Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen4 (CTLA-4), an inhibitory molecule typically expressed on T cells. Blockade of CTLA-4 induces an overall activation of T cells, including an immune-mediated anti-tumour response. Unfortunately, this broad T cell stimulation also causes immune-related adverse events (irAEs), such as dermatitis, colitis, hepatitis and hypophysitis. Ipilimumab is currently available in Belgium as a second line of treatment for patients with advanced melanoma, and is used at a dose of 3 mg/kg of body weight, although higher doses were previously used (up to 10 mg/kg). We performed a retrospective analysis to identify melanoma patients treated with ipilimumab at the Ghent University Hospital between 2010 and 2013. Data on symptoms, stage and timing of ipilimumab, response and adverse events were collected with a special attention to endocrine disturbances, going from a limited involvement of one endocrine axis to development of a hypophysitis. We identified a total of 39 patients with stage III (No. = 7) or stage IV (No. = 32) melanoma, who received a dose of 3 (No. = 31) or 10 (No. = 8) mg/kg. Six patients developed a severe form of irAEs, including one case of colitis (2 %), one case of sarcoidosis (2 %) and 4 cases (10 %) of hypophysitis. Hypophysitis developed between the second and fourth cycle of ipilimumab administration and was independent of the dose used. We describe four cases of involvement of the pituitary gland during treatment with ipilimumab. When managed with vigilant monitoring and high-dose corticosteroids, the acute symptoms resolve, but lifelong hormone substitution therapy can be necessary. Involvement of the pituitary axes is a severe side effect of treatment with ipilimumab with an urgent need for the correct medical intervention

The addition of bevacizumab to standard chemotherapy in breast cancer : which patient benefits the most?

Bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor, is an effective and well-tolerated treatment option for patients with breast cancer. Bevacizumab has demonstrated a gain in progression-free survival and a trend towards an overall survival benefit in various subgroups of breast cancer. Given the lack of a predictive biomarker, we performed a literature search with regard to efficacy and tolerability of bevacizumab in different subgroups of breast cancer patients and in different settings. In the metastatic setting, the efficacy of bevacizumab has been most extensively studied and demonstrated in patients with triple-negative breast cancer, the most difficult-to-treat population among patients with advanced disease and also the group with the biggest need for new treatment options. Overall, bevacizumab is well tolerated with very few serious adverse events. Bevacizumab is also an active and feasible treatment option for patients above 70 years of age

CA 15.3 measurements for separating FDG PET/CT positive from negative findings in breast carcinoma recurrence

In breast cancer CA 15.3 is considered the tumour marker of choice. CA 15.3 is directly related to the disease extent and to hormone status (estrogen receptor ER+/ ER-, progesterone receptor PR+/PR-). This study was designed to assess the impact of disease extent, hormone receptor and HER2-status, and circulating blood volume on the area-under the ROC-curve of CA 15.3 to separate FDG PET positive from negative findings. Patients, methods: We retrospectively evaluated 379 FDG PET/CT examinations performed in 80 patients with breast cancer. Blood volumes were derived using the formulas by Nadler and multiplied by their corresponding CA 15.3 measurement. Results: ROC-curve analysis revealed an AUC of 0.695 (p = 0.0001) for CA 15.3 to separate FDG PET positive from negative findings. AUC measurements to separate normal scan findings from loco-regional disease and metastatic disease were 0.527 (p = 0.587) and 0.732 (p = 0.0001), respectively. AUC measurements for CA 15.3 to separate positive from negative FDG PET findings, in ER+ and ER-patients, were respectively 0.772 (p = 0.0001) and 0.596 (p = 0.143). AUC measurements for CA 15.3 to separate positive from negative FDG PET findings, in PR+ and PR-patients, were respectively 0.675 (p = 0.0001) and 0.694 (p = 0.0001). In HER2-positive and -negative patients, the AUC measurements were respectively 0.594 (p = 0.178) and 0.701 (p = 0.0001) to separate positive from negative FDG PET findings. Conclusion: The AUC for CA 15.3 measurements to separate FDG PET positive from negative findings in breast cancer patients with suspected recurrence proved to be directly related to the extent of the recurrent disease and hormone receptor status and inversely related to HER2-status. Correcting CA 15.3 measurements for blood volumes did not impact the AUC

Psoriasis vulgaris exacerbation during treatment with a PD-1 checkpoint inhibitor : case report and literature review

Objective: The incidence of immune-related adverse events is growing as the use of checkpoint inhibitors is exponentially increasing. Cutaneous adverse events are among the most frequent immune-related adverse events. The purpose of this case report and literature review is to highlight psoriasis as a potential adverse event with need for early recognition. Case Report and Literature Review: We describe the case of a 65-year-old woman with psoriasis exacerbation while treated with nivolumab (anti-PD-1) for a stage IV melanoma. She had a history of scalp psoriasis but she presented with psoriatic lesions on both lower and upper limbs. Our patient was treated with topical steroids. So far, 34 other cases with an exacerbation of psoriasis during treatment with anti-PDL-1 or PD-1 therapy have been reported in the literature. A broad range of therapies are described, without any available guidelines for this particular condition. Conclusion: Psoriasis exacerbation is an established side effect of PD-1/PDL-1 checkpoint inhibitors with 35 reported cases. Early recognition and management are challenging as there are no clear guidelines available. A close collaboration between oncologist and dermatologist is mandatory to manage this immune-related adverse event

Throughput efficiency and service quality after process redesign at a cancer day care unit: Two sides of the coin?

This study was designed to focus on the patient perspective in a reorganisation of care processes at a cancer day care unit (CDU). The effects of dose banding and of taking blood samples one day (or more) before the day care treatment (on Day -1) are investigated in terms of throughput efficiency and perceived service quality. Data were collected by mapping patient processes in detail and surveying patients in two CDUs at a university hospital (n=308). A univariate model was used to investigate the effect of these factors on patient throughput time, and perceived service quality was examined with multiple linear regression. Taking blood samples on Day -1 decreases patient throughput time and increases the perceived service quality by improving the patient's perception of technical expertise and the outcome. This has a globally positive effect on patients' perceived service quality. Dose banding affected neither patient throughput time nor perceived service quality. Taking the pretreatment blood sample on Day -1 can be considered an important process design characteristic, as it increases both efficiency and service quality

A phase II trial of stereotactic body radiotherapy with concurrent anti-PD1 treatment in metastatic melanoma : evaluation of clinical and immunologic response

Background: Antibodies blocking programmed cell death 1 (PD-1) have encouraging responses in patients with metastatic melanoma. Response to anti-PD-1 treatment requires pre-existing CD8+ T cells that are negatively regulated by PD-1-mediated adaptive immune resistance. Unfortunately, less than half of melanoma tumours have these characteristics. Combining anti-PD-1 treatment with other immunomodulating treatments to activate CD8+ T cells is therefore of vital importance to increase response rates and long-term survival benefit in melanoma patients. Both preclinical and retrospective clinical data support the hypothesis that radiotherapy increases the response rates to anti-PD-1 treatment by stimulating the accumulation and activation of CD8+ T cells in the tumour microenvironment. Combining radiotherapy with a PD-1 blocking antibody might therefore increase response rates and even induce long-term survival. The current phase II study will be testing these hypotheses and aims to improve local and distant tumour responses by exploiting the pro-immunogenic effects of radiotherapy in addition to anti-PD-1 treatment. Methods: The trial will be conducted in patients with metastatic melanoma. Nivolumab or pembrolizumab, both antibodies that target PD-1, will be administrated according to the recommended dosing schedule. Prior to the 2nd cycle, radiotherapy will be delivered in three fractions of 8 Gy to the largest FDG-avid metastatic lesion. The primary endpoint is the proportion of patients with a partial or complete response in non-irradiated metastases according to RECIST v1.1. Secondary endpoints include response rate according to immune related response criteria, metabolic response, local control and survival. To identify peripheral blood biomarkers, peripheral blood mononuclear cells and serum samples will be collected prospectively before, during and after treatment and subjected to flow cytometry and cytokine measurement. Discussion: The current phase II trial aims at exploring the suggested benefits of combining anti-PD-1 treatment and radiotherapy. The translational focus on immunologic markers might be suitable for predicting efficacy and monitoring the effect so to improve patient selection for future clinical applications

Managing viral hepatitis in cancer patients under immune checkpoint inhibitors : should we take the risk?

More patients with chronic hepatitis B and C infection are being exposed to immune checkpoint inhibitors (ICIs), but the safety and efficacy of ICIs in patients with chronic viral hepatitis are still poorly described. To explore this interaction, we identified eight studies of cancer patients with viral hepatitis treated with one or more ICIs, formally assessed tumor responses and safety by grading liver dysfunction. ICIs appear to be relatively safe in HBV/HCV-infected patients, and hepatitis related to viral reactivation is rare. In some patients, viral load regressed during ICI treatment, so immune checkpoints may play a role in viral clearance. HBV/HCV do not appear to be a contraindication to ICIs, although careful clinical and biochemical follow-up is recommended and, whenever necessary, antiviral therapy commenced