The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management ...challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 39-year-old, previously healthy man presented with a left testicular mass, confirmed on ultrasound. He underwent left inguinal orchiectomy, which disclosed testicular carcinoma composed of 90% choriocarcinoma, 9% seminoma, and 1% teratoma. Imaging revealed numerous metastases in the lungs, liver, and brain. Prechemotherapy levels of serum tumor markers were alpha-fetoprotein (AFP) 2.0 ng/mL, human chorionic gonadotropin (hCG) 151,111 IU/L, and lactate dehydrogenase 588 U/L. He received four courses of etoposide, ifosfamide, and cisplatin chemotherapy, given without bleomycin because of the anticipated need for postchemotherapy thoracic surgery. He had an incomplete response to induction chemotherapy. The serum hCG level was 8.1 IU/L, and there were residual lesions in the liver and lungs whereas the brain metastases had nearly resolved. His Eastern Cooperative Oncology Group performance status was zero. He had no symptoms of ototoxicity or peripheral neurotoxicity. Repeat serum hCG levels after chemotherapy were 12.3 IU/L at 2 weeks and 325 IU/L at 4 weeks. He was referred to discuss optimal ongoing treatment.
The optimal sequence of cytoreductive nephrectomy and targeted therapy of metastatic renal cell carcinoma is unclear. We compared overall survival between patients with metastatic renal cell ...carcinoma treated with initial cytoreductive nephrectomy with or without subsequent targeted therapy vs initial targeted therapy with or without subsequent cytoreductive nephrectomy.
We evaluated the records of cases in the National Cancer Database diagnosed with metastatic renal cell carcinoma between 2006 and 2013 who were treated with cytoreductive nephrectomy and/or targeted therapy. Receipt of targeted therapy after initial cytoreductive nephrectomy and cytoreductive nephrectomy after initial targeted therapy were evaluated on competing risks analyses. To account for treatment selection bias, inverse probability of treatment weighting was performed based on the propensity to receive initial cytoreductive nephrectomy or initial targeted therapy. Overall survival was compared between the groups by Kaplan-Meier analysis and Cox proportional hazards regression.
Of the 15,068 patients included in study 6,731 underwent initial cytoreductive nephrectomy and 8,337 received initial targeted therapy. Six months after initial cytoreductive nephrectomy 48.0% of patients received targeted therapy, of whom 15.3% died after initial cytoreductive nephrectomy prior to targeted therapy. Six months after initial targeted therapy 4.7% of patients underwent cytoreductive nephrectomy, of whom 44.9% died after initial targeted therapy prior to cytoreductive nephrectomy. Initial cytoreductive nephrectomy (OR 2.02, 95% CI 1.69–2.43, p <0.001) and cytoreductive nephrectomy after initial targeted therapy (HR 2.6, 95% CI 1.69–4.01, p <0.001) were more likely to be performed at academic vs community institutions. On inverse probability of treatment weighting analysis initial cytoreductive nephrectomy was associated with improved overall survival compared to initial targeted therapy (median 16.5 vs 9.2 months, HR 0.61, 95% CI 0.59–0.64, p <0.001).
Given the greater likelihood of receiving multimodal therapy and the associated overall survival benefit, these data support cytoreductive nephrectomy as the initial approach to metastatic renal cell carcinoma in appropriate surgical candidates. Continued efforts are warranted to establish the optimal multimodal approach in these patients.
Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is ...critical for clinical practice.
To evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types.
PubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018.
Published clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included.
Trial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis.
Incidences of treatment-related adverse events and differences between different drugs and cancer types.
This systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio OR, 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54).
Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.
Clinical features characteristic of small-cell prostate carcinoma (SCPC), "anaplastic," often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based ...chemotherapy in patients meeting at least one of seven prospectively defined "anaplastic" clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy.
A 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity.
Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months 95% confidence interval (CI), 13.6-19.0 months. Of the seven "anaplastic" criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy.
Our findings support the hypothesis that patients with "anaplastic" prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population.
Men with penile squamous cell carcinoma and regional lymph node involvement have a low probability of survival with lymphadenectomy alone. A multimodal approach to treatment is desirable for such ...patients. We performed a phase II study of neoadjuvant chemotherapy with the objective of determining the response rate, time to progression (TTP), and overall survival (OS) among patients with bulky adenopathy.
Eligible patients had stage N2 or N3 (stage III or stage IV) penile cancer without distant metastases. Neoadjuvant treatment (four courses every 3-4 weeks) consisted of paclitaxel 175 mg/m(2) administered over 3 hours on day 1; ifosfamide 1,200 mg/m(2) on days 1 to 3; and cisplatin 25 mg/m(2) on days 1 to 3. Clinical and pathologic responses were assessed, and patient groups were compared for TTP and OS.
Thirty men received chemotherapy of whom 15 (50.0%) had an objective response and 22 (73.3%) subsequently underwent surgery. Three patients had no remaining tumor on histopathology. Nine patients (30.0%) remained alive and free of recurrence (median follow-up, 34 months; range, 14-59 months), and two patients died of other causes without recurrence. Improved TTP and OS were significantly associated with a response to chemotherapy (P < .001 and P = .001, respectively), absence of bilateral residual tumor (P = .002 and P = .017, respectively), and absence of extranodal extension (P = .001 and P = .004, respectively) or skin involvement (P = .009 and P = .012, respectively).
The neoadjuvant regimen of paclitaxel, ifosfamide, and cisplatin induced clinically meaningful responses in patients with bulky regional lymph node metastases from penile cancer.
Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current ...approaches to presenting the evidence in user-friendly formats are fraught with limitations.
To maintain living evidence for contemporary first-line treatment for previously untreated mRCC.
We have created a living, interactive systematic review (LISR) and network meta-analysis for first-line treatment of mRCC using data from randomized controlled trials comparing contemporary treatment options with single-agent tyrosine kinase inhibitors. We applied an advanced programming and artificial intelligence–assisted framework for evidence synthesis to create a living search strategy, facilitate screening and data extraction using a graphical user interface, automate the frequentist network meta-analysis, and display results in an interactive manner.
As of October 22, 2020, the LISR includes data from 14 clinical trials. Baseline characteristics are summarized in an interactive table. The cabozantinib + nivolumab combination (CaboNivo) is ranked the highest for the overall response rate, progression-free survival, and overall survival, whereas ipilimumab + nivolumab (NivoIpi) is ranked the highest for achieving a complete response (CR). NivoIpi, and atezolizumab + bevacizumab (AteBev) were ranked highest (lowest toxicity) and CaboNivo ranked lowest for treatment-related adverse events (AEs). Network meta-analysis results are summarized as interactive tables and plots, GRADE summary-of-findings tables, and evidence maps.
This innovative living and interactive review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated mRCC. Trial-level comparisons suggest that CaboNivo is likely to cause more AEs but is ranked best for all efficacy outcomes, except NivoIpi offers the best chance of CR. Pembrolizumab + axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk. Although network meta-analysis provides rankings with statistical adjustments, there are inherent biases in cross-trial comparisons with sparse direct evidence that does not replace randomized comparisons.
It is challenging to decide the best option among the several treatment combinations of immunotherapy and targeted treatments for newly diagnosed metastatic kidney cancer. We have created interactive evidence summaries of multiple treatment options that present the benefits and harms and evidence certainty for patient-important outcomes. This evidence is updated as soon as new studies are published.
This innovative living and interactive systematic review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated metastatic renal cell carcinoma. The cabozantinib + nivolumab combination is likely to cause more adverse events but is ranked best for all efficacy outcomes, except for ipilimumab in combination with nivolumab (NivoIpi), which offers the best chance of a complete response. Pembrolizumab-axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk.
Objective To retrospectively estimate the efficacy of various treatments used in men with metastatic penile cancer that progresses after first-line chemotherapy. Methods Patients were from a ...30-patient cohort with stage TxN2-3M0 penile squamous cell carcinoma treated with neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy before planned lymphadenectomy. Nineteen patients (63.3%) had tumor progression or recurrence, and we evaluated the response to subsequent treatment and survival. Results Seventeen had received ≥1 salvage therapies; their median survival from first treatment failure was 5.7 months (range, 1.4-30.3 months). Four patients underwent salvage surgery, all of whom experienced further disease progression within 2 months. Four patients received chemoradiotherapy, 1 with stable disease for 13.5 months and 3 with no apparent benefit. Two of 5 evaluable patients (40%) who had received bleomycin, methotrexate, and cisplatin had objective responses (1 complete, 1 partial) but 1 developed fatal pneumonitis. There were no other documented responses to systemic therapy. Median overall survival was 5.6 months for patients who had received a second cisplatin-based treatment at any time and 4.3 months for those who had not ( P = .4). Conclusion Patients whose metastatic penile carcinoma progresses through or recurs after front-line cisplatin-based chemotherapy experience poor responses to the described salvage treatments, with a median overall survival time of <6 months. Emphasis should be placed on clinical trials for development of effective therapy in this setting.
Penile cancer is an uncommon malignancy in the United States and most developed countries, with higher incidence in the developing nations of Africa, Asia, and South America. Standard treatment ...involves a urologist, medical oncologist, and radiation oncologist to deliver multimodal treatment in an integrated fashion. This article will discuss the patterns of specialty referral that are important for men affected by penile cancer.
An electronic literature search using PubMed was conducted. Clinical experience also informed the article.
Nurses and other health care providers caring for patients with penile cancer do not always have prior experience with this rare disease. Referral to a high-volume specialty center for multidisciplinary management is often appropriate. Additionally, evidence suggests that men affected by penile cancer experience a range of unmet supportive care needs involving their physical, psychological, and sexual well-being. Timely and appropriate specialty referrals are a means for helping patients maintain an acceptable quality of life.
It is important that oncology nurses understand and anticipate the need for referrals to specialized centers for definitive treatment of locoregional penile cancer. Nurses are also positioned to facilitate specialty referrals and deliver complex supportive care interventions.
Discovery of effective systemic therapies for patients with advanced penile cancer has been slow to occur. Comprehensive genomic profiling from several studies shed light on the molecular oncogenesis ...of penile squamous cell carcinoma (PSCC) and differences between HPV-related and unrelated tumors. While these two subsets of PSCC appear distinct in their biology, there are not yet specific treatment strategies recommended on that basis. Cell surface proteins have been identified that may potentially serve as drug targets for monoclonal antibodies or small molecule inhibitors. Here, we review some of the new biological insights regarding PSCC that could lead to improved therapies, as well as the related clinical trials recently completed or in progress. We conclude that antibody-drug conjugates are especially promising, as are the combinations of immune checkpoint inhibitors with other types of drugs.
Before the introduction of modern imaging techniques and the recent developments in molecular diagnosis, tumor markers (TMs) were among the few available diagnostic tools for the management of cancer ...patients. Easily obtained from serum or plasma samples, TMs are minimally invasive and convenient, and the associated costs are low. Single TMs were traditionally used but these have come under scrutiny due to their low sensitivity and specificity when used, for example, in a screening setting. However, recent research has shown superior performance using a combination of multiple TMs as a panel for assessment, or as part of validated algorithms that also incorporate other clinical factors. In addition, newer TMs have been discovered that have an increased sensitivity and specificity profile for defined malignancies. The aim of this review is to provide a concise overview of the appropriate uses of both traditional and newer TMs and their roles in diagnosis, prognosis, and the monitoring of patients in current clinical practice. We also look at the future direction of TMs and their integration with other diagnostic modalities and other emerging serum based biomarkers, such as circulating nucleic acids, to ultimately advance diagnostic performance and improve patient management.
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