273 lesions.

PURPOSE: Nonmelanoma skin cancer is the most commonly diagnosed malignancy in the United States. A modern version of surface brachytherapy, "topographic applicator brachytherapy" (TAB), can be used to treat early-stage nonmelanoma skin cancer (ES-NMSC). The purpose of this study was to evaluate the acute toxicity, chronic toxicity, and recurrence rates of patients with ES-NMSC treated with TAB. METHODS AND MATERIALS: From 2010 to 2013, 172 patients with 273 ES-NMSC tumors were consecutively treated with TAB. A custom applicator was created using a thermoplastic mold with Harrison Anderson Mick applicators. Dose fractionation schemes included 40 Gy in eight fractions delivered twice per week or 48 Gy in 16 fractions delivered four times per week. RESULTS: Of the 273 tumors treated, 23.8% were located on the nose, 54.2% were basal cell carcinoma, 76.2% were Stage I, 89.3% were treated definitively, 98.9% completed treatment, and 75.5% received 40 Gy in eight fractions. Median followup was 25.0 months (0.5-71.0 months). Maximum acute toxicity was G0, 0.4%; G1, 33.3%; G2, 48.7%; G3, 12.1%; and G4, 5.1%. Local recurrence was 4.8% at 25 months, with median time to recurrence being 9 months. There was no regional or distant metastasis documented during the followup. Chronic toxicities included erythema (4.4%), chronic ulceration (4.0%), telangiectasia (2.6%), and pigmentation changes (2.2%). CONCLUSIONS: TAB was able to provide excellent local control (95.2%) with low rates of Grades 3 and 4 toxicities for treatment of ES-NMSC. TAB is a reasonable alternative to surgical resection when there is concern of poor cosmesis/wound healing.

Optimal epidural analgesia for patients diagnosed as having gynecologic cancer undergoing interstitial brachytherapy.

STUDY OBJECTIVE: To determine the optimal epidural analgesia for patients receiving interstitial brachytherapy (ISBT) for gynecologic cancers. DESIGN: Retrospective analysis. SETTING: Operating room and hospital ward. PATIENTS: Seventy-three patients diagnosed as having gynecologic cancer and undergoing ISBT. INTERVENTIONS: Twelve patients received ropivacaine alone, 14 patients received ropivacaine with fentanyl, and 45 patients received ropivacaine with hydromorphone by epidural infusion. MEASUREMENTS: Numeric Rating Scale pain scores, amounts of nonnarcotic and narcotic pain medications used in intravenous morphine equivalents (IVMEs), and amount of antiemetic or antipruritic medications used. MAIN RESULTS: Patients receiving ropivacaine alone had higher pain scores the morning of day 2 (4.2 vs 1.71 vs 0.6, P=.001), the afternoon of day 2 (4.9 vs 2.5 vs 1.7, P=.005), and the night of day 2 (2.4 vs 2.0 vs 0.6, P<.001). Patients receiving opioids in their epidural had lower pain scores on the night of placement (P=.050), the morning of day 2 (P<.001), the afternoon of day 2 (P=.002), and the night of day 2 (P<.001). Patients receiving ropivacaine alone used more oral narcotics than did those receiving ropivacaine with fentanyl or ropivacaine with hydromorphone on day 3 (5.9 vs 3.8 vs 2.8mg IVME) and received more intravenous opioids day 1 (5.8 vs 0.0 vs 0.7mg IVME, P=.004) and day 2 (20.6 vs 4.8 vs 1.0mg IVME, P=.042). There were no differences in antiemetic or diphenhydramine usage at any time point. No epidural complications occurred. CONCLUSIONS: For patients receiving ISBT for gynecologic cancer, epidural analgesia provides safe and effective pain control. Combined modality epidural analgesia improves pain control and lessens oral and intravenous opioid requirements without increased risk of adverse effects compared with epidural analgesia with local anesthetic alone.

Computed tomography-planned interstitial brachytherapy for locally advanced gynecologic cancer: Outcomes and dosimetric predictors of urinary toxicity.

PURPOSE: To identify dosimetric predictors of outcome and toxicity in patients receiving CT-planned interstitial brachytherapy (ISBT) for gynecologic cancers. METHODS AND MATERIALS: Patients who received ISBT between 2009 and 2014 were reviewed. Demographic, disease specific, treatment, and toxicity data were collected. Logistic regression was used to model toxicity. A least absolute shrinkage and selection operator penalty was used to identify relevant predictors. Receiver operating characteristic curves were used to analyze the relation between dosimetric factors and urinary toxicity. RESULTS: Seventy-three patients received ISBT (21 at time of cancer recurrence and 52 at the first presentation). Thirty-six patients had cervical cancer, 16 had vaginal cancer, 13 had uterine cancer, and 8 had vulvar cancer. ISBT was performed using both high-dose-rate and low-dose-rate 192Ir sources (27 low dose rate and 46 high dose rate). With a median followup of 12 months, Grade 3 vaginal, urinary, and rectal toxicity occurred in 17.8%, 15.1%, and 6.8% of patients, respectively. No patients experienced Grade 4 or 5 toxicity. Dose to 0.1cc of urethra predicted for development of Grade 3 urinary toxicity (area under the curve of 0.81; 95% confidence interval: 0.66, 0.96). A 10% probability of a Grade 3 urinary toxicity associated with a dose of 23.1 equivalent dose in 2 Gy fractions (95% confidence interval: 9.51, 36.27 equivalent dose in 2 Gy fractions). CONCLUSIONS: ISBT is a safe treatment for gynecologic malignancies. The dose to 0.1cc significantly predicts for severe urinary toxicity. Our data suggests that dose to a small urethral volume may be the most significant predictor of urinary toxicity in patients receiving ISBT for gynecologic cancer.

Computed tomography planned interstitial brachytherapy for recurrent gynecologic cancer.

PURPOSE: To report outcomes and identify predictors of toxicity in patients undergoing reirradiation with interstitial brachytherapy (ISBT) for recurrent cancers of the female reproductive tract. METHODS AND MATERIALS: Twenty-one patients received ISBT performed using (192)Ir sources (10 low dose rate and 11 high dose rate) at our institution between 2009 and 2013. Demographic, disease specific, treatment, toxicity, and outcome data were collected. Kaplan-Meier and proportional hazard models were used to estimate survival and logistic regression to model toxicity. A least absolute shrinkage and selection operator penalty was used to identify relevant predictors of outcome and toxicity. RESULTS: Eleven patients had uterine cancer, 7 patients had cervical cancer, and 3 patients had vulvar cancer. One-year actuarial freedom from local-regional failure, progression-free survival (PFS), and overall survival were 71.5%, 66.0%, and 82.2%, respectively. Tumor size was a significant predictor of worse PFS and overall survival (1 cm increase in tumor size = hazard ratio [HR], 1.61; 95% confidence interval [CI]: 1.16, 2.62 for PFS; HR, 2.02; 95% CI: 1.21, 3.38). Grade 3 or higher vaginal, urinary, and rectal toxicity occurred in 28.5%, 9.5%, and 19% of patients, respectively. Urethra D0.1cc predicted for grade 2 or higher urinary toxicity (one equivalent dose in 2 Gy fraction increase = HR, 1.156; 95% CI: 1.001, 1.335). CONCLUSIONS: Reirradiation with ISBT is both safe and effective. In patients with recurrent cancer, urethra D0.1cc predicts for increased urinary toxicity. Increased tumor size is a negative prognostic factor in patients receiving ISBT for cancer recurrence.

Tumor volume change with stereotactic body radiotherapy (SBRT) for early-stage lung cancer: evaluating the potential for adaptive SBRT.

OBJECTIVES: To quantify gross tumor volume (GTV) change during stereotactic body radiotherapy (SBRT) and on first follow-up, as well as to evaluate for any predictive prognostic risk factors related to GTV decrease. An attempt was also made to identify the potential timing for adaptive SBRT. METHODS: Twenty-five tumors in 24 consecutive patients were treated with SBRT to total dose of 50 Gy in 5 fractions. Median age was 72.5 years. Tumor stage was T1, 68%; T2, 20%; and other, 12%. The GTVs of on the 5 cone-beam computed tomographies (CBCT1-5) obtained before each fraction and the first follow-up CT (CTPOST) were analyzed. RESULTS: Median time from diagnosis to initiation of radiotherapy was 64 days. GTV on CBCT1 was the baseline for comparison. GTV decreased by a mean of 7% on CBCT2 (P=0.148), 11% on CBCT3 (P=0.364), 19% on CBCT4 (P=0.0021), and 32% on CBCT5 (P=0.0004). Univariate analyses of GTV shrinkage was significantly associated with "time from CBCT5 to CTPOST" (P=0.027) and "T-stage" (P=0.002). In multivariate analyses, "T-stage" remained significant with T1 tumors showing greater GTV shrinkage than T2 tumors. CONCLUSIONS: Significant decrease in GTV volume based on daily CBCT was demonstrated during SBRT treatment. Adaptive SBRT has the potential to minimize integral dose to the surrounding normal tissues without compromising GTV coverage.

Radon and lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Radon exposure is the second leading cause of lung cancer, following tobacco smoke. Radon is not only an independent risk factor; it also increases the risk of lung cancer in smokers. Numerous cohort, case-control, and experimental studies have established the carcinogenic potential of radon. The possibility of radon having a causative effect on other cancers has been explored but not yet proven. One of the postulated mechanisms of carcinogenesis is DNA damage by alpha particles mediated by the production of reactive oxygen species. The latter are also thought to constitute one of the common mechanisms underlying the synergistic effect of radon and tobacco smoke. With an estimated 21,000 lung cancer deaths attributable to radon in the United States annually, the need for radon mitigation is well acknowledged. The Environmental Protection Agency (EPA) has established an indoor limit of 4 picocuries (pCi)/L, and various methods are available for indoor radon reduction when testing shows higher levels. Radon mitigation should accompany smoking cessation measures in lung cancer prevention efforts.