The expectation for survival in patients with advanced melanoma now exceeds 50% at 5 years in patients treated with first-line combination ipilimumab and nivolumab, despite this regimen being ...associated with substantial toxicity. We discuss the latest updates from the Checkmate-067 study, framing the role of this combination in practice today.
Non-clear cell renal cell carcinoma (nccRCC) is an entity comprised of a heterogeneous constellation of RCC subtypes. Genomic profiling has broadened our understanding of molecular pathogenic ...mechanisms unique to individual nccRCC subtypes. To date, clinical trials evaluating the use of immunotherapies and targeted therapies have predominantly been conducted in patients with clear cell histology. A comprehensive review of the literature has been undertaken in order to describe molecular pathogenic mechanisms pertaining to each nccRCC subtype, and concisely summarise findings from therapeutic trials conducted in the nccRCC space.
Highlights • Role of immune checkpoint inhibition in the management of key malignancies. • Description of rates of immune-related adverse events and timing of their onset. • Management strategies for ...immune-related toxicities.
Reported here is a case of rapidly progressive metastatic castration-resistant prostate cancer treated with 177LuLu-PSMA-617 in the setting of severe renal impairment and impending ureteric ...obstruction. PSMA is expressed on renal tubular cells, raising the possibility of radiation-induced nephrotoxicity, and this level of renal impairment would typically exclude the patient from 177LuLu-PSMA-617 therapy. Multidisciplinary input, individualized dosimetry, and patient-specific dose reduction were used to ensure the cumulative dose to the kidneys remained within acceptable limits. He was initially planned for treatment with six cycles of 177LuLu-PSMA-617. However, he had an excellent response to therapy following four cycles of treatment and the last two cycles were omitted. He has been followed for 1-year posttherapy without evidence of disease recurrence. No acute or chronic nephrotoxicity was observed. This case report highlights the utility of 177LuLu-PSMA-617 therapy in severe renal impairment and provides evidence of relative safety in patients who would otherwise not be considered candidates for therapy.
Plain language summary
This report presents a case of a man with aggressive metastatic prostate cancer who received 177LuLu-PSMA-617 therapy, despite having severely reduced kidney function and worsening ureter obstruction. This treatment could have potential side effects on kidney function, but the medical team used a personalized approach to reduce patient risk. The man was initially planned to have six cycles of therapy, but his excellent response to treatment after four cycles meant the last two cycles were not given. The man has been followed for 1 year after treatment and has not experienced any worsening kidney function. This case shows the safe and effective use of 177LuLu-PSMA-617 therapy in a patient with severely reduced kidney function who would not normally qualify for this treatment.
Other reported presentations involving the CNS are: aseptic meningitis (15% of patients with neurological irAES in Cuzzubbo’s review of 59 clinical trials (9)) - CSF in such cases often has a ...lymphocyte predominance and symptoms are generally steroid-responsive (11); and multiple sclerosis-like syndromes including transverse myelitis and optic neuritis (7,11). Compared with a control group of patients with idiopathic MG, those with ICI-related MG had a predilection for more a severe and rapidly deteriorating disease course, including respiratory muscle involvement and myasthenic crisis warranting respiratory support (13). Investigations Investigating patients with suspected neurological irAEs requires exclusion of differential diagnoses, which may often require urgent treatment to prevent life-threatening complications, such as hypophysitis, malignancy (parenchymal or leptomeningeal disease or paraneoplastic syndromes) infection or stroke (12). Where other potentially life-threatening conditions form part of the differential diagnosis, these should also be treated empirically, for instance, viral or bacterial meningitis.
Neurological adverse events from immune checkpoint inhibition are increasingly recognised, especially with combination anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) and anti-programmed death receptor ...1 (anti-PD-1) therapies. Their presenting symptoms and signs are often subacute and highly variable, reflecting the numerous components of the nervous system. Given the risk of substantial morbidity and mortality, it is important to inform patients of symptoms that may be of concern, and to assess any suspected toxicity promptly. As with other immune-related adverse events, the cornerstone of management is administration of corticosteroids. Specialist neurology input is vital in this group of patients to guide appropriate investigations and tailor treatment strategies.
The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 ...macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.
•Stereotactic ablative body radiotherapy.•Stereotactic ablative radiotherapy.•Renal Cell Carcinoma Oligometastasis.•Renal Cell Carcinoma Oligoprogression.•Patient selection for stereotactic ablative ...radiotherapy.
Stereotactic ablative body radiotherapy (SABR) aims to accurately deliver a higher than conventional dose of radiotherapy to a well-defined target tumour incorporating advanced immobilisation and imaging techniques. SABR is an emerging treatment option for primary kidney cancer especially when surgery is contraindicated. Increasingly, SABR is being incorporated into the management of low-volume stage IV kidney cancers to delay the need for systemic therapy or to prolong the duration of ongoing systemic treatment. This review will evaluate the evidence and limitations of SABR for oligometastatic renal cell carcinoma.
Standard approved systemic treatment options for the management of renal cancer have entirely transformed in the last 15 years and now comprise molecularly targeted therapies against the vascular ...endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR) as well as immune checkpoint inhibitors. These agents may be used alone as monotherapies but increasingly are used in various combinations. The associated important improvements in cancer control and survival have therefore been accompanied by a range of new toxicities. Good management of these toxicities is important for patient safety and quality of life, and also to optimize patients’ opportunity to continue with and therefore benefit from these therapies. The most common toxicities associated with VEGFR tyrosine kinase inhibitors are fatigue, skin rashes, gastrointestinal, stomatitis, hypertension and other cardiovascular toxicities, and hematological and endocrine dysfunction. Common side effects of mTOR inhibitors include asthenia, stomatitis, skin rashes, pneumonitis, metabolic changes and infections. Checkpoint inhibitors can lead to toxicities of any organ system with those seen most frequently including dermatologic, gastrointestinal and hepatic, endocrine, musculoskeletal, and pulmonary, whilst renal, hematological, ophthalmic, cardiac and neurological toxicities are seen less often. In general terms, toxicity management should start preemptively with patient education and may also include a combination of supportive approaches, dose reduction, schedule alteration, treatment interruption and occasionally treatment cessation. Treatment of individual toxicities is dependent on the likely causative agent and is guided by its grade or severity. Specific recommendations for management are discussed in this chapter.
BackgroundImmune-related diarrhoea/colitis (ir-D/C) is a common adverse event of immune checkpoint inhibitor (ICI) therapy. Guidelines recommend corticosteroid (CS) treatment; however, the average ...treatment duration for ir-D/C remains poorly defined.MethodsAll advanced melanoma patients treated with ICI therapy at the Royal Marsden Hospital between 2011 and 2016 were reviewed to identify ir-D/C cases alongside clinical variables.Results117 any-grade ir-D/C episodes occurred in 109 (21%) patients out of a total of 519 patients treated (ipilimumab=77 episodes, anti-PD1=17 (nivolumab or pembrolizumab), ipilimumab and nivolumab=23 (ipi+nivo)) (seven patients had ir-D/C more than once on different lines of treatment) and >/=grade 3 ir-D/C occurred most frequently (63/519 patients (12%) vs 29/519 (5%) grade 1, and 25/519 (5%) grade 2). Median onset (days) of all-grade ir-D/C after starting ICI therapy was 41 for ipilimumab (IQR 24 to 59, n=77), 91 for anti-PD1 (IQR 46 to 355, n=17) and 45 for ipi+nivo (IQR 24 to 67, n=23). In 71/117 (61%) patients, ir-D/C episodes were treated with CS (17% grade 2; 79% grade 3/4): 54 being steroid-responsive; 17 being steroid-refractory and received additional anti-tumor necrosis factor (TNF) treatment. Median grade 3 ir-D/C CS duration was similar across treatments, averaging 58 days. Median overall CS duration (days) was longer in the grade 3/4 D/C steroid-refractory group (94 vs 45 days). Infection developed in 11/71 (15%) CS recipients and in 6/17 (35%) anti-TNF recipients. In 65/117 (55%) patients, ir-D/C episodes were investigated with flexible sigmoidoscopy. Of these patients, 38/65 (58%) had macroscopic colitis and 12/65 (18%) had microscopic colitis. The steroid-refractory group had more macroscopic changes, 13/17 (76%), than the steroid-responsive group, 22/41 (54%).ConclusionRates of grade 3 ir-D/C were higher than reported in clinical trials. The 58-day median duration of CS therapy for grade 3 ir-D/C places a significant number of patients at risk of complications. We demonstrate that microscopic colitis is an important subgroup, advocating biopsies in ir-D/C even with macroscopically normal bowel.
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