Amaury Daste

Immune checkpoint inhibitors and elderly people: A review

Immune checkpoint inhibitors, including targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte antigen 4 pathways, are a new type of cancer treatment. This approach of targeting the immune system has demonstrated dramatic efficacy for several cancers, and various drugs have been approved by health authorities and are used in clinical practice. Elderly patients (≥65 years) represent most of the cancers diagnosed and deaths by age group, with an increase expected over the next decade. However, this subgroup of patients is under-represented in clinical trials. Ageing is also associated with a decrease in the effectiveness of the immune system and in alterations to it. Few specific trials have been carried out for immunotherapy in elderly people, with most patients considered to be fit. In this review, we discuss the impact of ageing and immunosenescence on immune system functions, and we assess the safety and efficacy of immune checkpoint inhibitors in elderly patients, principally from the data of pivotal clinical trials with subgroup analysis. Tolerance in elderly patients seems similar to younger people, but efficacy seems different between younger and elderly patients according to the type of cancer, some showing no difference and others less efficacy in the elderly subgroup. However, the numbers in elderly groups are small and more investigation is needed, with specific clinical trials for elderly cancer patients.

Optimal management of renal cell carcinoma in the elderly: a review

Both the aging population and the incidence of renal cell carcinoma (RCC) are growing, making the question of tumor management in the elderly a real challenge. Doctors should be aware of the importance of assessing this specific subpopulation. An aggressive therapeutic approach may be balanced by the benefit of the treatment — care or cure — and the life expectancy and willingness of the patient. The treatment for local disease can be surgery (radical or partial nephrectomy) or ablative therapies (radiofrequency, cryotherapy). Even if in most cases surgery is safe, complications such as alteration of renal function may occur, especially in the elderly, with physiological renal impairment at baseline. More recently, another option has been developed as an alternative: active surveillance. In the past decade, new drugs have been approved in the metastatic setting. All the phase 3 trials have included patients without a limit on age. Nevertheless, data concerning the elderly are still poor and concern only a very selective subpopulation. The toxicity profile of targeted agents may interfere with pre-existent comorbidities. Furthermore, the metabolism of several agents via cytochrome P450 can cause drug interaction. The importance of quality of life is a major factor with regard to management of therapy. Finally, to date, there is no recommendation of systematic a priori dose reduction in the elderly. In this review we describe the various possibilities of treatment for localized RCC or metastatic RCC in an aging population.

Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer—clinical aspects and relationship with tumour response: a single-centre prospective cohort study

Objectives To evaluate the prevalence and type of rheumatic immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs), as well as the correlation with tumour response. Methods This was a single-centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs and tumour response was assessed on a regular basis. Patients who experienced musculoskeletal symptoms were referred to the department of rheumatology for clinical evaluation and management. Results From September 2015 to May 2017, 524 patients received ICIs and 35 were referred to the department of rheumatology (6.6%). All but one of the rheumatic irAEs occurred with anti-programmed cell death protein 1(PD-1)/PD-1 ligand 1(PD-L1) antibodies, with a median exposure time of 70 days. There were two distinct clinical presentations: (1) inflammatory arthritis (3.8%) mimicking either rheumatoid arthritis (n=7), polymyalgia rheumatica (n=11) or psoriatic arthritis (n=2) and (2) non-inflammatory musculoskeletal conditions (2.8%; n=15). One patient with rheumatoid arthritis was anti-cyclic citrullinated peptide (anti-CCP) positive. Nineteen patients required glucocorticoids, and methotrexate was started in two patients. Non-inflammatory disorders were managed with non-steroidal anti-inflammatory drugs, analgesics and/or physiotherapy. ICI treatment was pursued in all but one patient. Patients with rheumatic irAEs had a higher tumour response rate compared with patients without irAEs (85.7% vs 35.3%; P<0.0001). Conclusion Since ICIs are used with increasing frequency, knowledge of rheumatic irAEs and their management is of major interest. All patients were responsive either to low-to-moderate doses of prednisone or symptomatic therapies and did not require ICI discontinuation. Furthermore, tumour response was significantly higher in patients who experienced rheumatic irAEs.

Protein kinase inhibitors in renal cell carcinoma

Introduction: Metastatic Renal Cell Carcinoma (mRCC) was historically treated with cytokine therapy with a poor outcome. In the last decade, new therapies targeting vascular endothelial growth factor (VEGF) or the mammalian target of rapamycin (m-TOR) pathways demonstrated efficacy in mRCC. Protein kinase inhibitors as well as monoclonal antibodies targeting these pathways have become the standard treatment of renal cell carcinoma (RCC) in the first-line setting and beyond. Areas covered: This review describes the various Phase III trials concerning protein kinase inhibitors including anti-angiogenic tyrosine kinase inhibitors (TKIs) and m-TOR serine/threonine kinase inhibitors, which have demonstrated a benefit in the treatment of mRCC. It focuses on efficacy, safety and management. Expert opinion: VEGF TKI and m-TOR inhibitors have significantly improved the outcome of mRCC and offer a gain in survival by sequential treatments for the majority of patients. But they induce a particular toxicity profile. An adequate management of each drug and its sequence in treatment is essential to optimise the outcome and preserve the quality of life (QoL) of patients with mRCC. In forthcoming years, pending results should indicate whether VEGF TKI are of interest in an adjuvant setting and if new drugs targeting will challenge the current standard guidelines in the metastatic setting.

Pulmonary Aspergilloma: An Unexpected Complication of Radiofrequency Ablation in the Management of Targeted Therapy for a Patient With Metastatic Renal Cell Carcinoma

Introduction The medical treatment of metastatic renal cell carcinoma (mRCC) is based on targeted therapy: vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) or mammalian target of rapamycin inhibitor, but the management strategy for mRCC includes local treatment of metastases in selected patients. This has been reported in a retrospective study with an increased rate of survival. This treatment option can be considered for patients with accessible lung lesion(s), offering a clinical benefit (partial response or stable disease) over a long period ( 12-24 months) after targeted therapy. A complete macroscopic local response can be achieved using surgery, radiotherapy, or radiofrequency ablation. We report herein the case of a patient who developed pulmonary aspergilloma in a cavity formed after percutaneous radiofrequency ablation. The patient had previously had long exposure to tyrosine kinase inhibitors (TKIs).

Induction chemotherapy with the EXTREME regimen in frail patients with locally advanced head and neck squamous cell carcinoma

BackgroundInduction chemotherapy (IC) with TPF (docetaxel, cisplatin, 5FU) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) is limited to fit patients.ObjectiveWe conducted a retrospective cohort study to assess the use of the EXTREME regimen (platinum-based therapy, 5FU, cetuximab) as IC in frail patients with LAHNSCC.Patients and methodsRetrospective analysis of all consecutive patients with unresectable LAHNSCC treated with the EXTREME regimen, with or without 5FU as IC, from two French centers from 2008 to 2015. We assessed the rate of completed sequence defined as at least two cycles of IC and definitive radiation therapy.ResultsWe included 34 patients with a median age of 56 years [44-70]. The primary site of tumor development was the oropharynx (67%, n=23, all HPV negative), hypopharynx (21%, n=7) and the oral cavity (12%, n=4). At inclusion, patients presented: T4 76, 5% (n=26), N2c 41% (n=14), N3 26% (n=9), stage disease IVa 62% (n=21), IVb 38% (n=13), ECOG PS2 38% (n=13), decreased weight (10% in one month or 15% in 6 months) 74% (n=25). The sequence was achieved for 76% (n=26) of patients and 80% (n=27) presented a clinical response after the chemotherapy course with notably increased weight (40%, n=11) or general status (75%, n=26). Median PFS and OS were 5.7 and 15.5 months, respectively. Disease progression at 3 months was significantly associated with decreased median overall survival (13.6 versus 21.9 months, p=0.01).ConclusionThis is the first study to report the use of the EXTREME regimen as induction chemotherapy, and although this IC was used in a very frail population, the majority completed the sequence with significant clinical benefit.

Treatment of spinal metastases in renal cell carcinoma: A critical review

Kidney cancer is the 9th most common cancer in men and the 14th most common in women worldwide. Renal cell carcinoma (RCC) constitutes 90% of all malignancies of the kidney. RCC, is known to be highly vascular and relatively radioresistant. Bone metastases are one of the most common metastatic sites and occur in around 30% of RCCs. They significantly impact the quality of life of patients causing pain and pathological fractures. Spinal metastases represent a particular case with regard to symptoms and treatment. Indeed, neurological pain is often added to the nociceptive pain caused by metastases. More importantly, neurological impairment can be seen, caused by spinal cord or nerve root compression (MSCC). Due to close contact with the spinal cord, the treatment of spinal bone metastases is challenging and requires a multidisciplinary approach. Specific treatment is currently focused on 4 main avenues which are surgery, radiotherapy, interventional radiology and systemic treatment. In June 2017 we carried out an extensive search on PubMed, Web of Science, and Cochrane Library to review the various treatment options and to establish a treatment strategy. This article presents the result of our critical review of the literature, given our expertise in the field.

Pulmonary arterial hypertension due to an intratumoral shunt: an unexpected side effect of sunitinib

Department of Medical Oncology, Saint-André Hospital, University Hospital, CHU Bordeaux, France Bordeaux University, Bordeaux, France Department of Cardiology, Saint-André Hospital, University Hospital, CHU Bordeaux, France Department of Urology, Hôpital Pellegrin, University of Bordeaux-CHU Bordeaux, France *Author for correspondence: amaury.daste@chu-bordeaux.fr

Drug Interaction With Sunitinib and the Evidence of Therapeutic Drug Monitoring: A Case Report and Review of the Literature

Sunitinib has demonstrated efficacy, notably in metastatic renal cell carcinoma, but has also induced frequent diverse adverse events and has a large panel of drug interaction, notably with CYP 450. Sunitinib needs close monitoring for frail patients with high risk of side effects or drug interaction. We describe a successful therapeutic pharmacokinetic drug monitoring plan for a patient with a cardiac transplant presenting with metastatic renal cell carcinoma while adapting the dose of sunitinib.

m-TOR inhibitor as potential radiosensitizer for head and neck squamous cell carcinoma: A case report of an organ transplant patient and review of the literature.

A 60-year old patient presented a cT3N2cM0 squamous cell carcinoma of the larynx. Past medical history included a renal transplantation in 2004 due to an IgA nephropathy and 20-pack year smoking history stopped one year before. He received an immunomodulation treatment with mycophenolate mofetil and sirolimus (1 mg/day). Treatment with radiation therapy with 7000 cGy in 35 fractions and weekly cetuximab was decided. Doxycycline was given orally for the prevention of cutaneous toxicity. He presented at the first concomitant dose of cetuximab and radiation therapy a Grade 1 erythema of the head according to CTCAE. At 1000 cGy, the patient presented a Grade 1 mucositis, Grade 1 radio-epithelitis and Grade 2 acneiform rash of the trunk. The dose of cetuximab was then decreased to 200 mg/m (20% decrease). At 2000 cGy, due to the increase of the radio-epithelitis to Grade 2, the dose of cetuximab was again decreased to 125 mg/m (50%). At 4000 cGy, mucositis increased to Grade 4, radio-epithelitis to Grade 2 and consequently cetuximab was definitely withdrawn. Radiation therapy was carried on to completion but the patient required hospitalization for general status alteration and severe pain management requiring intravenous morphine chlorhydrate and feeding tube. Cutaneous toxicity continued to increase to radio-epithelitis Grade 4 but acneiform rash decreased. Sirolimus blood level was normal during the radiation therapy. The cutaneous toxicity and mucositis were still present 1 and 4 months (Photo 1) after the end of radiation therapy (Grade 1). The nasopharyngeal laryngoscopy at 3 months found a complete remission of the laryngeal tumour. The CT scan confirmed the complete response (tumour and lymph nodes). Four months after the end of radiation therapy the patient was hospitalized for staphylococcal cervical spondylitis complicated by neurological deficit. Evolution was favorable under antibiotics with residual neurological deficit. One year later the skin was completely healed with residual depigmentation and there was no sign of relapse of the carcinoma (see Fig. 1). Discussion