Search

New combinations of antiangiogenic tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) or dual ICI have been shown to be effective in phase III trials compared to sunitinib in the first-line treatment of metastatic renal cell cancer. While ICI doublet is already used in other indications, TKI/ICI combinations are more recent and the management of their adverse effects (AEs) are less well known, particularly with regard to the accountability of each therapeutic class. The objective of this article is to analyze the safety data from the main phase III studies to provide clinicians with practical advice for managing the AEs from these combinations. Their management depends largely on the type of combination and their grade. In the case of a TKI/ICI combination, discontinuation of the 2 molecules is considered from grade 2. Rapid improvement in symptoms suggests that the AE is related to the TKI. It is then possible, after resolution, to reintroduce the TKI, if needed by reducing the dose, and to continue the ICI. Otherwise, the blame falls on the ICI and treatment usually involves corticosteroids. Management also depends on the type of AE and its severity. In some cases (dysthyroidism), treatment with TKI/ICI may be continued. In other situations (cardiac or neurological toxicity), it should be discontinued from grade 1 and hospitalization and corticosteroid therapy should be considered immediately. In all cases, information and education are integral parts of the prevention and proper management of potential AEs., (Copyright © 2022. Published by Elsevier Masson SAS.)

Castration-resistant prostate cancer was subjected to a paradigm switch from hormone resistance to androgen deprivation therapy resistance during the last decade. Indeed, new therapeutics targeting the androgen receptor showed clinical efficacy in patients with progressive disease under castration. Thus, it is a proof that the AR remains a dominant driver of oncogenesis in earlier-called hormone resistant prostate cancer. This review summarizes the molecular mechanisms involved in castration-resistant prostate cancer., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Sunitinib was the first targeted therapy improving progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) in the first line of treatment. Classically, sunitinib is administered at a dose of 50 mg/day during four weeks followed by two weeks off (schedule 4/6). This schedule has two pitfalls: intermittent exposure with two weeks "off" and the increase in toxicity during the fourth week. Several alternative prescription schedules were studied with the aim of limiting the intensity of toxicity while maintaining efficacy. This review summarizes the published data on alternative schedules of sunitinib in terms of safety and efficacy. All articles and abstracts on alternative schedule of sunitinib in the mRCC were reviewed. Clinical trials were also searched. Studies evaluating the continuous schedule have not provided evidence of its superiority compared to the 4/6 schedules in terms of activity, tolerance or dose-intensity. Retrospective data of patients treated in a schedule two weeks of treatment "on" one week "off" (schedule 2/3) with sunitinib 50 mg/day show PFS that seem superior to those obtained with a schedule 4/ 6, while having a better safety profile. The alternating schedule of sunitinib 2/3 (50 mg/day) may be a better alternative to schedule 4/6 in terms of tolerance. If toxicity occurs with 50 mg/day on a schedule 4/6, it would probably offer a better alternative in terms of efficiency than dose reduction. The results of ongoing and future studies are expected to prospectively validate the concept.

In 2010, results of the TROPIC study demonstrated that, when compared to mitxantrone, the novel taxane cabazitaxel improved median overall survival of patients with metastatic castration-resistant prostate cancer who progressed on or after docetaxel treatment. We report the data on efficacy and toxicity observed in the subgroup of patients included in the French centers. In this phase III randomized international trial, patients received prednisone and were treated with either 25 mg/m(2) cabazitaxel or 12 mg/m(2) mitoxantrone intravenously every three weeks. The primary endpoint was overall survival. The secondary endpoints included progression-free survival (PFS) and safety. Analyses were performed on the intention-to-treat population. Among the 90 patients enrolled in France, the median overall survival was 18 months for the cabazitaxel arm versus 14.3 months for the mitoxantrone arm. An improvement in PFS was also observed, with a median of 1.4 months for the mitoxatrone arm compared to a median of 2.5 months for the cabazitaxel arm. The most common grade ≥ 3 adverse events were hematologic with neutropenia, usually afebrile and digestive with 4 % of patients reporting diarrhea. These results are comparable to those reported for the overall population and the safety profile remains favorable without any toxic death related to cabazitaxel.

Advanced or metastatic renal carcinoma represents a frequent disease in oncologic practice. Few years ago, in immunotherapy era, treatments had quickly reached deadlock. New therapies targeting vascular endothelial growth factors and their receptors (VEGF-R), sorafenib, sunitinib and bevacizumab, and the mammalian target of rapamycin (mTOR), temsirolimus and everolimus, have modified these patients prognosis and their quality of life in a few years. Nevertheless, patients included in randomized trials presented severe inclusion criteria. Then in the daily practice, patients have distinctive characteristics which were not evaluated in large pivotal studies: poor performance status, older patients, renal dysfunction, cerebral metastases or non clear cell renal cancer. In published trials, a few data concerning these situations are reported, and these studies have often included small samples, were retrospective or not randomised. However compared to global population, tolerance have not been very different in geriatric patients, or patients with poor performance status, or with central neurological metastases, or with papillary and chromophobe sub-types. On the contrary progression free or overall survivals increases are more difficult to confirm. Also before starting treatment, ratio between potential benefit and possible toxicities have to be evaluated. In patients with renal insufficiency, VEGF receptor inhibitors seem to be cautiously initiated at reduced doses, and to be increased according to tolerance. Due to these poor proof levels, clinical trials are needed for these specific populations.

Radical cystectomy with bilateral pelvic lymph node dissection is the standard of care for patients with muscle-invasive bladder cancer, with 5-year survival rates not exceeding 60%. Consequently a multidisciplinary approach including perioperative chemotherapy and/or radiation therapy is required to improve these results. Data from clinical trials and meta-analyses with neoadjuvant chemotherapy have shown a significant benefit in overall survival, with a 5% absolute benefit at five years, provided cisplatin-based combination chemotherapy is used. Reported trials do not support the routine use of adjuvant chemotherapy. The current role of radiation therapy is limited to highly selected cases with a combination of external radiotherapy, partial cystectomy and interstitial brachytherapy.

Identification of prognostic factors in renal cell carcinoma is very important today for three goals: providing patient information, giving appropriate treatments and selecting patients for adapted treatment schedules as well as new clinical trials. Prognostic factors in RCC include: anatomical (TNM classification), histological (Fuhrmann grade and histological subtype), clinical (symptoms and performance status) and molecular factors. For improving predicative accuracy of prognostic systems such as the TNM classification, new prognostic algorithms or nomograms have been designed combining independent prognostic variables. UISS and SSIGN are the 2 most effective prognostic systems within localized RCC. In metastatic disease, the two main systems that have been used for predicting response to immunotherapy are the model of the French Group of Immunotherapy and the Motzer model. With the arrivals of new molecular factors, these systems will perhaps have to evaluate: these new systems will require further validation as part of large prospective clinical trials.

The daily management of urogenital cancers is currently based on prognostic classifications derived from the identification of independent clinical or biological indicators of overall survival. These classifications are used for patient stratification in clinical trials and definition of appropriate strategies according to prognostic groups. Their knowledge is therefore essential for optimizing treatment decisions. Metastatic germ cell tumours and renal cell cancers as well as localised prostate cancers are classical models for the development of such classifications. The emergence of targeted therapies and the identification of predictive parameters for treatment efficacy should represent a further step towards the emergence of individualized treatments in the near future.

Angiogenesis targeting with inhibitors of VEGF receptors is currently modifying in depth the treatment strategy of metastatic clear cell renal carcinoma. Although immunotherapy remains prescribed in selected patients with good prognosis, sunitinib and sorafenib are presently the most active agents in this malignancy. The results available, in terms of response as in terms of progression-free survival, argue in favour of the use of sunitinib in first line. The two agents have distinct toxicity profiles, which may lead in the future to select the treatment as a function of an individual patient basis. Preliminary results suggest the possibility of partial cross-resistance between them.