Interaction between Radiation Therapy and Targeted Therapies in HER2-Positive Breast Cancer: Literature Review, Levels of Evidence for Safety and Recommendations for Optimal Treatment Sequence.

Purpose: Over the past twenty years, anti-HER2 targeted therapies have proven to be a revolution in the management of human epidermal growth receptor 2 (HER2)-positive breast cancers. Anti-HER2 therapies administered alone or in combination with chemotherapy have been specifically studied. Unfortunately, the safety of anti-HER2 therapies in combination with radiation remains largely unknown. Thus, we propose a literature review of the risks and safety of combining radiotherapy with anti-HER2 therapies. We will focus on the benefit/risk rationale and try to understand the risk of toxicity in early-stage and advanced breast cancer. Methods: Research was carried out on the following databases: PubMed, EMBASE, ClinicalTrial.gov, Medline, and Web of Science for the terms "radiotherapy", "radiation therapy", "radiosurgery", "local ablative therapy", and "stereotactic", combined with "trastuzumab", "pertuzumab", "trastuzumab emtansine", "TDM-1", "T-Dxd", "trastuzumab deruxtecan", "tucatinib", "lapatinib", "immune checkpoint inhibitors", "atezolizumab", "pembrolizumab", "nivolumab", "E75 vaccine", "interferon", "anti-IL-2", "anti-IL 12", and "ADC". Results: Association of radiation and monoclonal antibodies such as trastuzumab and pertuzumab (with limited data) seems to be safe, with no excess risk of toxicity. Preliminary data with radiation and of antibody-drug conjugate of trastuzumab combined cytotoxic (trastuzumab emtansine, trastuzumab deruxtecan), given the underlying mechanism of action, suggest that one must be particularly cautious with the association. The safety of the combination of a tyrosine kinase inhibitor (lapatinib, tucatinib) and radiation remains under-studied. The available evidence suggests that checkpoint inhibitors can be safely administrated with radiation. Conclusions: HER2-targeting monoclonal antibodies and checkpoint inhibitors can be combined with radiation, apparently with no excess toxicities. Caution is required when associating radiation with TKI and antibody drugs, considering the limited evidence.

Pathologic Response to Neoadjuvant Sequential Chemoradiation Therapy in Locally Advanced Breast Cancer: Preliminary, Translational Results from the French Neo-APBI-01 Trial.

BACKGROUND: Radiation therapy (RT), a novel approach to boost the anticancer immune response, has been progressively evaluated in the neoadjuvant setting in breast cancer (BC). PURPOSE: We aimed to evaluate immunity-related indicators of response to neoadjuvant chemoradiation therapy (NACRT) in BC for better treatment personalization. PATIENTS AND METHODS: We analyzed data of the first 42 patients included in the randomized phase 2 Neo-APBI-01 trial comparing standard neoadjuvant chemotherapy (NACT) and NACRT regimen in locally advanced triple-negative (TN) and luminal B (LB) subtype BC. Clinicopathological parameters, blood counts and the derived parameters, total tumor-infiltrating lymphocytes (TILs) and their subpopulation, as well as TP53 mutation status, were assessed as predictors of response. RESULTS: Twenty-one patients were equally assigned to each group. The pathologic complete response (pCR) was 33% and 38% in the NACT and NACRT groups, respectively, with a dose-response effect. Only one LB tumor reached pCR after NACRT. Numerous parameters associated with response were identified, which differed according to the assigned treatment. In the NACRT group, baseline hemoglobin of ≥13 g/dL and body mass index of <26 were strongly associated with pCR. Higher baseline neutrophils-to-lymphocytes ratio, total TILs, and T-effector cell counts were favorable for pCR. CONCLUSION: This preliminary analysis identified LB and low-TIL tumors as poor responders to the NACRT protocol, which delivered RT after several cycles of chemotherapy. These findings will allow for amending the selection of patients for the trial and help better design future trials of NACRT in BC.

How did we take care of our older cancer patients during the first COVID-19 wave? The French experience.

BACKGROUND: The management of older cancer patients has been highly challenging for clinicians in a health-care system operating at maximum capacity during the COVID-19 pandemic. PATIENTS AND METHODS: We analyzed data from 9 different institutions. The primary endpoint was to assess the prevalence of adapted patient care during the pandemic for elderly cancer patients. The secondary endpoint was to assess the incidence of hospitalization and mortality due to COVID-19. All patients were older than 65years of age. RESULTS: We analyzed data from 332 outpatients' case files between 9th of March and 30th of April 2020. The median age was 75years (range: 65-101) and 53% were male. Because of the COVID-19 pandemic, more than half of the outpatients received modified patient care, defined as postponement or cancellation of surgery, irradiation scheme adapted, systemic treatment or the use of telemedicine. Among patients with localized cancer, 60% had a change in management strategy due to the pandemic. Changes in management strategy were made for 53% of patients at the metastatic stage. GCSF was used , in 83% of patients, increasing considerably in the context of the pandemic. Sixty-nine percent of physicians used telemedicine. In the final analysis, only one patient was hospitalized for COVID-19 infection. No deaths due to COVID-19 were reported in elderly cancer patients during this time period. CONCLUSION: Our study is the first to assess modification of patient care in elderly cancer outpatients during an epidemic. With this unprecedented crisis, our objective is to protect our patients from infection via protective barrier measures and social distancing, but also to guarantee the continuity of cancer care without overexposing this fragile population. Physicians were able to adapt their practice and used new forms of management, like telemedicine.

Radiation Therapy Delivery Challenges in Older Patients During Coronavirus Disease 2019 Pandemic.

PURPOSE: The management of older patients in radiation therapy (RT) departments has been challenging in the context of the Coronavirus Disease 2019 (COVID-19) outbreak. We report our experience of RT adapted schedules or strategy changes in older patients during the COVID-19 pandemic. METHODS AND MATERIALS: Patients aged ≥75 years were recruited during weekly chart rounds. All were potentially eligible for a specific intervention to reduce the frequency of patients' visits to the hospital. The effect of deferring radiation and hypofractionation of RT schedules was assessed in terms of the number of courses initially planned and replanned during the lockdown. RESULTS: Twenty patients were identified during the official lockdown in France (March 17 to May 11). Median age was 78 years (75-95 years). Most patients were male (n = 12, 60%) being treated in the postoperative setting (n = 17, 85%). RT was delayed in 11 cases (55%) with hormonal therapy prescribed in 10 cases (50%). Altered RT fractionation was proposed for 5 cases (25%); combinations of altered fractionation and deferral of radiation were applied in 3 cases (15%). The number of radiation courses initially planned and replanned according to the pandemic context: 563 and 197, respectively (-62%; P < .001). None presented recurrence when RT was initiated, and no patient developed symptomatic COVID-19 infection. CONCLUSIONS: In the context of the COVID-19 outbreak, individual risk-based radiation therapy seems to be safe. Systematic screening of patients for COVID-19 before starting radiation therapy is mandatory. In our department the oncogeriatrics expertise availability for daily practice was of great use during the pandemic. Other prospective studies are needed to validate such strategies in case of resurgence of similar outbreaks.

Evaluation of medical practices in oncology in the context of the COVID-19 pandemic in France: Physicians' point of view: the PRATICOVID study.

The cancer population seems to be more susceptible to COVID-19 infection and have worse outcomes. We had to adapt our medical practice to protect our patients without compromising their cancer prognosis. The national PRATICOVID study aims to describe the adaptation of cancer patient care for this population. We analyzed data from nine different institutions. The primary endpoint was to assess the prevalence of adapted patient care during the pandemic. The secondary endpoints were to describe the point of view of clinicians and patients during and after the pandemic. We analyzed 435 medical procedures between 9th of March and 30th of April. Because of the COVID-19 pandemic, 47.6% of the outpatients received modified patient care. Twenty-four percent of scheduled surgeries were postponed, or were performed without perioperative chemotherapy, 18.4% followed a hypofractioned schedule, and 57% had an adaptive systemic protocol (stopped, oral protocol, and spacing between treatments). Seventy percent of physicians used telemedicine. During this period, 67% of the physicians did not feel distressed taking care of their patients. However, 70% of physicians are worried about the aftermath of the lockdown, as regards future patient care. The PRATICOVID study is the first to assess modification of patient care in cancer outpatients during an epidemic. With this unprecedented crisis, physicians were able to adapt their practice in order to protect their patients against the virus while ensuring continuity of patient care. But physicians are worried about the aftereffects of the lockdown specifically in regard to care pathway issues.

Hemostatic radiotherapy for bladder cancer-related hematuria in patients unfit for surgery: is there any impact of fractionation schedule?

PURPOSE: The optimal schedule for palliative external beam radiotherapy (EBRT) in patients with bladder tumors with hematuria unfit for surgery remains undefined. This study aimed to assess the clinical hemostatic efficacy and safety of two EBRT hypofractionated schedules. METHODS: From February 2008 to October 2017, 31 patients were referred to our department for palliative hemostatic bladder irradiation. EBRT consisted of two schedules: "continuous" treatment (CRT) was delivered following consecutive 3-10 weekdays (3-6Gy/fraction (fr), to a total dose of 18-30Gy) (n=14); the "discontinuous" schedule (DRT) consisted of 23Gy in 4fr (6.5Gy/fr on days 1 and 3, followed by 5Gy/fr on days 15 and 17; n=12). The primary endpoint was the rate of hemostatic control (HC) at the end of the radiation course. Other endpoints included mid-term HC, toxicities and overall survival. Comparative analyses were performed by exact Fisher test with a cut-off of 0.05 for statistical significance. RESULTS: The rate of HC at the end of EBRT was 92% (n=24) with no differences between CRT and DRT (100% vs 86%; p=0.48). The median follow-up was 6 months, HC was achieved in 15/26 (58%) patients at the last follow-up, without meaningful differences between CRT and DRT (50% vs 67%; p=0.45). Three and two patients developed acute grade ≤2 diarrhea in CRT and DRT groups, respectively. CONCLUSION: Our study suggests that both hypofractionated "continuous" and "discontinuous" EBRT are well tolerated and represent acceptable schedules for patients with limited life expectancy. DRT schedule could be preferred for departments' organization to increase the slots for the treatment of other referred patients for radiotherapy.

Radiation Therapy Department Reorganization during the Coronavirus Disease 2019 (COVID-19) Outbreak: Keys to Securing Staff and Patients During the First Weeks of the Crisis and Impact on Radiation Therapy Practice from a Single Institution Experience.

PURPOSE: During the first weeks of the coronavirus disease 2019 (COVID-19) outbreak in France, it was necessary to clearly define organizational priorities in the radiation therapy (RT) departments. In this report, we focus on the urgent measures taken to reduce risk for both our staff and patients by reducing the number of patients receiving treatment. METHODS AND MATERIALS: We reviewed the fractionation schemes for all patients in our department, including those receiving treatment and those soon to start treatment. Our goals were to (1) decrease the number of patients coming daily to the hospital for RT, (2) adapt our human resources to continue patients' care in the department, and (3) help to cover understaffed COVID-19 sectors of the hospital. RESULTS: We identified 50 patients who were receiving treatment (n = 6), were going to start radiation after CT scan simulation (n = 41), or for whom the CT scan was pending (n = 3). The majority were women (64%) treated for breast cancer (54%). RT was delayed for 22 (44%) patients. The majority were offered hormone therapy as "waiting therapy." Hypofractionation was considered in 21 (42%) patients mainly with breast cancer (18 of 21, 86%). The number of courses initially planned and replanned as a result of the COVID-19 outbreak during the period of March 15 to May 31, 2020, were 1383 and 683, respectively, which represented a reduction of 50% (including delayed sessions) that allowed our reorganization process. CONCLUSIONS: To conserve resources during the pandemic, we successfully reduced the number of patients receiving treatment in a proactive fashion and adapted our organization to minimize the risk of COVID-19 contamination. Departments across the world may benefit from this same approach.

A review of the international early recommendations for departments organization and cancer management priorities during the global COVID-19 pandemic: applicability in low- and middle-income countries.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new virus that has never been identified in humans before. COVID-19 caused at the time of writing of this article, 2.5 million cases of infections in 193 countries with 165,000 deaths, including two-third in Europe. In this context, Oncology Departments of the affected countries had to adapt quickly their health system care and establish new organizations and priorities. Thus, numerous recommendations and therapeutic options have been reported to optimize therapy delivery to patients with chronic disease and cancer. Obviously, while these cancer care recommendations are immediately applicable in Europe, they may not be applicable in certain emerging and low- and middle-income countries (LMICs). In this review, we aimed to summarize these international guidelines in accordance with cancer types, making a synthesis for daily practice to protect patients, staff and tailor anti-cancer therapy delivery taking into account patients/tumour criteria and tools availability. Thus, we will discuss their applicability in the LMICs with different organizations, limited means and different constraints.

Axillary nodal irradiation practice in the sentinel lymph node biopsy era: Comparison of the contemporary available 3D and IMRT techniques.

OBJECTIVE: Our study aimed to compare regional node coverage and doses to the organ at risk (OAR) using conventional technique (CT) vs "AMAROS" (AT) vs intensity-modulated radiation therapy (IMRT) techniques in patients receiving regional nodal irradiation (RNI) for breast cancer (BC). METHODS: We included 30 consecutive patients with BC who received RNI including axillary nodes. Two independent and blinded dosimetric RNI plans were generated for all patients. For target volume coverage, we analyzed the V95%, the D95%, the mean and the minimal dose within the nodal station. For hotspots within nodal target volume, we used the V105%, the V108% and the maximal doses. For OAR, lung V20, mean lung and heart doses, the maximal dose to the brachial plexus and the axillary-lateral thoracic vessel junction region were compared between the three techniques. RESULTS: Target volume coverage and hotspots: Mean V95% in stations I, II, III and IV were 35.8% and 75% respectively with CV, 22.59 and 59.9% respectively with AT technique and 45.58 and 99.6% respectively with IMRT with statistically significant differences (p < 0.001). Mean V105% (cc) in axillary and supraclavicular stations were 21.3 and 6.4 respectively with CV, 1.2 and 0.02 respectively with AT technique and 0.5 and 0.4 respectively with IMRT with statistically significant differences (p < 0.001)..OARs: The mean ipsilateral lung V20 was 16.9%, 16.4 and 13.3% with CT, AT and IMRT respectively. The mean heart dose (Gy) was 0.3, 0.2 and 0.2 with CT, AT and IMRT respectively. The maximal dose to the plexus brachial (Gy) was 50.3, 46.3 and 47.3 with CT, AT and IMRT respectively. The maximal dose to the axillary-lateral thoracic vessel junction (Gy) was 52.3, 47.3 and 47.6 with CT, AT and IMRT respectively. The differences were statistically significant for all OAR (p < 0.001). CONCLUSION: AT is a valuable technique for RNI including axilla in patients with limited sentinel lymph node biopsy involvement without additional axillary lymph node dissection since it decreases hotspots in the target volume and lowers the radiation exposure of the OAR. For more advanced tumors or patients who did not respond to primary systemic therapy, CT or IMRT should be considered because of their better coverage of the potentially residual nodal disease. IMRT combines several advantages of offering high conformal plans, limited hotspots and protection of main OAR. The clinical impact of these dosimetric differences need to be addressed. ADVANCES IN KNOWLEDGE: This study is to our knowledge the first to compare conventional three-dimensional and IMRT techniques for regional nodal irradiation for each nodal station in breast cancer in a context of increasing utilization of axillary irradiation.

[Functional iron deficiency, inflammation and fatigue after radiotherapy]. / Carence martiale fonctionnelle, inflammation et fatigue après radiothérapie.

Radiation therapy is associated with a fatigue in the majority of patients with a relative variability according to the type of the tumour, comorbidities, associated treatments and the extent of the irradiation. Its origin is multifactorial. One explanation described is that fatigue could be related to the inflammation caused by irradiation exposure. One of the suspected mechanisms is a functional iron deficiency following pro-inflammatory cytokines synthesis, particularly the interleukins 1 and 6. This phenomenon is accompanied by a reduced availability of iron, while iron reserves are normal or increased. Thus, iron inaccessibility induces lower coefficient of transferrin saturation, which can lead to a non-regenerative normocytic or microcytic anaemia. The availability of iron is controlled by hepcidin that is synthesized in the liver as a response to radiation-induced inflammatory. The presence of hepcidin blocks iron absorption in the intestine and decreases its recycling from senescent red blood cells. A direct relationship between elevated levels of hepcidin, inflammation markers and radiation-induced side effects have been reported. The aim of the article is to review the literature related to fatigue in radiotherapy and understand the mechanisms involved or worsening its occurrence to consider better care and improve patients' quality.

[Cervical cancer: particularities in HIV patients]. / Cancer du col utérin : spécificités chez les patientes séropositives pour le VIH.

Cervical cancer is the second most common cancer in women worldwide. It represents one of the most challenging public health problems in developing countries. HIV-infected women have a higher risk of cervical cancer which is an AIDS defining cancer. Cervical cancer treatment in HIV-infected and non-infected women is the same. HIV naive women must be prescribed combination antiretroviral therapy at the moment of HIV cancer diagnosis. A close collaboration between oncologist and infectiologist is mandatory to optimize HIV treatment. Among HIV-infected women, PAP-smear screening for early detection and treatment of precancerous cervical lesions is recommended. HPV vaccination is also recommended with the same efficacy and safety profile as the general population.