Predictors of Acute Hematologic Toxicity in Women Receiving Extended-Field Chemoradiation for Cervical Cancer: Do Known Pelvic Radiation Bone Marrow Constraints Apply?

Purpose: Patients with cervical cancer who are at high risk for para-aortic lymphatic involvement may receive extended-field chemoradiation (EF-CRT), with inclusion of the para-aortic region. Increased radiation to bone marrow (BM) may heighten hematologic toxicity (HT) and affect timely delivery of chemoradiation. Factors associated with HT in this setting have not been well studied. Methods and Materials: This study was a retrospective analysis of women treated with EF-CRT from 2012 to 2018 with platinum-based chemotherapy. Factors including age, body mass index (BMI), race, Charlson Comorbidity Index (CCI), and nadirs for white blood cell count, absolute neutrophil count, hemoglobin, and platelet count were collected. The BM metrics included V5Gy, V10Gy, V15Gy, V20Gy, V25Gy, V30Gy, V35Gy, V40Gy and V45Gy (VxGy was defined as the percentage of BM volume receiving x Gy). Hematologic toxicity was defined as grade ≥2 (Cooperative Group Common Toxicity Criteria) leukopenia, anemia, neutropenia, or thrombocytopenia. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the χ2 test, the Fisher exact test, and logistic regression. Previously published dosimetric BM constraints were examined as detailed in each respective study. Results: Fifty-two women underwent EF-CRT with cisplatin. UVA showed no association between HT and age, BMI, or CCI. When accounting for race, V5Gy ≥98% was associated with grade ≥2 leukopenia (P = .02) and grade ≥2 HT (P = .05). Most previously described radiation metrics were not reproduced in our cohort, but a similar constraint, V20Gy <70%, was associated with reduced leukopenia of grade ≥2 on UVA (P = .02) and MVA (P < .05). Conclusions: Acute HT in patients receiving EF-CRT was associated with large volumes of low-dose radiation to the BM and was also associated with race. Restricting the BM V20Gy to less than 70% to 75% may be beneficial in reducing HT, but other pelvic radiation BM constraints may not be applicable to this population.

Opioid Use in Patients With Cervical Cancer at Two Urban Medical Centers.

Purpose: Patients with cervical cancer are at high risk for opioid use. This study aimed to characterize opioid prescribing patterns at 2 urban hospitals. Methods and Materials: Data from patients with cervical cancer treated with curative intent from 2011 to 2018 were retrospectively collected. Women with unrelated chronic opioid use before diagnosis, persistent/recurrent disease at 3 months after initiation of treatment, or initiation of opioids >6 months after treatment were excluded. Demographics, disease characteristics, treatment, and outpatient prescription practices were collected. Endpoints included duration of opioid use ≥6 and ≥12 months. Results: There were 106 women included, of whom 83% received definitive radiation. Most patients (n = 91, 85.8%) received outpatient opioids. Most common timing of prescriptions were before cancer therapy (35.9%), postprocedure (26.4%), and during radiation therapy (17.0%). Median duration was 3 (interquartile range, 1-11) months; 35.2% of these patients received opioids ≥6 months and 22% received opioids ≥12 months. Greater International Federation of Gynaecology and Obstetrics (FIGO) stage, recurrent/residual disease, initiation of opioids before treatment, history of depression or anxiety, and use of gabapentin or steroids were associated with long-term opioid use. Conclusions: Most patients were prescribed outpatient opioids, many of whom used opioids for 12 months. Improvement in provider communication and education, increased posttreatment monitoring, and further evaluation of nonopioid therapies are needed in this patient population to reduce long-term opioid use.

Local Control and Use of External Beam Parametrial Boost in the Era of Image-Guided Brachytherapy for Locally Advanced Cervical Cancer.

OBJECTIVE: Historically, external beam parametrial boost (EBPB) has been used in locally advanced cervical cancers to supplement radiation dose. However, it has become controversial in the era of image-guided brachytherapy. Modern 3D imaging and brachytherapy techniques have improved delineation and coverage of tumor. Outcomes with and without parametrial boost were analyzed. METHODS: Women with cervical cancer involving the parametria (clinically or radiographically) diagnosed between 2001 and 2017 were identified. Clinicopathologic and treatment features, survival and patterns of failure data were collected. Univariate and multivariable data analysis was performed to evaluate association of these variables, including parametrial boost, with local failure-free survival and overall survival. Competing risks analysis was performed for cumulative incidence of local failure, with death and other failures treated as competing events. RESULTS: A total of 100 women were identified (median follow-up 26.8 mo). Forty-one (41%) received EBPB; these patients were less likely to have received magnetic resonance imaging, positron emission tomography, interstitial, or high-dose rate brachytherapy. Magnetic resonance imaging, positron emission tomography, dose rate, and treatment era were highly correlated (Cramer's V: 0.43 to 0.68, P<0.01). Two-year overall survival and local failure were 78% and 12% for the entire cohort. While the use of EBPB was not associated with any outcome on multivariable analysis, treatment year after 2009 was highly associated with improved outcomes in all models. CONCLUSIONS: In this study, omission of EBPB did not compromise local control or survival in the modern era, supporting a decreased need for standardized use of parametrial boost.

Goals of care discussions: perceptions of radiation and medical oncologists.

BACKGROUND: Goals of care discussions (GOCD) are essential when counseling patients with cancer. Respective roles of radiation oncologists (RO) and medical oncologists (MO) in GOCD can be unclear. This study aims to clarify the dynamics and barriers to GOCD. METHODS: Five hundred and fifty-four ROs and 1604 MOs at NCI-designated comprehensive cancer centers were sent an anonymous electronic survey regarding demographics, opinions, training in GOCD, GOCD frequency, and three vignettes. Response formats were Yes/No, Likert-type, and free response. Chi-square and Wilcoxon rank-sum tests were performed. Likert-type scores were reported as median [interquartile range]. RESULTS: There were 76 (13.7%) RO and 153 (9.5%) MO who completed surveys. Sixty-three percent of RO and 66% of MO reported GOCD with > 50% of patients (p = 0.90). GOCD were initiated for declining performance status (74%) and poor life expectancy (69%). More MO (42%) received formal GOCD training compared to RO (18%) (p < 0.01). MO were more comfortable conducting GOCD than RO (p < 0.01). RO-conducted GOCD were rated to be less important by MO compared to RO (p < 0.05). Thirty-six percent of MO reported being "not at all" or "somewhat" comfortable with RO-conducted GOCD. RO-initiated GOCD with new patients were rated less appropriate by RO compared to MO perceptions of RO-initiated GOCD (p < 0.01). CONCLUSIONS: While MO and RO conduct GOCD with similar frequency, MO are more comfortable conducting GOCD and are more likely to have formal training. MO rate importance of RO involvement lower than RO. Further research is needed to understand interdisciplinary dynamics that may impact GOCD and subsequent patient care outcomes.

The use of complementary and integrative therapies as adjunct interventions during radiotherapy: a systematic review.

PURPOSE: Literature supporting the efficacy of complementary and integrative medicine (CIM) alongside radiotherapy is fragmented with varying outcomes and levels of evidence. This review summarizes the available evidence on CIM used with radiotherapy in order to inform clinicians. METHODS: A systematic literature review identified studies on the use of CIM during radiotherapy. Inclusion required the following criteria: the study was interventional, CIM therapy was for human patients with cancer, and CIM therapy was administered concurrently with radiotherapy. Data points of interest were collected from included studies. A subset was identified as high-quality using the Jadad scale. Fisher's exact test was used to assess the association between study results, outcome measured, and type of CIM. RESULTS: Overall, 163 articles met inclusion. Of these, 68 (41.7%) were considered high-quality trials. Articles published per year increased over time (p < 0.01). Frequently identified therapies were biologically based therapies (47.9%), mind-body therapies (23.3%), and alternative medical systems (13.5%). Within the subset of high-quality trials, 60.0% of studies reported a favorable change with CIM while 40.0% reported no change. No studies reported an unfavorable change. Commonly assessed outcome types were patient-reported (41.1%) and provider-reported (21.5%). Rate of favorable change did not differ based on type of CIM (p = 0.90) or outcome measured (p = 0.24). CONCLUSIONS: Concurrent CIM may reduce radiotherapy-induced toxicities and improve quality of life, suggesting that physicians should discuss CIM with patients receiving radiotherapy. This review provides a broad overview of investigations on CIM use during radiotherapy and can inform how radiation oncologists advise their patients about CIM.

Circulating tumor-tissue modified HPV DNA analysis for molecular disease monitoring after chemoradiation for anal squamous cell carcinoma: a case report.

Squamous cell carcinoma (SCC) of the anus typically arises after human papillomavirus (HPV) infection. We report on the use of molecular disease monitoring using a novel blood test measuring circulating tumor-tissue -modified HPV DNA in two patients with anal cancer. Two patients with anal SCC received concurrent chemotherapy and radiation therapy (chemoRT) with curative intent, one with a T2N0 anal margin squamous cell carcinoma with a history of AIDS, and one with a T3N0 anal squamous cell carcinoma and a history of concurrent prostate cancer. HPV genotyping at diagnosis confirmed the presence of HPV16 DNA in both cases. Circulating, tumor-tissue-modified HPV DNA (TTMV-HPV DNA) was measured in the peripheral blood utilizing digital PCR at baseline and in follow-up. Disease burden was assessed post-treatment with standard anoscopy, biopsy, and PET/CT. Plasma TTMV-HPV DNA levels were elevated at diagnosis, and decreased during and after chemoRT completion in both cases. During post treatment surveillance, TTMV-HPV DNA levels correlated with disease status including one case with progressive local recurrence within 2 months, and one case with 12 months of local control both confirmed by biopsy. These case studies present the first use of circulating tumor-tissue-modified HPV DNA as a biomarker for anal cancer. Further study of this blood test an adjunct to standard treatment and monitoring is warranted in HPV-positive anal cancer.

Radiation-Induced Sarcoma After Heterotopic Ossification Prophylaxis: A Case Report.

CASE: Heterotopic ossification (HO) is a pathological formation of bone in nonosseous tissue and is a common complication of orthopaedic procedures. Radiotherapy is often used to prevent HO despite the small risk of secondary malignancy. Here, we report a case of a patient who developed a periprosthetic, radiation-induced sarcoma after delivery of a single fraction of 7 Gy for HO prophylaxis. This sarcoma was found to lie entirely within the treatment field and occurred within 5 years of radiation. CONCLUSION: Appropriate counseling regarding radiation-induced sarcoma formation should be provided to patients considering radiotherapy for this HO prophylaxis.

Adjuvant vaginal brachytherapy and chemotherapy versus pelvic radiotherapy in early-stage endometrial cancer: Outcomes by risk factors.

OBJECTIVE: To report on patterns of care as well as evaluate the two treatment regimens using a large retrospective hospital-based registry to identify possible subgroups of patients who may experience benefit with VBT + CT vs. EBRT. METHODS: Patients from the National Cancer Database (NCDB) were identified who met the inclusion criteria for GOG 249 and were treated with either VBT + CT or WPRT. Demographic, clinicopathologic, and treatment factors were collected. Association of treatment type and other variables with overall survival was analyzed using Cox proportional hazards model. Subset analyses were performed based on a variety of risk factors, including high risk pathologies, surgical nodal sampling, and grade. RESULTS: A total of 4,602 patients were included in the analysis, with 41% receiving VBT + CT and 59% receiving WPRT. For the entire cohort, VBT + CT was associated with improved survival, with 3-year overall survival 89.6% vs. 87.8% (hazard ratio 1.24, 95%CI 1.01-1.52, p = 0.04). On subset analysis, patients with serous histology experienced benefit with VBT + CT, while high-grade endometrial patients without lymph node dissection experienced improved survival associated with EBRT. After exclusion of serous histology, there was no survival difference associated with treatment type. CONCLUSIONS: VBT + CT was associated with superior survival outcomes in patients with early-stage serous carcinoma. For non-serous histology, treatment modality was not associated with a difference in survival, although patients with high-grade disease and no nodal dissection experienced benefit from EBRT.

Literature Review of Vaginal Stenosis and Dilator Use in Radiation Oncology.

PURPOSE: Guidelines for the care of women undergoing pelvic radiation therapy (RT) recommend vaginal dilator therapy (VDT) to prevent radiation-induced vaginal stenosis (VS); however, no standard protocol exists. This review seeks to update our current state of knowledge concerning VS and VDT in radiation oncology. METHODS AND MATERIALS: A comprehensive literature review (1972-2017) was conducted using search terms "vaginal stenosis," "radiation," and "vaginal dilator." Information was organized by key concepts including VS definition, time course, pathophysiology, risk factors, and interventions. RESULTS: VS is a well-described consequence of pelvic RT, with early manifestations and late changes evolving over several years. Strong risk factors for VS include RT dose and volume of vagina irradiated. Resultant vaginal changes can interfere with sexual function and correlational studies support the use of preventive VDT. The complexity of factors that drive noncompliance with VDT is well recognized. There are no prospective data to guide optimal duration of VDT, and the consistency with which radiation oncologists monitor VS and manage its consequences is unknown. CONCLUSIONS: This review provides information concerning VS definition, pathophysiology, and risk factors and identifies domains of VDT practice that are understudied. Prospective efforts to monitor and measure outcomes of patients who are prescribed VDT are needed to guide practice.

Current recommendations and recent progress in endometrial cancer.

Endometrial cancer is the most common gynecologic cancer in the United States, and its incidence is rising. Although there have been significant recent advances in our understanding of endometrial cancer biology, many aspects of treatment remain mired in controversy, including the role of surgical lymph node assessment and the selection of patients for adjuvant radiation or chemotherapy. For the subset of women with microsatellite-instable, metastatic disease, anti- programmed cell death protein 1 immunotherapy (pembrolizumab) is now approved by the US Food and Drug Administration, and numerous trials are attempting to build on this early success.

Clinical and Dosimetric Implications of Intrafractional Cylinder Movement During Vaginal Cuff Brachytherapy.

Introduction To quantify the dosimetric and clinical effects of intrafractional cylinder movement in patients receiving high-dose-rate vaginal cuff brachytherapy (VBT) without a formal immobilization device and the implication of motion on institutional clinical outcomes. Methods From 2013-2018, 119 patients were treated with VBT with no formal immobilization device at a single institution. As a quality assessment study, pre-and post-cylinder brachytherapy kilovoltage (kV) images were acquired for 37 fractions in nine consecutive patients who underwent VBT and clinical care representative of institutional practice standards. The D90 and D90 EqD2 were calculated according to each patient's average intrafractional movement throughout the treatment course. The D2cc for organs-at-risk (OARs) were also re-evaluated following the simulated movements. The survival outcomes and toxicity were recorded from the 119 patients. Toxicity was graded as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results The measured mean ± standard deviation movement was 5.0 mm ± 3.5, with 62% moving caudad. The D90 from each patient's maximum and average movements were lower than the pre-planned doses: 71%, and 89%, respectively. The doses to the OARs were lower than the pre-planned doses. After a median follow-up of 20 months, there were three local recurrences with a median time of 14.5 months (range: 10-31). There were two acute grade 3+ toxicities and one late grade 3+ toxicity. There was a moderate correlation (r = 0.40) between body mass index (BMI) and intrafraction movement with caudad being more common in smaller BMIs (p = 0.0216). Conclusions Intrafractional vaginal cylinder movement without a table fixation device is about 5.0 mm, with the majority of movements moving caudad. While institutional outcomes suggest that local control may not be compromised, consideration of more formal immobilization devices is warranted, especially for those patients with lower BMIs.

Late toxicity after post-prostatectomy intensity modulated radiation therapy: Evaluating normal-tissue sparing guidelines.

PURPOSE: Dose-volume histogram (DVH) toxicity relationships are poorly defined in men who receive radiation after radical prostatectomy (RP). We evaluated Radiation Therapy Oncology Group (RTOG) study 0534 and institutional intact normal-tissue sparing guidelines, as well as dose to bladder trigone, for ability to minimize late toxicity. METHODS AND MATERIALS: 164 men received intensity modulated radiation therapy (RT) to a median prostate bed dose of 66.6 Gy at a median of 22 months after RP. 46% of men were prescribed androgen deprivation therapy and pelvic lymph node irradiation to a median dose of 50.4 Gy. DVH relationships for the rectum, bladder, trigone, and bladder excluding the clinical target volume (bladder-CTV) were analyzed against the Common Terminology Criteria for Adverse Events late grade 2 + (G2+) gastrointestinal (GI) and genitourinary (GU) toxicity by log-rank test. RTOG 0534 (rectum V65, 40 Gy ≤35, 55%, and bladder-CTV V65, 40 ≤50, 70%) and intact prostate RT institutional guidelines (rectum V70, 65, 40 ≤20, 40, 80% and bladder V70, 65, 40 ≤30, 60, 80%, respectively) guidelines were evaluated. RESULTS: With a median follow-up time of of 33 months, the 4-year freedom from G2 + GI and GU toxicity were both 91%. G2 + GI (n = 12) and GU (n = 15) toxicity included 4% diarrhea (n = 6), 4% hemorrhage (n = 6), 1% proctitis (n = 1), and 4% urinary frequency (n = 7), 1% obstructive (n = 2), 2% cystitis (n = 3), and 3% incontinence (n = 5), respectively. RTOG 0534 rectum and bladder goals were not achieved in 65% and 41% of cases, while the institutional intact prostate goals were not achieved in 21% and 25% of cases, respectively. Neither dose to the bladder trigone nor any of the proposed normal tissue goals were associated with late toxicity (P > .1). In the univariate analysis, age, pelvic RT, RT dose, anticoagulation use, androgen deprivation therapy, time from RP to RT, and tobacco history were not associated with toxicity. CONCLUSIONS: More than 90% of men were free from late G2 + toxicity 4 years after post-RP intensity modulated RT. No tested parameters were associated with late toxicity. In the absence of established normal-tissue DVH guidelines in the postoperative setting, the use of intact guidelines is reasonable.

Optimizing the Role of Surgery and Radiation Therapy in Urethral Cancer Based on Histology and Disease Extent.

PURPOSE: Urethral cancer is rare, with limited data guiding treatment. A national hospital-based registry was used to evaluate the role of local therapy in these patients. METHODS AND MATERIALS: We performed a retrospective cohort study of patients who, between 2004 and 20013, received a diagnosis of T0-4N0-2 M0 urethral cancer. Local therapy was radiation therapy (RT), surgery (S), or S and RT (S+RT). The Cox proportional hazards model was used to assess the impact of therapy type on overall survival (primary endpoint). Subgroup analysis by extent of disease (early stage [T0-2 N0] vs locally advanced [T3+ or N+]) and histology was performed. RESULTS: In our study, 2614 patients had a median follow-up of 28 months. Three-year overall survival was 54%. In 501 patients with locally advanced disease, S+RT was associated with improved survival versus S alone (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.42-0.80). There was no difference for patients with squamous cell carcinoma by treatment type, but patients with adenocarcinoma (RT vs S: HR 0.20; 95% CI, 0.07-0.60) or transitional cell carcinoma (S+RT vs S: HR 0.45, 95% CI, 0.26-0.77) had improved OS with RT as part of treatment. In 1705 early-stage patients, there was no association with survival when comparing S+RT versus S. CONCLUSIONS: For patients with locally advanced disease and transitional cell carcinoma undergoing S, the addition of RT is associated with improved overall survival and should be considered. An RT-based approach may be preferred for adenocarcinoma, but there was no clear association with survival by therapy type for squamous cell carcinoma. This study is hypothesis generating; prospective trials are necessary.

Potential role of radiation therapy in augmenting the activity of immunotherapy for gynecologic cancers.

Immune checkpoint inhibitors have become an area of intense interest in oncology and are actively being studied in a variety of cancer types with a wide range of success. In vitro data suggest mechanisms by which radiation can activate the immune system, and ongoing studies are exploring the potential interaction of checkpoint inhibitors with radiotherapy in both preclinical and clinical settings. Gynecologic malignancies are a heterogeneous group of tumors with varying prognoses, intrinsic immunogenicity, and potential for response to immune-based therapies. In this review, we focus on the rationale for immunotherapy and opportunities for augmentation by photon radiotherapy in cancers of the cervix, endometrium, and ovary.

Estimating prognosis at the time of repeat whole brain radiation therapy for multiple brain metastases: The reirradiation score.

PURPOSE: Whole brain radiation therapy (WBRT) remains the standard of care for patients with multiple brain metastases, but more than half of treated patients will develop intracranial progression. Because there is no clear consensus on the optimal therapeutic approach, a prognostic index would be helpful to guide treatment options at progression. We explored whether the recursive partitioning analysis (RPA) score prior to repeat WBRT is predictive of survival. METHODS AND MATERIALS: This multi-institutional pooled analysis included patients with 2 or more brain metastases from any solid primary tumor that was treated with 2 courses of WBRT. Information on demographics, disease characteristics, and intervals between courses was collected. RPA class was abstracted or retrospectively assigned, and descriptive statistics calculated. Median survival (MS) was determined using the Kaplan-Meier method and compared using log rank tests. Univariate and multivariate analyses were performed via Cox regression analysis. RESULTS: For 205 patients, the median age was 55 years (range, 25-83 years), 68% were female, 40.5% had non-small cell lung cancer, and 31.2% had small cell lung cancer. Prior to the second WBRT, 4.9% of patients were RPA class 1, 36.6% were RPA2, and 58.5% were RPA3, with an MS of 7.5 months (95% confidence interval [CI], 4.7-10.3), 5.2 months (95% CI, 3.7-6.7 months), and 2.9 months (95% CI, 2.2-2.9 months), respectively (P = .001). On univariate and multivariate analyses, a Karnofsky Performance Status of <80, extracranial metastases, interval between courses <9 months, small cell lung cancer histology, and uncontrolled primary significantly correlated with shorter MS. By assigning a score of 1 to each of these factors, a new prognostic index was created, the reirradiation (ReRT) score. Survival on the basis of ReRT score grouping ranged from 2.2 to 7.2 months and demonstrated significant differences in MS. CONCLUSIONS: In the largest reported cohort to receive repeat WBRT, application of the RPA score was not predictive of MS. The new ReRT score is a simple tool based on readily available clinical information.