Immunotherapy and Radiotherapy for Older Cancer Patients during the COVID-19 Era: Proposed Paradigm by the International Geriatric Radiotherapy Group.

BACKGROUND: Older cancer patients with locally advanced or metastatic disease may benefit from chemotherapy alone or combined with radiotherapy. However, chemotherapy is often omitted either because of physician bias or because of its underlying comorbidity, thus compromising their survival. The coronavirus disease 19 (COVID-19) pandemic is compounding this issue because of the fear of immunosuppression induced by chemotherapy on the elderly which makes them more vulnerable to the virus. SUMMARY: Immunotherapy has less effect on the patient bone marrow compared to chemotherapy. The potential synergy between radiotherapy and immunotherapy may improve local control and survival for older patients with selected cancer. Preliminary data are encouraging because of better survival and local control in diseases which are traditionally resistant to radiotherapy and chemotherapy such as melanoma and renal cell carcinoma. Key Message: We propose a new paradigm combining immunotherapy at a reduced dose and/or extended dosing intervals and hypofractionated radiotherapy for older patients with selected cancer which needs to be tested in future clinical trials.

Feasibility of image-guided radiotherapy and concurrent chemotherapy for locally advanced nonsmall cell lung cancer.

A retrospective review of 32 patients with stage III nonsmall cell lung cancer who underwent chemoradiation with image-guided radiotherapy (IGRT) was recorded. Acute grade 3-4 hematologic and esophageal toxicities developed in 6 and 13 patients respectively. At a median follow-up of 14.5 months, only one patient developed grade 3 pneumonitis. The median survival was estimated to be 17 months. Five patients (15%) developed loco-regional recurrences, and 17 patients (53%) distant metastases. Grade 3-4 toxicities remained significant during chemoradiation with IGRT. However, the reduced rate of severe pneumonitis despite a high tumor dose is encouraging and needs to be investigated in future prospective studies.

Immunotherapy and radiotherapy for older patients with locally advanced rectal cancer unfit for surgery or decline surgery: a practical proposal by the International Geriatric Radiotherapy Group.

The standard of care for locally advanced rectal cancer is total neoadjuvant therapy followed by surgical resection. Current evidence suggests that selected patients may be able to delay or avoid surgery without affecting survival rates if they achieve a complete clinical response (CCR). However, for older cancer patients who are too frail for surgery or decline the surgical procedure, local recurrence may lead to a deterioration of patient quality of life. Thus, for clinicians, a treatment algorithm which is well tolerated and may improve CCR in older and frail patients with rectal cancer may improve the potential for prolonged remission and potential cure. Recently, immunotherapy with check point inhibitors (CPI) is a promising treatment in selected patients with high expression of program death ligands receptor 1 (PD- L1). Radiotherapy may enhance PD-L1 expression in rectal cancer and may improve response rate to immunotherapy. We propose an algorithm combining immunotherapy and radiotherapy for older patients with locally advanced rectal cancer who are too frail for surgery or who decline surgery.

Mycoplasma pneumonia with severe cold agglutinin hemolysis, thrombocytosis, leukemoid reaction and acute renal failure.

Mycoplasma pneumoniae (M. pneumoniae) is a common cause of community acquired pneumonia and although most cases are mild, complications sometimes occur. Cold agglutinin hemolysis is a known complication of M. pneumoniae infection, and usually presents as a mild and transient hemolysis. Here we present a case of infection with M. pneumoniae in a 64-year-old male that caused life threatening hemolysis that required multiple blood transfusions. The patient also presented with acute kidney failure and a marked leukemoid reaction and thrombocytosis. This is a very rare combination of symptoms that could have led the clinicians to suspect a more virulent etiology than M. pneumoniae, thereby delaying adequate antibiotic treatment.

Perceptions of Health and Wellbeing Among Employees in a Work Integration Social Enterprise in Sweden.

Background: Work Integration Social Enterprises (WISEs) constitute an important vehicle for providing employment opportunities for disadvantaged groups. Objective: The goal of this qualitative case study is to explore perceptions of health and wellbeing among employees working in a WISE located in the Gävleborg region, in east central Sweden. Methods: Data were gathered using 16 in-depth, semi-structured interviews with the social enterprise employees. Results: Findings were categorized into three main categories: the importance of financial independence and societal benefits; team spirit and a sense of belonging; and improved quality of life and wellbeing. Conclusion: The participants perceived that working in the WISE gave them a feeling of freedom and increased their self-esteem because of the possibility to earn an income. Also, they were satisfied with their job (e.g., with regard to work quality and flexibility) and believed that their work contributed to society. Moreover, through working in a WISE, the participants felt a sense of belonging and togetherness through interaction with co-workers and managers, and an improved quality of life for themselves and their families.

Immunotherapy and Hypofractionated Radiotherapy in Older Patients with Locally Advanced Cutaneous Squamous-Cell Carcinoma of the Head and Neck: A Proposed Paradigm by the International Geriatric Radiotherapy Group.

Cutaneous skin carcinoma is a disease of older patients. The prevalence of cutaneous squamous-cell carcinoma (cSCC) increases with age. The head and neck region is a frequent place of occurrence due to exposure to ultraviolet light. Surgical resection with adjuvant radiotherapy is frequently advocated for locally advanced disease to decrease the risk of loco-regional recurrence. However, older cancer patients may not be candidates for surgery due to frailty and/or increased risk of complications. Radiotherapy is usually advocated for unresectable patients. Compared to basal-cell carcinoma, locally advanced cSCC tends to recur locally and/or can metastasize, especially in patients with high-risk features such as poorly differentiated histology and perineural invasion. Thus, a new algorithm needs to be developed for older patients with locally advanced head and neck cutaneous squamous-cell carcinoma to improve their survival and conserve their quality of life. Recently, immunotherapy with checkpoint inhibitors (CPIs) has attracted much attention due to the high prevalence of program death ligand 1 (PD-L1) in cSCC. A high response rate was observed following CPI administration with acceptable toxicity. Those with residual disease may be treated with hypofractionated radiotherapy to minimize the risk of recurrence, as radiotherapy may enhance the effect of immunotherapy. We propose a protocol combining CPIs and hypofractionated radiotherapy for older patients with locally advanced cutaneous head and neck cancer who are not candidates for surgery. Prospective studies should be performed to verify this hypothesis.

Impact of COVID-19 pandemic on older cancer patients: Proposed solution by the International Geriatric Radiotherapy Group.

Older cancer patients are disproportionally affected by the Coronavirus 19 (COVID-19) pandemic. A higher rate of death among the elderly and the potential for long-term disability have led to fear of contracting the virus in these patients. This fear can, paradoxically, cause delay in diagnosis and treatment that may lead to a poor outcome that could have been prevented. Thus, physicians should devise a policy that both supports the needs of older patients during cancer treatment, and serves to help them overcome their fear so they seek out to cancer diagnosis and treatment early. A combination of telemedicine and a holistic approach, involving prayers for older cancer patients with a high level of spirituality, may improve vaccination rates as well as quality of life during treatment. Collaboration between health care workers, social workers, faith-based leaders, and cancer survivors may be crucial to achieve this goal. Social media may be an important component, providing a means of sending the positive message to older cancer patients that chronological age is not an impediment to treatment.

Feasibility of image-guided radiotherapy based on helical tomotherapy to reduce contralateral parotid dose in head and neck cancer.

BACKGROUND: To evaluate the feasibility of image-guided radiotherapy based on helical Tomotherapy to spare the contralateral parotid gland in head and neck cancer patients with unilateral or no neck node metastases. METHODS: A retrospective review of 52 patients undergoing radiotherapy for head and neck cancers with image guidance based on daily megavoltage CT imaging with helical tomotherapy was performed. RESULTS: Mean contralateral parotid dose and the volume of the contralateral parotid receiving 40 Gy or more were compared between radiotherapy plans with significant constraint (SC) of less than 20 Gy on parotid dose (23 patients) and the conventional constraint (CC) of 26 Gy (29 patients). All patients had PTV coverage of at least 95% to the contralateral elective neck nodes. Mean contralateral parotid dose was, respectively, 14.1 Gy and 24.7 Gy for the SC and CC plans (p < 0.0001). The volume of contralateral parotid receiving 40 Gy or more was respectively 5.3% and 18.2% (p < 0.0001) CONCLUSION: Tomotherapy for head and neck cancer minimized radiotherapy dose to the contralateral parotid gland in patients undergoing elective node irradiation without sacrificing target coverage.

Effectiveness of prophylactic retropharyngeal lymph node irradiation in patients with locally advanced head and neck cancer.

BACKGROUND: The aim of the study is to assess the effectiveness of intensity-modulated radiotherapy (IMRT) or image-guided radiotherapy (IGRT) for the prevention of retropharyngeal nodal recurrences in locally advanced head and neck cancer. METHODS: A retrospective review of 76 patients with head and neck cancer undergoing concurrent chemoradiation or postoperative radiotherapy with IMRT or IGRT who were at risk for retropharyngeal nodal recurrences because of anatomic site (hypopharynx, nasopharynx, oropharynx) and/or the presence of nodal metastases was undertaken.The prevalence of retropharyngeal nodal recurrences was assessed on follow-up positron emission tomography (PET)-CT scans. RESULTS: At a median follow-up of 22 months (4-53 months), no patient developed retropharyngeal nodal recurrences. CONCLUSION: Prophylactic irradiation of retropharyngeal lymph nodes with IMRT or IGRT provides effective regional control for individuals at risk for recurrence in these nodes.

Stereotactic Body Radiotherapy and Immunotherapy for Older Patients with Oligometastases: A Proposed Paradigm by the International Geriatric Radiotherapy Group.

The standard of care for metastatic disease is systemic therapy. A unique subset of patients with limited metastatic disease defined as distant involvement of five anatomic sites or less (oligometastases) have a better chance of remission or improved survival and may benefit from local treatments such as surgery or stereotactic body radiotherapy (SBRT). However, to prevent further spread of disease, systemic treatment such as chemotherapy, targeted therapy, and hormonal therapy may be required. Older patients (70 years old or above) or physiologically frail younger patients with multiple co-morbidities may not be able to tolerate the conventional chemotherapy due to its toxicity. In addition, those with a good performance status may not receive optimal chemotherapy due to concern about toxicity. Recently, immunotherapy with checkpoint inhibitors (CPI) has become a promising approach only in the management of program death ligand 1 (PD-L1)-positive tumors. Thus, a treatment method that elicits induction of PD-L1 production by tumor cells may allow all patients with oligometastases to benefit from immunotherapy. In vitro studies have demonstrated that high dose of radiotherapy may induce formation of PD-L1 in various tumors as a defense mechanism against inflammatory T cells. Clinical studies also corroborated those observations. Thus, SBRT, with its high precision to minimize damage to normal organs, may be a potential treatment of choice for older patients with oligometastases due to its synergy with immunotherapy. We propose a protocol combining SBRT to achieve a minimum radiobiologic equivalent dose around 59.5 Gy to all tumor sites if feasible, followed four to six weeks later by CPI for those cancer patients with oligometastases. All patients will be screened with frailty screening questionnaires to identify individuals at high risk for toxicity. The patients will be managed with an interdisciplinary team which includes oncologists, geriatricians, nurses, nutritionists, patient navigators, and social workers to manage all aspects of geriatric patient care. The use of telemedicine by the team may facilitate patient monitoring during treatment and follow-up. Preliminary data on toxicity, local control, survival, and progression-free survival may be obtained and serve as a template for future prospective studies.

Is immunotherapy at reduced dose and radiotherapy for older patients with locally advanced non-small lung cancer feasible?-a narrative review by the international geriatric radiotherapy group.

Background and Objective: The standard of care for locally advanced non-small cell lung cancer (NSCLC) is either surgery followed by adjuvant chemotherapy with or without radiotherapy or concurrent chemotherapy and radiotherapy. However, older patients (70 years old or above) with multiple co-morbidities may not be able to tolerate the combined treatment due to its toxicity. Since lung cancer prevalence increases significantly with age, a new algorithm needs to be investigated to allow curative treatment for those with locally advanced disease. Methods: A literature search of the literature was conducted through PubMed and Google Scholar using search terms such as locally advanced NSCLC, older cancer patients, immunotherapy with check point inhibitors (CPI), and image-guided radiotherapy (IGRT). Abstracts were screened, full articles fitting the article topic were reviewed, and duplicated and non-English articles were excluded. Key Content and Findings: Recently, CPI has been introduced and proven effective for selected patients with increased program death ligand 1 (PD-L1) expression (50% or above). A reduced dose for CPI (RDCPI) may be as effective as a full dose and may decrease treatment cost. New radiation technique such as IGRT may also minimize radiotherapy complication through normal lung and cardiac sparing. Conclusions: IGRT and RDCPI may be an innovative option for older patients with locally advanced NSCLC and high PD-L1 expression and needs to be investigated in future prospective studies.

Immunotherapy and Modern Radiotherapy Technique for Older Patients with Locally Advanced Head and Neck Cancer: A Proposed Paradigm by the International Geriatric Radiotherapy Group.

The standard of care for locally advanced head and neck cancer is concurrent chemoradiation or postoperative irradiation with or without chemotherapy. Surgery may not be an option for older patients (70 years old or above) due to multiple co-morbidities and frailty. Additionally, the standard chemotherapy of cisplatin may not be ideal for those patients due to oto- and nephrotoxicity. Though carboplatin is a reasonable alternative for cisplatin in patients with a pre-existing hearing deficit or renal dysfunction, its efficacy may be inferior to cisplatin for head and neck cancer. In addition, concurrent chemoradiation is frequently associated with grade 3-4 mucositis and hematologic toxicity leading to poor tolerance among older cancer patients. Thus, a new algorithm needs to be developed to provide optimal local control while minimizing toxicity for this vulnerable group of patients. Recently, immunotherapy with check point inhibitors (CPI) has attracted much attention due to the high prevalence of program death-ligand 1 (PD-L1) in head and neck cancer. In patients with recurrent or metastatic head and neck cancer refractory to cisplatin-based chemotherapy, CPI has proven to be superior to conventional chemotherapy for salvage. Those with a high PD-L1 expression defined as 50% or above or a high tumor proportion score (TPS) may have an excellent response to CPI. This selected group of patients may be candidates for CPI combined with modern radiotherapy techniques, such as intensity-modulated image-guided radiotherapy (IM-IGRT), volumetric arc therapy (VMAT) or proton therapy if available, which allow for the sparing of critical structures, such as the salivary glands, oral cavity, cochlea, larynx and pharyngeal muscles, to improve the patients' quality of life. In addition, normal organs that are frequently sensitive to immunotherapy, such as the thyroid and lungs, are spared with modern radiotherapy techniques. In fit or carefully selected frail patients, a hypofractionated schedule may be considered to reduce the need for daily transportation. We propose a protocol combining CPI and modern radiotherapy techniques for older patients with locally advanced head and neck cancer who are not eligible for cisplatin-based chemotherapy and have a high TPS. Prospective studies should be performed to verify this hypothesis.

Feasibility of tomotherapy for Graves' ophthalmopathy: Dosimetry comparison with conventional radiotherapy.

PURPOSE: To compare the dosimetry of tomotherapy and the conventional half-beam technique (HBT) or non-split beam technique (NSBT) for target coverage and radiation dose to the lacrimal glands and lens. PATIENTS AND METHODS: A retrospective review of 7 patients with Graves' ophthalmopathy who had radiotherapy because of disease progression on high steroid dose is reported: 3 patients were treated with tomotherapy and 4 patients with HBT. RESULTS: Compared to HBT, tomotherapy may provide better target coverage and significant reduction of radiation dose to the lacrimal glands and a higher dose to the lens. The NSBT improved target coverage but resulted in significantly higher doses to the lens and lacrimal glands. CONCLUSION: Tomotherapy may provide better coverage of the target volume and may be more effective in reducing severe exophthalmos compared to the conventional radiotherapy technique.

Older breast cancer undertreatment: unconscious bias to undertreat-potential role for the international geriatric radiotherapy group?

The prevalence of breast cancer increases with age. Older breast cancer patients often present with locally advanced disease at presentation because mammography, which diagnosed early stage disease, is not recommended after the age of 75. In addition, they are often undertreated even when they are physically fit and have non-metastatic disease. As a result, survival is often poor. Physicians bias may be a factor in their undertreatment and lack of representation in prospective clinical trials. Physicians should be educated that chronological age is not a contraindication to curative treatment for older breast cancer patients. As a research group devoted to older cancer patients, women, and minorities, the International Geriatric Radiotherapy Group (IGRG) plans to conduct prospective trials to assess biomarkers for frailty, the controversial issue of mammography for older breast cancer patients, and the incorporation of frailty index for curative breast cancer treatment. The data obtained may help to decrease physician bias and to establish future guidelines for older breast cancer patients treatment.

Older Cancer Patients during the COVID-19 Epidemic: Practice Proposal of the International Geriatric Radiotherapy Group.

The coronavirus disease 19 (COVID-19) pandemic is unprecedented as it reached all countries in the world within a record short period of time. Even though COVID-19 infection may be just severe in any adults, older adults (65-year-old or older) may experience a higher mortality rate. Among those affected, cancer patients may have a worse outcome compared to the general population because of their depressed immune status. As the health resources of most countries are limited, clinicians may face painful decisions about which patients to save if they require artificial ventilation. Cancer patients, especially the older ones, may be denied supportive care because of their shorter life expectancy. Thus, special considerations should be taken to prevent infection of older cancer patients and to provide them with adequate social support during their cancer treatment. The following proposal was reached: (1) Education of health care providers about the special needs of older cancer patients and their risks of infection. (2) Special consideration such as surgical masks and separate scheduling should be made to protect them from being infected. (3) Social services such as patient navigators should be provided to ensure adequate medical supply, food, and daily transportation to cancer centers. (4) Close monitoring through phone calls, telecommunication to ensure social distancing and psychological support from patient family to prevent anxiety and depression. (5) Shorter course of radiotherapy by use of hypofractionation where possible to decrease the needs for daily transportation and exposure to infection. (6) Enrollment of older cancer patients in clinical trials for potential antiviral medications if infection does occur. (7) Home health care telemedicine may be an effective strategy for older cancer patients with COVID-19 infection to avoid hospital admission when health care resources become restricted. (8) For selected patients, immunotherapy and targeted therapy may become the systemic therapy of choice for older cancer patients and need to be tested in clinical trials.

Whole-lung Low Dose Irradiation for SARS-Cov2 Induced Pneumonia in the Geriatric Population: An Old Effective Treatment for a New Disease? Recommendation of the International Geriatric Radiotherapy Group.

A cytokine storm induced by SARS-Cov2 may produce pneumonitis which may be fatal for older patients with underlying lung disease. Hyper-elevation of Interleukin1 (IL-1), Tumor necrosis factor-1alfa (TNF-1 alfa), and Interleukin 6 (IL-6) produced by inflammatory macrophage M1 may damage the lung alveoli leading to severe pneumonitis, decreased oxygenation, and potential death despite artificial ventilation. Older patients may not be suitable candidates for pharmaceutical intervention targeting IL-1/6 blockade or artificial ventilation. Low dose total lung (LDTL) irradiation at a single dose of 50 cGy may stop this cytokine cascade, thus preventing, and/or reversing normal organs damage. This therapy has been proven in the past to be effective against pneumonitis of diverse etiology and could be used to prevent death of older infected patients. Thus, LDRT radiotherapy may be a cost-effective treatment for this frail patient population whom radiation -induced malignancy is not a concern because of their advanced age. This hypothesis should be tested in future prospective trials.

Aspiration risk and postoperative radiation for head and neck cancer.

The aim of the study was to assess the aspiration risk following postoperative radiation for head and neck cancer. Thirty-seven patients had Modified Barium Swallow before and following treatment. Dysphagia severity was graded from 1 to 7. Before treatment there were sixteen grade 1, seventeen grade 2, three grade 3 and one grade 5. Following postoperative radiation, two patients had grade 1, eleven patients had grade 2, thirteen patients had grade 3, four patients had grade 4, four patients had grade 5, one patients had grade 6, and two patients had grade 7. Nineteen percent (7/37) of the patients developed aspiration (grade 5-7). Aspiration is life-threatening and may develop for all tumor sites and stages.

Circulating cytokine levels in prostate cancer patients undergoing radiation therapy: influence of neoadjuvant total androgen suppression.

BACKGROUND: The purpose of this study was to investigate the immunological impact of combining neoadjuvant total androgen suppression (TAS) with radiotherapy (xRT) in the treatment of prostate cancer by monitoring blood cytokine levels. PATIENTS AND METHODS: Participants were stage I-II prostate cancer patients receiving xRT alone (n=18) or TAS+xRT (n=19) under the procedures outlined in RTOG protocols #94-08 and #94-13. Peripheral blood samples were collected immediately prior to TAS (xRT+TAS group), immediately prior to xRT, 24 hours after initiation of xRT, and weekly during xRT. Samples were monitored for the immunoregulatory cytokines interleukin (IL)-1beta, IL-6 and transforming growth factor (TGF)beta using ELISA procedures. RESULTS: Following initiation of xRT, both patient groups demonstrated an immediate elevation of the proinflammatory cytokines IL-1beta and IL-6 in their plasma. These cytokine levels appeared to peak after 1-2 weeks of xRT before returning toward pre xRT levels. In contrast, the profibrotic cytokine TGFbeta appeared to decrease immediately following initiation of xRT, but, subsequently, underwent two distinct waves of elevation, occurring at 1-2 weeks and 5-6 weeks into the xRT. Surprisingly, while the temporal pattern of plasma cytokine response was similar in both treatment groups, the magnitude of cytokine expression was noticeably different, appearing to be significantly affected by the addition of TAS. Indeed, administration of neoadjuvant TAS appeared to bring about a marked elevation of IL-1beta and IL-6 and a significant reduction in TGFbeta when compared to patients receiving xRT alone. CONCLUSION: The precise mechanisms underlying this TAS-related increase of the proinflammatory cytokines IL-1beta and IL-6 and decrease of the profibrotic cytokine TGFbeta remain unclear. However, previous reports have documented that androgens tend to be immunosuppressive in nature. It is conceivable, therefore, that administration of TAS shifts the ratio of proinflammatory and profibrotic cytokines toward a more immunostimulatory state.

Challenges Facing Radiation Oncologists in The Management of Older Cancer Patients: Consensus of The International Geriatric Radiotherapy Group.

The management of older cancer patients remains difficult because of data paucity. Radiation oncologists need to identify potential issues which could affect treatment of those patients. A workshop was organized in Barcelona among international radiation oncologists with special interest in the management of older cancer patients on April 22, 2018. The following consensus was reached: 1. Older cancer patients often faced unconscious discriminating bias from cancer specialists and institutions because of their chronological age. 2. Advances in radiotherapy techniques have allowed patients with multiple co-morbidities precluding surgery or systemic therapy to achieve potential cure in early disease stages. 3. The lack of biomarkers for frailty remains an impediment to future research. 4. Access to healthcare insurance and daily transportation remains an issue in many countries; 5. Hypofractionation, brachytherapy, or stereotactic techniques may be ideally suited for older cancer patients to minimize transportation issues and to improve tolerance to radiotherapy. 6. Patients with locally advanced disease who are mentally and physically fit should receive combined therapy for potential cure. 7. The role of systemic therapy alone or combined with radiotherapy for frail patients needs to be defined in future clinical trials because of targeted agents or immunotherapy may be less toxic compared to conventional chemotherapy.

Sensitivity of HIV type 1 primary isolates to human anti-CD40 antibody-mediated suppression is related to coreceptor use.

The effect of CD40 ligation on infection by HIV-1 primary isolates with different R5 phenotypes was evaluated with a novel set of anti-CD40 monoclonal antibodies originating from a human phage display library. Five human monoclonal anti-CD40 antibodies of IgG1 subtype characterized by the ability to activate B cells via CD40 were tested for induction of the CC-chemokines RANTES and MIP-1alpha and inhibition of HIV-1 replication in primary monocyte-derived macrophages (MDM). All activating anti-CD40 antibodies were able to induce CC-chemokines in MDM. We chose the most potent antibody, clone B44, for further experiments. This antibody had a suppressive effect on HIV-1 isolates of the R5 phenotype with limited use of CCR5/CXCR4 chimeric receptors. In comparison, HIV-1 isolates with broader use of CCR5/CXCR4 chimeric receptors or with CXCR4 use were less sensitive to anti-CD40-induced suppression. The results indicate that HIV-1 replication is inhibited by human anti-CD40 monoclonal antibodies through the mechanism of CC-chemokine induction. This effect is thus restricted to HIV-1 isolates sensitive to inhibition by CC-chemokines.