The American Brachytherapy Society and Indian Brachytherapy Society consensus statement for the establishment of high-dose-rate brachytherapy programs for gynecological malignancies in low- and middle-income countries.

PURPOSE: The global cervical cancer burden is disproportionately high in low- and middle-income countries (LMICs), and outcomes can be governed by the accessibility of appropriate screening and treatment. High-dose-rate (HDR) brachytherapy plays a central role in cervical cancer treatment, improving local control and overall survival. The American Brachytherapy Society (ABS) and Indian Brachytherapy Society (IBS) collaborated to provide this succinct consensus statement guiding the establishment of brachytherapy programs for gynecological malignancies in resource-limited settings. METHODS AND MATERIALS: ABS and IBS members with expertise in brachytherapy formulated this consensus statement based on their collective clinical experience in LMICs with varying levels of resources. RESULTS: The ABS and IBS strongly encourage the establishment of HDR brachytherapy programs for the treatment of gynecological malignancies. With the consideration of resource variability in LMICs, we present 15 minimum component requirements for the establishment of such programs. Guidance on these components, including discussion of what is considered to be essential and what is considered to be optimal, is provided. CONCLUSIONS: This ABS/IBS consensus statement can guide the successful and safe establishment of HDR brachytherapy programs for gynecological malignancies in LMICs with varying levels of resources.

Factors associated with increased financial toxicity after the completion of radiation treatment for gynecologic cancer.

PURPOSE: We evaluated financial toxicity (FT) in patients with gynecologic cancer treated with radiation and assessed the impact of the COVID-19 pandemic on patients' financial wellbeing. METHODS: Patients completed a survey 1 month after completing radiation from August 2019-March 2020 and November 2020-June 2021. The survey included the COmprehensive Score for Financial Toxicity (COST) tool, EQ-5D to measure quality of life (QOL) and pandemic-related questions for the second survey period. High FT was COST score ≤ 23. RESULTS: Of 97 respondents (92% response rate), 49% completed the survey pre-pandemic and 51% after; the majority were white (76%) and had uterine cancer (64%). Sixty percent received external beam radiation with or without brachytherapy; 40% had only brachytherapy. High FT was associated with worse QOL (r = -0.37, P < 0.001), younger age and type of insurance (both p ≤ 0.03). Respondents with high FT were 6.0 (95% CI 1.0-35.9) times more likely to delay/avoid medical care, 13.6 (95% CI 2.9-64.3) times more likely to borrow money, and 6.9 (95% CI 1.7-27.2) times as likely to reduce spending on basic goods. The pandemic cohort had a smaller proportion of respondents with high FT than the pre-pandemic cohort (20% vs. 35%, p = 0.10) and a higher median COST score (32 (IQR 25-35) vs. 27 (IQR 19-34), p = 0.07). CONCLUSION: Privately insured, younger respondents who received radiation for gynecologic cancer were at risk for FT. High FT was associated with worse QOL and economic cost-coping strategies. We observed less FT in the pandemic cohort, though not statistically different from the pre-pandemic cohort.

External Beam, Brachytherapy, or Chemotherapy? Defining Adjuvant Therapy for Early-Stage and High- and High-Intermediate-Risk Endometrial Cancer.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 54-year-old postmenopausal female with a history of stroke and carotid endarterectomy presented with 3 weeks of vaginal bleeding with passage of clots. Gynecologic exam revealed a 3-cm barrel-shaped cervix with friability at the os and no appreciable parametrial involvement. Cervical biopsy showed high-grade endometrioid adenocarcinoma. Pelvic magnetic resonance imaging demonstrated a 9.9-cm × 4.5-cm × 6.2-cm mass extending from the uterus to the cervix with greater than 50% myometrial invasion (MMI; Fig 1 ). Total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy revealed International Federation of Gynecology and Obstetrics (FIGO) stage II endometrial cancer: a 12-cm grade 3 endometrioid adenocarcinoma with 80% MMI and lymphovascular invasion (LVI) involving the outer half of the cervical stroma ( Fig 1 ), and without pelvic lymph node involvement.

Long-term quality of life after definitive treatment for prostate cancer: patient-reported outcomes in the second posttreatment decade.

Definitive treatment for prostate cancer includes radical prostatectomy (RP), external beam radiation therapy (EBRT), and brachytherapy (BT). The different side effect profiles of these options are crucial factors for patients and clinicians when deciding between treatments. This study reports long-term health-related quality of life (HRQOL) for patients in their second decade after treatment for prostate cancer. We used a validated survey to assess urinary, bowel, and sexual function and HRQOL in a prospective cohort of patients diagnosed with localized prostate cancer 14-18 years previously. We report and compare the outcomes of patients who were initially treated with RP, EBRT, or BT. Of 230 eligible patients, the response rate was 92% (n = 211) and median follow-up was 14.6 years. Compared to baseline, RP patients had significantly worse urinary incontinence and sexual function, EBRT patients had worse scores in all domains, and BT patients had worse urinary incontinence, urinary irritation/obstruction, and sexual function. When comparing treatment groups, RP patients underwent larger declines in urinary continence than did BT patients, and EBRT and BT patients experienced larger changes in urinary irritation/obstruction. Baseline functional status was significantly associated with long-term function for urinary obstruction and bowel function domains. This is one of the few prospective reports on quality of life for prostate cancer patients beyond 10 years, and adds information about the late consequences of treatment choices. These data may help patients make informed decisions regarding treatment choice based on symptoms they may experience in the decades ahead.

Dosimetric consequences of interobserver variability in delineating the organs at risk in gynecologic interstitial brachytherapy.

PURPOSE: To investigate the dosimetric variability associated with interobserver organ-at-risk delineation differences on computed tomography in patients undergoing gynecologic interstitial brachytherapy. METHODS AND MATERIALS: The rectum, bladder, and sigmoid of 14 patients treated with gynecologic interstitial brachytherapy were retrospectively contoured by 13 physicians. Geometric variability was calculated using κ statistics, conformity index (CIgen), and coefficient of variation (CV) of volumes contoured across physicians. Dosimetric variability of the single-fraction D0.1cc and D2cc was assessed through CV across physicians, and the standard deviation of the total EQD2 (equivalent dose in 2 Gy per fraction) brachytherapy dose (SD(TOT)) was calculated. RESULTS: The population mean ± 1 standard deviation of κ, CIgen, and volume CV were, respectively: 0.77 ± 0.06, 0.70 ± 0.08, and 20% ± 6% for bladder; 0.74 ± 06, 0.67 ± 0.08, and 20% ± 5% for rectum; and 0.33 ± 0.20, 0.26 ± 0.17, and 82% ± 42% for sigmoid. Dosimetric variability was as follows: for bladder, CV = 31% ± 19% (SD(TOT) = 72 ± 64 Gy) for D0.1cc and CV = 16% ± 10% (SD(TOT) = 9 ± 6 Gy) for D2cc; for rectum, CV = 11% ± 5% (SD(TOT) = 16 ± 17 Gy) for D0.1cc and CV = 7% ± 2% (SD(TOT) = 4 ± 3 Gy) for D2cc; for sigmoid, CV = 39% ± 28% (SD(TOT) = 12 ± 18 Gy) for D0.1cc and CV = 34% ± 19% (SD(TOT) = 4 ± 4 Gy) for D2cc. CONCLUSIONS: Delineation of bladder and rectum by 13 physicians demonstrated substantial geometric agreement and resulted in good dosimetric agreement for all dose-volume histogram parameters except bladder D0.1cc. Small delineation differences in high-dose regions by the posterior bladder wall may explain these results. The delineation of sigmoid showed fair geometric agreement. The higher dosimetric variability for sigmoid compared with rectum and bladder did not correlate with higher variability in the total brachytherapy dose but rather may be due to the sigmoid being positioned in low-dose regions in the cases analyzed in this study.

Intensity-modulated versus conventional radiation therapy for oropharyngeal carcinoma: long-term dysphagia and tumor control outcomes.

BACKGROUND: The purpose of this study was to determine the relative clinical benefits of intensity-modulated radiation therapy (IMRT) versus conventional radiotherapy (CRT) in the treatment of patients with oropharyngeal carcinoma. METHODS: We compared tumor control and toxicity outcomes in 132 patients with stage III to IVA/B oropharyngeal carcinoma treated with definitive chemoradiation in the human papillomavirus (HPV) era. RESULTS: Patients treated with IMRT had lower rates of xerostomia (p = .01) and shorter duration of gastrostomy-tube dependence (p < .0001), but increased risk of cervical esophageal stricture (p = .03). The overall rates of late dysphagia were not different between the 2 groups (p = .40). In multivariate analysis, IMRT was a significant predictor of decreased disease-specific mortality (hazard ratio [HR] = 0.24; p = .03) after adjustment for T-category and active smoking. After adjustment for T classification, IMRT use was associated with a trend toward a significant decrease in locoregional failure (HR = 0.17; p = .08). CONCLUSION: The incidence of late dysphagia is similar in IMRT and CRT, but the mechanism of dysphagia is different.

Clinical factors predicting for prolonged enteral supplementation in patients with oropharyngeal cancer treated with chemoradiation.

OBJECTIVES: The purpose of this study is to determine the pre-treatment clinical factors associated with prolonged enteral feeding in patients with oropharyngeal cancer treated with chemoradiation. MATERIALS AND METHODS: One hundred and nine patients with stage III-IVB oropharyngeal carcinoma treated with definitive chemoradiation were analyzed. Feeding tube usage was defined as the duration of active usage for nutritional purposes. RESULTS: Median follow-up was 4.4 years and median feeding tube usage was 2.5 months. On multivariate analysis, increasing duration of feeding tube usage was associated with narcotic use before treatment (p = 0.04), living alone at the time of treatment (p = 0.04), and larger pre-treatment decrease in body-mass index (p = 0.01). Prolonged feeding tube usage was associated with decreased overall survival (p = 0.06) and disease-free survival (p = 0.02) in univariate analysis. CONCLUSIONS: By identifying patients at risk for prolonged feeding tube usage, aggressive measures can be attempted to prevent feeding tube dependence.

Prevention and management of complications after radiotherapy for skull base tumors: a multidisciplinary approach.

Radiotherapy is an important treatment approach for a variety of benign and malignant skull base tumors. For patients with malignant skull base tumors, radiation therapy is usually given with surgery and chemotherapy. While patient- and tumor-specific factors can affect the risk of radiation-related complications, surgery and chemotherapy also play a large causal role. As surgery and chemotherapy can lower the radiation dose tolerance of the normal tissues in the skull base, a multidisciplinary team approach is necessary in the initial treatment decision-making process. Radiation can delay wound healing and increase complications after reconstructive surgery, and so surgical planning between surgeons and radiation oncologists is critical to ensure the successful repair. In this article, we will discuss the etiology, risk factors and management of osteonecrosis and sinonasal-cutaneous fistula, the two major complications after multimodality treatment of skull base tumors. Careful consideration of specific tumor-, patient- and treatment-related factors in a multidisciplinary manner is vital in minimizing these complications.

Four-dimensional versus 3-dimensional computed tomographic planning for gastric mucosa associated lymphoid tissue lymphoma.

PURPOSE: This study compares dosimetric parameters of 4-dimensional (4D) and 3-dimensional (3D) computed tomographic (CT) planning for gastric mucosa-associated lymphoid tissue (MALT) lymphoma in an attempt to identify any potential benefit of 4DCT planning. METHODS AND MATERIALS: We identified 18 patients who received definitive 4DCT radiation planning from September 2006 to September 2011 for gastric MALT lymphoma at our institution. In addition to the kidneys and liver, we contoured an internal target volume (ITV) and static clinical target volume (sCTV) for each patient based on the 4D and 3D images, respectively, to develop 3D conformal radiation plans. Using the static and motion plans, we measured the volume of ITV covered by at least 95% of the prescribed dose (V95), the minimum dose received by 95% of the ITV (D95), and the volume of organs receiving at least 20 Gy or 30 Gy (V20 or V30). RESULTS: Volumes of the ITV, motion liver, left kidney, and right kidney were significantly larger than their static counterparts. The static plan significantly lowered the ITV V95 and D95 compared with the motion plan. However, this undercoverage was significantly associated with the superior-inferior (SI) respiratory excursions. A V95 of >98% was observed in 92% of patients with SI excursions <15 mm versus 33% of patients with SI excursions >15 mm (P = .02). When compared with the motion plan, the static plan also significantly lowered the liver V30 and left kidney V20. CONCLUSIONS: The 3DCT planning can result in undercoverage of the ITV and altered estimation of doses to normal structures. However, in patients with limited respiratory excursions (<15 mm), 4D and 3D images generated similar ITV coverage.

Upfront androgen deprivation therapy with salvage radiation may improve biochemical outcomes in prostate cancer patients with post-prostatectomy rising PSA.

PURPOSE: The addition of androgen deprivation therapy (ADT) to definitive external beam radiation therapy (RT) improves outcomes in higher-risk prostate cancer patients. However, the benefit of ADT with salvage RT in post-prostatectomy patients is not clearly established. Our study compares biochemical outcomes in post-prostatectomy patients who received salvage RT with or without concurrent ADT. METHODS AND MATERIALS: Of nearly 2,000 post-prostatectomy patients, we reviewed the medical records of 191 patients who received salvage RT at the University of Pennsylvania between 1987 and 2007. Follow-up data were obtained by chart review and electronic polling of the institutional laboratory database and Social Security Death Index. Biochemical failure after salvage RT was defined as a prostate-specific antigen of 2.0 ng/mL above the post-RT nadir or the initiation of ADT after completion of salvage RT. RESULTS: One hundred twenty-nine patients received salvage RT alone, and 62 patients received combined ADT and salvage RT. Median follow-up was 5.4 years. Patients who received combined ADT and salvage RT were younger, had higher pathologic Gleason scores, and higher rates of seminal vesicle invasion, lymph node involvement, and pelvic nodal irradiation compared with patients who received salvage RT alone. Patients who received combined therapy had improved biochemical progression-free survival (bPFS) compared with patients who received RT alone (p = 0.048). For patients with pathologic Gleason scores ≤7, combined RT and ADT resulted in significantly improved bPFS compared to RT alone (p = 0.013). CONCLUSIONS: These results suggest that initiating ADT during salvage RT in the post-prostatectomy setting may improve bPFS compared with salvage RT alone. However, prospective randomized data are necessary to definitively determine whether hormonal manipulation should be used with salvage RT. Furthermore, the optimal nature and duration of ADT and the patient subgroups in which ADT could provide the most benefit remain open questions.

Isoform-specific ras activation and oncogene dependence during MYC- and Wnt-induced mammary tumorigenesis.

We have previously shown that c-MYC-induced mammary tumorigenesis in mice proceeds via a preferred secondary pathway involving spontaneous activating mutations in Kras2 (C. M. D'Cruz, E. J. Gunther, R. B. Boxer, J. L. Hartman, L. Sintasath, S. E. Moody, J. D. Cox, S. I. Ha, G. K. Belka, A. Golant, R. D. Cardiff, and L. A. Chodosh, Nat. Med. 7:235-239, 2001). In contrast, we now demonstrate that Wnt1-induced mammary tumorigenesis proceeds via a pathway that preferentially activates Hras1. In addition, we find that expression of oncogenic forms of Kras2 and Hras1 from their endogenous promoters has markedly different consequences for the progression of tumors to oncogene independence. Spontaneous activating Kras2 mutations occurring in either MYC- or Wnt1-induced tumors were strongly associated with oncogene-independent tumor growth following MYC or Wnt1 downregulation. In contrast, Hras1-mutant Wnt1-induced tumors consistently remained oncogene dependent. Additionally, Kras2-mutant tumors exhibited substantially higher levels of ras-GTP, phospho-Erk1/2, and phospho-Mek1/2 compared to Hras1-mutant tumors, suggesting the involvement of the ras/mitogen-activated protein kinase (MAPK) pathway in the acquisition of oncogene independence. Consistent with this, by use of carcinogen-induced ras mutations as well as knock-in mice harboring a latent activated Kras2 allele, we demonstrate that Kras2 activation strongly synergizes with both c-MYC and Wnt1 in mammary tumorigenesis and promotes the progression of tumors to oncogene independence. Together, our findings support a model for tumorigenesis in which c-MYC and Wnt1 select for the outgrowth of cells harboring mutations in specific ras isoforms and that these secondary mutations, in turn, determine the extent of ras/MAPK pathway activation and the potential for oncogene-independent growth.

Lack of sustained regression of c-MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation.

Recent studies of oncogene dependence in conditional transgenic mice have suggested the exciting possibility that transient or prolonged MYC inactivation may be sufficient for sustained reversal of the tumorigenic process. In contrast, we report here that following oncogene downregulation, the majority of c-MYC-induced mammary adenocarcinomas grow in the absence of MYC overexpression. In addition, residual neoplastic cells persist from virtually all tumors that do regress to a nonpalpable state and these residual cells rapidly recover their malignant properties following MYC reactivation or spontaneously recur in a MYC-independent manner. Thus, MYC-induced mammary tumor cells subjected to either brief or prolonged MYC inactivation remain exquisitely sensitive to its oncogenic effects and characteristically progress to a state in which growth is MYC-independent.