Addressing challenges in low-income and middle-income countries through novel radiotherapy research opportunities.

Although radiotherapy continues to evolve as a mainstay of the oncological armamentarium, research and innovation in radiotherapy in low-income and middle-income countries (LMICs) faces challenges. This third Series paper examines the current state of LMIC radiotherapy research and provides new data from a 2022 survey undertaken by the International Atomic Energy Agency and new data on funding. In the context of LMIC-related challenges and impediments, we explore several developments and advances-such as deep phenotyping, real-time targeting, and artificial intelligence-to flag specific opportunities with applicability and relevance for resource-constrained settings. Given the pressing nature of cancer in LMICs, we also highlight some best practices and address the broader need to develop the research workforce of the future. This Series paper thereby serves as a resource for radiation professionals.

The biology of hope: Inflammatory and neuroendocrine profiles in ovarian cancer patients.

INTRODUCTION: Although the concept of hope is highly relevant for cancer patients, little is known about its association with cancer-relevant biomarkers. Here we examined how hope was related to diurnal cortisol and interleukin-6 (IL-6), a pro-inflammatory cytokine previously associated with tumor biology and survival in ovarian cancer. Secondly, we examined whether hope and hopelessness are distinctly associated with these biomarkers. METHOD: Participants were 292 high-grade ovarian cancer patients who completed surveys and provided saliva samples 4x/daily for 3 days pre-surgery to assess diurnal cortisol. Blood (pre-surgery) and ascites were assessed for IL-6. Hope and hopelessness were assessed using standardized survey items from established scales (Center for Epidemiological Studies Depression Scale; Profile of Mood States, Functional Assessment of Cancer Therapy). Two hopeless items were z-scored and combined into a composite for analysis. Regression models related these variables to nocturnal cortisol, cortisol slope, plasma and ascites IL-6, adjusting for cancer stage, BMI, age, and depression. RESULTS: Greater hope was significantly related to a steeper cortisol slope, ß = -0.193, p = 0.046, and lower night cortisol, ß = -0.227, p = 0.018, plasma IL-6, ß = -0.142, p = 0.033, and ascites IL-6, ß = -0.290, p = 0.002. Secondary analyses including both hope and hopelessness showed similar patterns, with distinct relationships of hope with significantly lower nocturnal cortisol ß = -0.233,p = 0.017 and ascites IL-6, ß = -0.282,p = 0.003, and between hopelessness and a flatter cortisol slope, ß = 0.211, p = 0.031. CONCLUSIONS: These data suggest a biological signature of hope associated with less inflammation and more normalized diurnal cortisol in ovarian cancer. These findings have potential clinical utility but need replication with more diverse samples and validated assessments of hope.

Dispositional hope as a potential outcome parameter among patients with advanced malignancy: An analysis of the ENABLE database.

BACKGROUND: Hopefulness, whether inherently present (dispositional hope) or augmented (by enhancement techniques), may affect outcomes. This study was performed to determine the association of dispositional hope with survival among patients diagnosed with advanced cancer. METHODS: Data from ENABLE (Educate, Nurture, Advise, Before Life Ends), a palliative care intervention, were reanalyzed to determine the association of higher dispositional hope and patient survival. This was a secondary analysis of data combined from the ENABLE II and ENABLE III randomized controlled trials (RCTs) with respect to dispositional hope and survival. A dispositional hope index was created from 3 hope items from 2 validated baseline questionnaires. Dispositional hope and survival data were collected during the 2 RCTs. In ENABLE II, participants were randomly assigned to the ENABLE intervention or to usual care. In ENABLE III, participants were randomly assigned to receive the intervention immediately or 12 weeks after enrollment. RESULTS: In all, 529 persons were included in Cox proportional hazards regression analyses to model the effects of dispositional hope on survival. An initial analysis without covariates yielded a significant effect of hope (Wald statistic, 8.649; hazard ratio, 0.941; confidence interval, 0.904-0.980; P = .003), such that higher dispositional hope was associated with longer survival. In a subsequent analysis that included all covariates, the effect of dispositional hope approached statistical significance (Wald statistic, 2.96; hazard ratio, 0.933; confidence interval, 0.863-1.010; P = .085). CONCLUSIONS: Higher levels of dispositional hope were associated with longer survival in patients with advanced cancer. Prospective trials are needed to determine the effects of dispositional and augmented hope on the outcomes of patients with advanced cancer.

The science of hope.

Hope is a contextual term that has different connotations depending on the setting. We analyse the concept of hope with respect to its applicability for oncology. We review studies that present hope as a direct or secondary mediator of outcome. We posit that an individual's level of hope is often determined by innate personality characteristics and environmental factors, but can also be physiologically influenced by immune modulators, neurotransmitters, affective states, and even the underlying disease process of cancer. We argue that hope can be a therapeutic target and review evidence showing the effects of hope-enhancing therapies. Given the potential for hope to alter oncological outcomes in patients with cancer and the opportunity for improvement in quality of life, we suggest further research directions in this area.

Emmanuel Levinas: A Doctrine for Doctors.

This narrative introduces the philosophy of Emmanuel Levinas and its potential to affect clinical practice.

A critical assessment of the quality of radiation therapy in Israel: time to initiation of treatment of spinal cord compression as an index of efficiency.

INTRODUCTION: Radiotherapy departments function under workload pressure. We examined the process from referral to treatment initiation for spinal cord compression (SCC), one of the most daunting clinical scenarios in oncology. METHODS: We identified 235 patients with SCC, treated between 2013-2015. Two physicians classified cases as "emergent" or "urgent" (treatment within 24 or 72 h, respectively). RESULTS: The distribution of referrals over the week was uniform for inpatients. In contrast, there was a referral peak (62.27%) during the first two workdays for emergency ambulatory patients (p = 0.011). There were few weekend referrals in all groups (3.0%). There was a statistically shorter interval between referral and treatment for emergent versus urgent cases (0.94 days vs. 4.17 days; p < 0.0001, Bonferroni correction p < 0.0005). CONCLUSION: Time elapsed between referral and treatment of SCC may constitute a quality index in neuro-oncology. Modern departments of radiotherapy should determine the degree to which they can successfully implement such treatment. Patients with cancer and their physicians should be taught to recognize signs of SCC to expedite intervention.

Neurocognitive evaluation of brain metastases patients treated with post-resection stereotactic radiosurgery: a prospective single arm clinical trial.

PURPOSE: Post-operative radiation therapy for brain metastases (BM) has become standard treatment. Concerns regarding the deleterious cognitive effects of Whole Brain Radiation Therapy spurred a trend to use focal therapies such as stereotactic radiosurgery (SRS). The purpose of this study was to prospectively evaluate the neuropsychological effects following post-resection SRS treatment since limited data exist in this context. METHODS: We conducted a prospective single arm cohort study of patients with 1-2 BM, who underwent resection of a single BM between May 2015 to December 2016. Patients were evaluated for cognitive functions (NeuroTrax computerized neuropsychological battery; Modiin, Israel) and quality of life (QOL; QLQ-30, QLQ-BN20) before and 3 months following post-resection SRS. RESULTS: Twelve out of 14 patients completed pre- and post-SRS neurocognitive assessments. Overall, we did not detect significant neurocognitive or QOL changes 3 months following SRS. In a subgroup analysis among patients younger than 60 years, median global cognitive score increased from a pre-treatment score of 88 (72-102) to 95 (79-108), 3 months following SRS treatment, p = 0.042; Wilcoxon paired non-parametric test. Immediate verbal memory and executive functions scores increased from 86 (72-98) to 98 (92-112) and 86 (60-101) to 100 (80-126), respectively, p = 0.043. No significant cognitive changes were discovered among patients at the age of 60 or older. CONCLUSIONS: Post-resection radiosurgery has a safe neuro-cognitive profile and is associated with preservation of nearly all quality of life parameters. Patients younger than 60 years benefit most and may even regain some cognitive functions within a few months after treatment.

Combined treatment approach to cerebral arteriovenous malformation in pediatric patients: stereotactic radiosurgery to partially Onyx-embolized AVM.

PURPOSE: Treatment of cerebral arteriovenous malformations (AVM)-the most common cause of stroke in the pediatric population-can be challenging due to the complexity of size, morphology, and location. There is a significant risk in comparison to AVM treatment among adults. Thus, AVM treatment in the pediatric population imposes unique challenges. Recent improvements include optimized catheter techniques and better embolization materials, such as Onyx, a non-adhesive liquid embolic agent used in the adult population. These improvements have increased the success rate of total and near-total obliteration of cerebral AVM. However, the use of Onyx causes significant distortion of the MR and CT images, which must be accounted for in any radiation treatment planning predicated on CT and MRI. These image distortions impact on the actual delivered dose to the nidus and behoove heterogeneity correction. Our group has previously shared a solution for heterogeneity correction in the adult population. The purpose of this study is to show our experience in this unique group of pediatric patients. METHODS: This is a retrospective review of pediatric patients, who were undergoing combined endovascular embolization followed by SRS. The cohort consists of 14 patients undergoing SRS treatment in our institute between November 2006 and December 2012 with a mean follow-up of 49.9 months. Within this cohort, we retrospectively reviewed 12 consecutive pediatric patients who underwent a combined endovascular and SRS approach with a mean follow-up of 52.1 months and two patients receiving SRS-only treatment were excluded. RESULTS: In our cohort of 14 patients, 7 (50%) were male, with a mean age of 17.3 years (12.0-22.9) at the time of radiosurgery treatment. Mean age of beginning the combined modality treatment was 15.3 years (8.4-20). The median time from diagnosis to SRS was 24.3 months (11.1-64.4 months) in the complete cohort and 25.6 months (11.1-64.4) in the multimodality group. The overall median follow-up period was 49.9 months (range 12.8-118.8 months) in the complete cohort and 52.1 months (range 12.8-118.8 months) in the multimodality group. Eleven (78.6%) patients had at least one episode of hemorrhage prior to treatment. Spezler-Martin grades at baseline ranged from 2 to 5 (mean 3.2). Fifty percent had grade IV and V. Patients underwent a median of 2 (range 1-5) embolization procedures. The radiosurgical treatment dose to the margin of the angiography-based nidus: median prescription dose of 21.49 Gy (14.39-27.51) with a median max dose of 27.77 Gy (18.93-32.52). The median treatment volume was 0.6 cm3 (0.1-7.3 cm3). The Onyx embolization reduced the nidus target volume by a median of 66.7% (12.0-92.7%). We confirmed 10/14 (71%) complete closures. In 2/14 (14.2%) additional patients, a significant flow reduction was noted. In 1/14 (7.1%) patients, no significant change was noted during the observation period and two (14.2%) patients were without follow-up information. In two patients, post-treatment edema was noted; however, none was clinically significant and resolved without additional intervention or treatment. CONCLUSIONS: This cohort comprises the largest combined Onyx-SRS pediatric experience in the literature. In conjunction with our adult group study, we show that the use of Onyx reduces the SRS treatment target volume significantly. Importantly, we implemented the heterogeneity correction to avoid increased radiation exposure to normal surrounding brain tissue. The combined approach appears to be safe provided that the above-mentioned corrections are implemented.

Volumetric Modulated Arc Therapy as an Example of the Advanced Capability of Modern Radiotherapy.

BACKGROUND: Family physicians and internal medicine specialists play an essential role in treating cancer patients. Modern technological advances in radiotherapy are not widely appreciated by primary care physicians. Bone metastases are a frequent complication of cancer. Palliative radiation therapy, as a component of modern advances in radiation treatments, should not subject normal bodily structures to excessive doses of irradiation. The sacrum is a common destination site for bone metastases, yet its concave shape along with its proximity to the rectum, intestines, and femoral heads creates treatment-planning challenges. OBJECTIVES: To investigated whether the volumetric modulated arc therapy (VMAT) technique is preferable to more conventional radiation strategies. METHODS: The study comprised 22 patients with sacral metastases who were consecutively treated between 2013 and 2014. Two plans were generated for the comparison: three-dimensional (3D) and VMAT. RESULTS: The planning target volume (PTV) coverage of the sacrum was identical in VMAT and 3D planning. The median values for the rectal dose for 3D and VMAT were 11.34 ± 5.14 Gy and 7.7 ± 2.76 Gy, respectively. Distal sacral involvement (S4 and S5) was observed in only 2 of 22 cases, while the upper pole of the rectum ended at the level above S3 in just 3 cases. CONCLUSIONS: Radiation therapy continues to be an integral component of the palliative armamentarium against painful metastases. Radiation oncologist, in conjunction with referral physicians, can tailor treatment plans to reflect the needs of a given patient.

Stereotactic radiosurgery (SRS) in high-grade glioma: judicious selection of small target volumes improves results.

We present a retrospective review of 55 Stereotactic Radiosurgery (SRS) procedures performed in 47 consecutive patients with high-grade glioma (HGG). Thirty-three (70.2%) patients were diagnosed with glioblastoma and 14 (29.8%) with grade III glioma. The indications for SRS were small (up to 30 mm in diameter) locally progressing lesions in 32/47 (68%) or new distant lesions in 15/47 (32%) patients. The median target volume was 2.2 cc (0.2-9.5 cc) and the median prescription dose was 18 Gy (14-24 Gy). Three patients (5.5% incidence in 55 treatments) developed radiation necrosis. In eight cases (17%) patients received a second salvage SRS treatment to nine new lesions detected during follow-up. In 22/55 SRS treatments (40.0%) patients received concurrent chemo- or biological therapy, including temozolamide (TMZ) (15 patients), bevacizumab (BVZ) (6 patients) and carboplatin in one patient. Median time to progression after SRS was 5.0 months (1.0-96.4). Median survival time after SRS was 15.9 months (2.3-109.3) overall median survival (since diagnosis) was 37.4 months (9.6-193.6 months). Long-lasting responses (>12 months) after SRS were observed in 25/46 (54.3%) patients. We compared a matched (histology, age, KPS) cohort of patients with recurrent HGG treated with BVZ alone with the current study group. Median survival was significantly longer for SRS treated patients compared to the BVZ only cohort (12.6 vs. 7.3 months, p = 0.0102). SRS may be considered an effective salvage procedure for selected patients with small volume, recurrent high-grade gliomas. Long-term radiological control was observed in more than 50% of the patients.

CogState computerized memory tests in patients with brain metastases: secondary endpoint results of NRG Oncology RTOG 0933.

Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre- and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi-institution clinical trials. Adult patients with brain metastases received HA-WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning Test (OCLT), at baseline, 2 and 4 months. Tests' completion rates were 52-53 % at 2 months and 34-42 % at 4 months. All baseline correlations between HVLT-R and CogState tests were significant (p ≤ 0.003). At baseline, both CogState tests and one component of HVLT-R differentiated those who were alive at 6 months and those who had died (p ≤ 0.01). At 4 months, mean relative decline was 7.0 % for HVLT-R Delayed Recall and 18.0 % for ISLT Delayed Recall. OCLT showed an 8.0 % increase. A reliable change index found no significant changes from baseline to 2 and 4 months for ISLT Delayed Recall (z = -0.40, p = 0.34; z = -0.68, p = 0.25) or OCLT (z = 0.15, p = 0.56; z = 0.41, p = 0.66). Study findings support the possibility that hippocampal avoidance may be associated with preservation of memory test performance, and that these computerized tests also may be useful and valid memory assessments in multi-institution adult brain tumor trials.

Calcification in high grade gliomas treated with bevacizumab.

Calcification is a rare phenomenon in high grade glioma (HGG). CT scans are sensitive to mineralization but used infrequently for tumor assessment in the MRI era. The presence of calcification can be overlooked on routine MRI. Calcification may reflect chronicity and natural changes in the tumor or its milieu over time and may be accelerated by certain treatments. Calcification may have clinical significance which could signal potential risk for stroke or hemorrhage related to particular therapies; or it may be a positive prognostic factor for treatment response. The true incidence and relevance of calcification in HGG and relation to therapy is unclear. During treatment of HGG patients with bevacizumab (BVZ) we observed significant tumor calcification on brain CT. We performed a retrospective review of HGG patients treated with BVZ to quantitate the incidence of calcification in this group compared to those treated with cytotoxic therapy alone. Sixty-two patients with progressive HGG were treated with BVZ and a cytotoxic agent. Among 19 patients treated for 6+ months, 12 had a CT scan performed. We observed an unexpected phenomenon of calcification in the CT scans of several patients. We were also able to comparatively quantitate the incidence of calcification in a control group of primary glioblastoma (GB) patients not exposed to BVZ therapy. The incidence of calcification in the general GB population is increased with longer survival. The phenomenon is increased with anti-angiogenic therapy for brain tumors. Calcification may have significance as a predictor for treatment response.

[Spiritual care in hospitals and other healthcare settings in Israel--a profession in the making].

Faced with a serious, incurable illness, disability, and other symptoms, both physical and mental, some patients find themselves wondering about the meaning of their Lives. They need the help of a professional who can perceive their mental turmoil and identify their spiritual needs, and who knows how to help them find meaning in their uncertain state. Spiritual care providers are professionals whose role it is to provide patients with support in their hour of need, to help them preserve their identity in life-threatening situations, and to help them re-endow their world with meaning, employing a special language and set of tools that enable patients to get in touch with their spiritual resources and internal powers of healing. Spiritual care providers serve on the medical staff in Western countries. In the United States, some 2,600 are employed in general hospitals, psychiatric hospitals, long-term care facilities, and palliative care units. Approximately ten years ago, the profession began developing in Israel. Today, dozens of spiritual care providers are now working in the healthcare system. There is a spiritual care network with 21 member organizations. Although the profession is laying down roots in the healthcare system in this country, it is still in its infancy and has to contend with substantial barriers and challenges, including professional recognition, creating positions, and identifying sources of funding for positions. The profession still has much room to grow as it is further incorporated into the healthcare system and continues undergoing adaptation to the Israeli cultural setting.

Hope during somber times: a defining moment.

In addition to the diverse educational materials the National Cancer Institute provides to patients, caregivers, and health-care professionals, the NCI maintains an online dictionary that provides concise definitions of terms used in modern oncology. The dictionary is regarded as a valuable data reserve because it is updated frequently and employs language that facilitates comprehension among lay users and professionals alike. In this commentary, we call attention to the absence of the word hope as an entry in this important digital resource. Moreover, we propose not only including the concept of hope in this vital reference text but also basing its meaning on C. R. Snyder's model of "hope theory," which stresses the importance of 3 entities: goals, pathways thinking, and agency. Finally, we argue that hope can be taught as a skill to relevant stakeholders (eg, patients, caregivers, and health-care professionals) through brief workshops that have recently been expanded from in-person encounters to virtual platforms revolving around a user-friendly mobile app called "Hopetimize."

Radiation Therapy Delivery During the 2023 Israel-Hamas War: Trust Prevails Over Fear.

Purpose: The attack by Hamas on Israeli civilians (October 7, 2023) triggered the ongoing war, which could be detrimental to cancer care in general and radiation therapy (RT) in particular. To assure continuity of care within the Radiation Oncology Department of Samson Assuta Ashdod University Hospital (SAAUH), which borders on Gaza, patient-centric measures were redoubled by our institution. This study describes the impact of these measures on patients' perception and their willingness to continue RT, despite fear of war. Methods and Materials: A survey questionnaire was designed to detect changes in attitude and treatment adherence during war. It was offered to the patients undergoing RT at SAAUH. A Pearson correlation between the items relating to desire to continue the therapy was calculated. Smallest space analysis was conducted to illustrate the association between the variables. Results: Forty-seven patients enrolled in this study reported a significantly lower feeling of personal safety during wartime in comparison with the confidence in the professionalism of the staff (paired samples t test, t(43) = 4.61; P < .001). Simultaneously, patients perceived that the impact of the national situation on their health was very low (mean of 1.59 on a scale of 1-6). Both the Pearson correlation test and smallest space analysis revealed that the desire to continue treatment in general and to continue treatment at the same department were significantly related to trust in the staff's professionalism. Conclusions: Fear of war can pose a major pitfall in providing daily RT care. This obstacle may be potentially overridden by creating deep, trusting relationships between the patients and the medical staff.

A topical BRAF inhibitor (LUT-014) for treatment of radiodermatitis among women with breast cancer.

Background: Modern radiotherapy is associated with dermatitis (RD) in approximately one-third of patients treated for breast cancer. There is currently no standard for treating RD. Objective: The objective of this study was to determine whether LUT014, a topical BRAF inhibitor which paradoxically activates mitogen-activated protein kinase, can safely improve RD. Methods: A phase I/II study was designed to first follow a small cohort of women with grade 2 RD regarding toxicity and response. Then, 20 patients were randomized to compare LUT014 to "vehicle" relative to safety and response (measured with common terminology criteria for adverse events, Dermatology Life Quality Index). Results: No substantial toxicity (eg, 0 serious adverse event) was associated with LUT014. All 8 women receiving LUT014 achieved treatment success (5-point Dermatology Life Quality Index reduction at day 14) compared to 73% (8/11) on the placebo arm (P = .591). The time to complete recovery was shorter in the treatment arm. Limitations: The sample size was limited. Only 2 hospitals were included. Conclusions: Topical LU014 is tolerable and may be efficacious for grade 2 RD.

International radiation oncology trainee decision making in the management of radiotherapy-induced nausea and vomiting.

PURPOSE: This study explored international radiation oncology trainee decision making in the management of radiotherapy-induced nausea and vomiting (RINV). METHODS: Radiation oncology trainees who were members of the national radiation oncology associations of the USA, Canada, Netherlands, Australia, New Zealand, France, Spain and Singapore completed a Web-based survey. Respondents estimated the risks of nausea and vomiting associated with six standardised radiotherapy-only clinical case vignettes modelled after international anti-emetic guidelines and then committed to prophylactic, rescue or no therapy as an initial management approach for each case. RESULTS: One hundred and seventy-six trainees from 11 countries responded. Only 28 % were aware of any anti-emetic guideline. In general, risk estimates and management approaches for the high-risk and minimal risk cases varied less and were more in line with guideline standards than were estimates and approaches for the moderate- and low-risk cases. Prophylactic therapy was the most common approach for the high-risk and a moderate-risk case (83 and 71 % of respondents respectively), while rescue therapy was the most common approach for a second moderate-risk case (69 %), two low-risk cases (69 and 76 %) and a minimal risk case (68 %). A serotonin receptor antagonist was the most commonly recommended prophylactic agent. On multivariate analysis, a higher estimated risk of nausea predicted for recommending prophylactic therapy, and a lower estimated risk of nausea predicted for recommending rescue therapy. CONCLUSIONS: Radiation oncology trainee risk estimates and recommended management approaches for RINV clinical case vignettes varied and matched guideline standards more often for high-risk and minimal risk cases than for moderate- and low-risk cases. Risk estimates of nausea specifically were strong predictors of management decisions.