Delphi consensus on stereotactic ablative radiotherapy for oligometastatic and oligoprogressive renal cell carcinoma-a European Society for Radiotherapy and Oncology study endorsed by the European Association of Urology.

The purpose of this European Society for Radiotherapy and Oncology (ESTRO) project, endorsed by the European Association of Urology, is to explore expert opinion on the management of patients with oligometastatic and oligoprogressive renal cell carcinoma by means of stereotactic ablative radiotherapy (SABR) on extracranial metastases, with the aim of developing consensus recommendations for patient selection, treatment doses, and concurrent systemic therapy. A questionnaire on SABR in oligometastatic renal cell carcinoma was prepared by a core group and reviewed by a panel of ten prominent experts in the field. The Delphi consensus methodology was applied, sending three rounds of questionnaires to clinicians identified as key opinion leaders in the field. At the end of the third round, participants were able to find consensus on eight of the 37 questions. Specifically, panellists agreed to apply no restrictions regarding age (25 [100%) of 25) and primary renal cell carcinoma histology (23 [92%] of 25) for SABR candidates, on the upper threshold of three lesions to offer ablative treatment in patients with oligoprogression, and on the concomitant administration of immune checkpoint inhibitor. SABR was indicated as the treatment modality of choice for renal cell carcinoma bone oligometatasis (20 [80%] of 25) and for adrenal oligometastases 22 (88%). No consensus or major agreement was reached regarding the appropriate schedule, but the majority of the poll (54%-58%) retained the every-other-day schedule as the optimal choice for all the investigated sites. The current ESTRO Delphi consensus might provide useful direction for the application of SABR in oligometastatic renal cell carcinoma and highlight the key areas of ongoing debate, perhaps directing future research efforts to close knowledge gaps.

Non-invasive stereotactic ablative boost in patients with locally advanced cervical cancer.

INTRODUCTION: The current literature is insufficient to guide care for patients with cervical cancer ineligible for brachytherapy. Stereotactic ablative radiotherapy boost is a clinical necessity for these patients, but highly debated among radiation oncologists. OBJECTIVE: To report toxicity and survival outcomes in a large cohort of patients with locally advanced cervical cancer treated with a non-invasive stereotactic ablative radiotherapy boost instead of brachytherapy METHODS: Patients with locally advanced cervical cancer were entered, between January 2008 and December 2018, who were recommended definitive intent external boost after pelvic radiotherapy to 45-50.4 Gy concurrent with weekly cisplatin and simultaneous/sequential nodal boost up to 55-66 Gy. Simulation CT was facilitated using radio-opaque fiducials, empty rectum, dedicated bladder filling, and whole body vaculoplastic immobilization. Kaplan-Meier survival estimates were used to report local/regional recurrences, distant metastases, cancer-specific survival, and overall survival. RESULTS: A total of 25 patients were analyzed. Median follow-up was 25 months (range 6-54). Patients received stereotactic ablative radiotherapy due to refusal of brachytherapy (9/25, 36%), medical co-morbidities limiting implantation (9/25, 36%), or technical infeasibility (7/25, 28%). Typical fractionation was 24-30 Gy in 4-5 fractions (24/25, 96%). The most common long-term toxicity was grade 1-2 vaginal dryness, discomfort, stenosis, and/or dyspareunia (4/25, 16%). One patient had new post-treatment grade 4 fistula in an area of previous tumor erosion (1/25, 4%). Overall survival, cancer specific survival, loco-regional control, and distant control were 95.5%, 100%, 95.5%, and 89.1%, respectively, at 2 years. CONCLUSION: Further study of stereotactic ablative radiotherapy boost for cervical cancer is needed; a brachytherapy-similar approach portends clinical success with 95.5% overall survival and loco-regional control at 2 years.

Timely delivery of PORT for head and neck squamous cell carcinoma in a county hospital.

Objectives: The objective of this study was to compare the rate of post-operative radiation therapy (PORT) initiation within 6 weeks for head and neck squamous cell carcinoma patients treated at a safety net, academic institutio between 2019 and 2021 versus those treated in 2022 after implementation of a new clinical pathway. Methods: A retrospective case-control study was performed at a single tertiary care, safety-net, academic institution. Patient demographics, tumor characteristics, dates of surgery, and other treatment dates were collected from the electronic medical record. The time from surgery to PORT was calculated. Patients who started radiation treatment within 42 days of surgery were regarded as having started PORT on time. The demographics, tumor characteristics, and rate of timely PORT for the two cohorts of patients were compared. Results: From 2018 to 2021, our rate of PORT initiation within 6 weeks of surgery was 12% (n = 57). In 2022, our rate of timely PORT was 88% (n = 16), p < 0.5. Patient demographics and characteristics were similar with the exception of marital status and use of free-flap reconstruction. The 2022 cohort was more likely to be single (p < 0.5), and all patients underwent free-flap reconstruction in 2022 (p < 0.05). Conclusion: Early referrals, frequent communication, and use of a secure registry were the key to the success found by our group despite the socioeconomic challenges of our underserved, safety-net hospital patient population. The changes made at our institution should serve as a template for other institutions seeking to improve the quality of care for their HNSCC patients.

Phase I / II trial of metformin as a chemo-radiosensitizer in a head and neck cancer patient population.

OBJECTIVES: Retrospective studies have shown that head and neck squamous cell carcinoma (HNSCC) patients taking metformin demonstrate superior survival compared to their counterparts. We sought to determine whether metformin combined with chemoradiation would improve HNSCC patient survival compared to historical controls. MATERIALS AND METHODS: We conducted a Phase I/II prospective, single arm clinical trial in patients with newly diagnosed HNSCC (NCT02949700). Patients received platinum-based chemoradiation in combination with orally dosed metformin at one of 2 doses- 850 mg BID or 1500 mg BID administered during radiation, with a 2-week lead-in phase. Toxicity, disease response and survival metrics were ascertained throughout the study period. RESULTS: A total of 25 patients were evaluable for toxicity and survival; 9 failed to reach the predetermined 70% compliance with the study drug. No dose limiting toxicities were identified in the Phase I component and there were no grade 4 adverse events likely related to metformin throughout the study. The primary outcome for the Phase II component was met with a response rate of 96%. Three-year overall survival was ∼70% in the per protocol p16 + cohort and 0% in the per protocol p16- cohort. Survival among participants with a ≥70% metformin compliance to <70% metformin compliance demonstrated a trend towards improvement in the ≥70% compliance cohort, though this did not reach significance. CONCLUSION: Metformin is well tolerated during concurrent chemoradiation for HNSCC. Its effectiveness as a chemo-radiosensitizer remains unclear and will require further study with randomized controlled clinical trials in this patient population.

A dose-response relationship for time to bone pain resolution after stereotactic body radiotherapy (SBRT) for renal cell carcinoma (RCC) bony metastases.

BACKGROUND: To investigate the utility of stereotactic body radiotherapy (SBRT) in the treatment of painful renal cell carcinoma (RCC) bone metastases, and for a possible dose effect on time to symptom relief. MATERIAL AND METHODS: Eighteen patients with 24 painful osseous lesions from metastatic RCC were treated with SBRT. The most common treatment regimens were 24 Gy in 3 fractions and 40 Gy in 5 fractions. The times from treatment to first reported pain relief and time to symptom recurrence were evaluated. Median follow-up was 38 weeks (1-156 weeks). RESULTS: Seventy-eight percent of all patients had pain relief. Patients treated with a BED > 85 Gy achieved faster and more durable pain relief compared to those treated with a BED < 85 Gy. There was decrease in time to pain relief after a change in treatment regimen to 8 Gy × 5 fractions (BED = 86). There was only one patient with grade 1 skin toxicity. No neurological or other toxicity was observed. CONCLUSIONS: SBRT can safely and effectively treat painful RCC bony metastases. There appears to be a relationship between radiation dose and time to stable pain relief.

Implementation of High-Dose-Rate, CT-Based Prostate Brachytherapy in an Academic Teaching Hospital and Residency Training Program.

Introduction Prostate brachytherapy provides the most durable local control for prostate adenocarcinoma among all radiation treatment options. However, likely due to decreased trainee familiarity with the technique and resource intensity, it has seen a decline in utilization. Here we outline our experience with starting a high-dose-rate (HDR) prostate brachytherapy program within a residency training program and present our outcome data. Methods Patients were identified and screened using clinical data and volume study for candidacy for brachytherapy implantation. Eligible candidates were implanted and subsequently had radiation planning and delivery in our clinic. Descriptive statistical analysis was performed on our outcomes and dosimetry data and presented in tabular form. Results Seventeen patients were treated for a total of 18 implants (one monotherapy). No implant was aborted. No acute urinary retention requiring catheterization or chronic urethral stricture occurred. Biochemical recurrence-free survival was 94% at a median follow-up of 28.5 months (range 8.2-50 months); the one failure occurred in a very high-risk patient at 37 months following treatment. Dosimetrically, prostate coverage, urethra sparing, and rectum sparing aims were met. Volumetric bladder aims were also met; however, the max point dose to the bladder neck was above the guideline. Conclusion Our department successfully implemented an HDR prostate brachytherapy program. Treatments were effective and there was no grade 3 toxicity to report.

Height impairment after lower dose cranial irradiation in children with acute lymphoblastic leukemia.

PURPOSE: The purpose of this study is to determine whether height measurements are affected by cranial radiation doses of 12-18 Gy. PATIENTS AND METHODS: From 1997 to 2007, 23 children received cranial RT for T-cell or pre-B-cell acute lymphoblastic leukemia (ALL). Dose fractionation schemes included 18 Gy in 9 fractions (n = 8), 18 Gy in 10 fractions (n = 5), 12.6 Gy in 7 fractions (n = 6), and 12 Gy in 8 fractions (n = 4). These patients were matched and compared to a control group of 23 patients who had ALL but no cranial RT. Height z-scores at diagnosis and last follow-up were compared using the paired Student's t-test. Differences in z-scores according to host and treatment parameters were compared using the unpaired Student's t-test. Median follow-up for irradiated patients was 63.5 months while for unirradiated patients was 91 months. RESULTS: The mean z-scores at initial diagnosis and last follow-up were 0.14 and -0.48 for patients receiving 12-12.6 Gy (P = 0.016), -0.16 and -0.89 for 18 Gy (P = 0.003), and 0.34 and 0.22 for no RT (P = 0.62). For children receiving RT, the mean difference in z-scores at initial diagnosis and last follow-up was -0.67 while for those not receiving RT, it was -0.10 (P = 0.043). CONCLUSION: Children receiving 12-18 Gy cranial RT for ALL were found to have height impairment compared to those not receiving RT.

Helical tomotherapy significantly reduces dose to normal tissues when compared to 3D-CRT for locally advanced rectal cancer.

Combined modality treatment (neoadjuvant chemoradiotherapy followed by surgery) for locally advanced rectal cancer requires special attention to various organs at risk (OAR). As a result, the use of conformal dose delivery methods has become more common in this disease setting. Helical tomotherapy is an image-guided intensity modulated delivery system that delivers dose in a fan-beam manner at 7 degree intervals around the patient and can potentially limit normal tissue from high dose radiation while adequately treating targets. In this study we dosimetrically compare helical tomotherapy to 3D-CRT for stage T3 rectal cancer. The helical tomotherapy plans were optimized in the TomoPlan system to achieve an equivalent uniform dose of 45 Gy for 10 patients with T3N0M0 disease that was at least 5cm from the anal verge. The GTV included the rectal thickening and mass evident on colonoscopy and CT scan as well as with the help of a colorectal surgeon. The CTV included the internal iliac, obturator, and pre-sacral lymphatic chains. The OAR that were outlined included the small bowel, pelvic bone marrow, femoral heads, and bladder. Anatom-e system was used to assist in delineating GTV, CTV and OAR. These 10 plans were then duplicated and optimized into 3-field 3D-CRT plans within the Pinnacle planning system.The V[45], V[40], V[30], V[20], V[10], and mean dose to the OAR were compared between the helical tomotherapy and 3D-CRT plans. Statistically significant differences were achieved in the doses to all OAR, including all volumes and means except for V[10] for the small bowel and the femoral heads. Adequate dosimetric coverage of targets were achieved with both helical tomotherapy and 3D-CRT. Helical tomotherapy reduces the volume of normal tissue receiving high-dose RT when compared to 3D-CRT treatment. Both modalities adequately dose the tumor. Clinical studies addressing the dosimetric benefits are on-going.

Evaluating Treatment Patterns for Small Cell Carcinoma of the Colon Using the National Cancer Database (NCDB).

OBJECTIVE(S): The objective of this study was to characterize the clinicopathological prognostic factors and treatment patterns for small cell carcinoma (SCC) of the colon, a rare disease without standard treatment guidelines. METHODS: We analyzed clinicopathological and treatment variables for 503 cases of histologically proven SCC colon entered into the National Cancer Database (NCDB) between 2004 and 2013. Survival curves were generated using Kaplan-Meier and compared by the log-rank test. Cox proportional hazard regression was used to control for covariates and evaluate the effect of different treatment modalities on overall survival. RESULTS: Four hundred seventy-two (93.8%) patients had complete clinical staging information and were therefore included in our analysis. Of these patients, 149 (31.5%) had limited stage disease (LD) and 323 (68.4%) had extensive stage disease (ED) at presentation. Median overall survival (OS) for patients with ED was significantly lower than for those with LD (4.04 months vs. 21.82 months; p < 0.001). Multivariate Cox regression analysis showed administration of chemotherapy was associated with improved survival in patients with LD and ED (p = 0.026, p < 0.001) while surgery was not associated with improved survival in patients with LD or ED (p = 0.943, p = 0.630). Radiation therapy was associated with improved survival in patients with ED (p = 0.044). CONCLUSIONS: SCC of the colon carries a poor prognosis, especially in patients presenting with metastatic disease. Surgery and chemotherapy are administered more frequently than radiation, and chemotherapy is associated with improved survival, unlike surgery.

Stereotactic body radiotherapy in the management of painful bone metastases.

More than 100,000 new cases of bone metastases are diagnosed each year, and they present an important clinical problem. They cause significant morbidity and quality-of-life issues in cancer patients. Conventional external-beam radiotherapy is currently the most common method to treat these metastases, with several randomized controlled trials showing no difference in effectiveness between multiple- and single-dosing treatment regimens. A newer technology to treat bone metastases is stereotactic body radiotherapy (SBRT), a radiation delivery method that allows for a large ablative dose to be accurately given to the target over one to a few fractions. This review details the role of SBRT in painful bone metastases, primarily in the vertebral column, but in other bony sites as well, its unique advantages and disadvantages, and its role in the treatment of tumors traditionally deemed radioresistant. Toxicity to surrounding normal tissues and patterns of local failures are also addressed.

Anticancer therapy and lung injury: molecular mechanisms.

INTRODUCTION: Chemotherapy and radiation therapy are two mainstream strategies applied in the treatment of cancer that is not operable. Patients with hematological or solid tumor malignancies substantially benefit from chemotherapeutic drugs and/or ionizing radiation delivered to the site of malignancy. However, considerable adverse effects, including lung inflammation and fibrosis, are associated with the use of these treatment modalities. Areas covered: As we move toward the era of precision health, we are compelled to understand the molecular basis of chemoradiation-induced pathological lung remodeling and to develop effective treatment strategies that mitigate the development of chronic lung disease (i.e. fibrosis) in cancer patients. The review discusses chemotherapeutic agents that are reported to induce or associate with acute and/or chronic lung injury. Expert commentary: There is a need to molecularly understand how chemotherapeutic drugs induce or associate with respiratory toxicities and whether such characteristics are inherently related to their antitumor effect or are collateral. Once such mechanisms have been identified and/or fully characterized, they may be able to guide disease-management decisions including effective intervention strategies for the adverse effects. In the meantime, radiation oncologists should be judicious on the dose of radiation delivered to the lungs, the volume of lung irradiated, and concurrent use of chemotherapeutic drugs.

Reducing the Time From Diagnosis to Treatment of Patients With Stage II/III Rectal Cancer at a Large Public Hospital.

Curative-intent therapy for stage II/III rectal cancer is necessarily complex. Current guidelines by the National Comprehensive Cancer Network recommend preoperative concurrent chemoradiation followed by resection and additional adjuvant chemotherapy. We used standard quality improvement methodology to implement a cost-effective intervention that reduced the time from diagnosis to treatment of patients with stage II/III rectal cancer by approximately 30% in a large public hospital in Houston, Texas. Implementation of the program resulted in a reduction in time from pathologic diagnosis to treatment of 29% overall, from 62 to 44 days. These gains were cost neutral and resulted from improvements in scheduling and coordination of care alone. Our results suggest that: (1) quality improvement methodology can be successfully applied to multidisciplinary cancer care, (2) effective interventions can be cost neutral, and (3) effective strategies can overcome complexities such as having multiple sites of care, high staff turnover, and resource limitations.

Is there an increase in genitourinary toxicity in patients treated with transurethral resection of the prostate and radiotherapy? A systematic review.

PURPOSE: Transurethral resection of the prostate (TURP) is considered by some as a risk factor for genitourinary (GU) toxicity after radiotherapy (RT). However, there are conflicting results regarding the interaction between RT and TURP with respect to GU toxicity. The purpose of this report is to review the published data concerning TURP before or after RT and its effect on urinary complication. METHODS AND MATERIALS: A systematic literature review based on database searches in MEDLINE, EMBASE, Pubmed, Ovid, and Chochrane Library. The eligibility criteria of final review were (1) definitive RT for prostate cancer is reported; (2) comparison of GU toxicities between patients with and without TURP is reported; (3) minimum 5 patients after TURP are included. RESULTS: Twelve articles regarding overall GU toxicity, 15 articles regarding urinary incontinence, and 13 articles regarding urinary or bladder neck stricture met eligibility criteria, and they were included in the final review. A quantitative synthesis from the data of selected articles was impossible because of variable grading systems and variable definitions in their comparisons between patients with and without TURP. However, most published articles demonstrated the increased risk of GU toxicity with TURP in patients treated with RT. CONCLUSIONS: Our systematic review strongly suggests that TURP is one of the risk factors of GU toxicity after RT. This needs to be taken seriously when prostate cancer patients with TURP are considered for RT either external beam or brachytherapy.

Emergence of integrated urology-radiation oncology practices in the State of Texas.

PURPOSE: Integrated urology-radiation oncology (RO) practices have been advocated as a means to improve community-based prostate cancer care by joining urologic and radiation care in a single-practice environment. However, little is known regarding the scope and actual physical integration of such practices. We sought to characterize the emergence of such practices in Texas, their extent of physical integration, and their potential effect on patient travel times for radiation therapy. METHODS AND MATERIALS: A telephone survey identified integrated urology-RO practices, defined as practices owned by urologists that offer RO services. Geographic information software was used to determine the proximity of integrated urology-RO clinic sites with respect to the state's population. We calculated patient travel time and distance from each integrated urology-RO clinic offering urologic services to the RO treatment facility owned by the integrated practice and to the nearest nonintegrated (independent) RO facility. We compared these times and distances using the Wilcoxon-Mann-Whitney test. RESULTS: Of 229 urology practices identified, 12 (5%) offered integrated RO services, and 182 (28%) of 640 Texas urologists worked in such practices. Approximately 53% of the state population resides within 10 miles of an integrated urology-RO clinic site. Patients with a diagnosis of prostate cancer at an integrated urology-RO clinic site travel a mean of 19.7 miles (26.1 min) from the clinic to reach the RO facility owned by the integrated urology-RO practice vs 5.9 miles (9.2 min) to reach the nearest nonintegrated RO facility (P<.001). CONCLUSIONS: Integrated urology-RO practices are common in Texas and are generally clustered in urban areas. In most integrated practices, the urology clinics and the integrated RO facilities are not at the same location, and driving times and distances from the clinic to the integrated RO facility exceed those from the clinic to the nearest nonintegrated RO facility.

Overexpression of ER and VDR is not sufficient to make ER-negative MDA-MB231 breast cancer cells responsive to 1alpha-hydroxyvitamin D5.

1alpha-hydroxyvitamin D(5) [1alpha(OH)D(5)] is an active vitamin D analog showing promising chemopreventive effect in breast carcinogenesis. We previously reported that estrogen receptor (ER)-positive breast cancer cells were sensitive, whereas ER-negative breast cancer cells were relatively resistant to their antiproliferative effects. In the present study, we used ER-negative MDA-MB231, ER-transfected MDA-MB231 (S30) and ER-positive BT474 cell lines to evaluate the possible association between ER status and cellular sensitivity to 1alpha(OH)D(5) treatment. Our results demonstrate that ER expression in ER-negative breast cancer cells (S30) did not increase the sensitivity to 1alpha(OH)D(5), whereas in ER-positive BT474 cells, the significant antiproliferative effect of 1alpha(OH)D(5) was correlated with the downregulation of ER and progesterone receptor expression. Further analysis indicated that both MDA-MB231 and S30 cells express low vitamin D receptor (VDR) at transcriptional level and protein level. However, transfection of VDR failed to restore the sensitivity to 1alpha(OH)D(5) in MDA-MB231 and S30 cells, although VDR direct target gene CYP24 was more responsive to 1alpha(OH)D(5) treatment in MDA-MB231 and S30 cells overexpressing VDR. In addition, nuclear receptor cofactors NCoR1 and SRC1 that could potentially affect VDR action were also low in both MDA-MB231 and S30 cells in comparison with ER-positive, vitamin D-sensitive BT474 cells. These results suggest that in addition to the increased ER and VDR expression, the intact VDR signaling machinery as present in ER-positive, vitamin D-sensitive cells is essential for the antiproliferative action of vitamin D, whereas the direct VDR target genes such as CYP24 can remain responsive to augmented VDR expression.