Prognostic risk stratification derived from individual patient level data for men with advanced penile squamous cell carcinoma receiving first-line systemic therapy

Pond, Gregory R.; Lorenzo, Giuseppe Di; Necchi, Andrea; Eigl, Bernhard J.; Kolinsky, Michael; Chacko, Raju Titus; Dorff, Tanya B.; Harshman, Lauren C.; Milowsky, Matthew I.; Lee, Richard J.; Galsky, Matthew D.; Federico, Piera; Bolger, Graeme B.; deShazo, Mollie; Mehta, Amitkumar; Goyal, Jatinder; Sonpavde, Guru

doi:10.1016/j.urolonc.2013.10.007

Cited by 33 publications

(18 citation statements)

References 29 publications

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“…The negative prognostic value of visceral disease observed in this study was consistent with a previously published retrospective analysis of 140 patients with penile squamous cell carcinoma receiving first-line systemic therapy, which showed visceral disease had an increased hazard ratio for death of 2.42 (95% CI: 1.47–4.00) (Pond et al, 2014). Also, in a study including 26 patients treated with concurrent chemo-radiotherapy for advanced penile cancer, a trend for a detrimental prognostic effect of visceral disease was reported (HR = 3.35; 95% CI: 0.69–16.21; P = 0.13).…”

Section: Discussionsupporting

confidence: 92%

“…Prognostic nomograms have been reported in patients with localized disease undergoing surgery (Kattan et al, 2006) and also in patients with metastatic disease receiving first-line systemic treatment (Pond et al, 2014), Unfortunately, there is a lack of such prognostic classifications for patients receiving second or later-line salvage systemic treatment for advanced penile cancer, i.e., locally advanced unresectable or metastatic disease. Prognostic classifications/models may be useful for the interpretation of phase II trial outcomes, especially in the particular case of penile carcinoma, since the rarity of the disease makes it difficult to conduct large, randomized-controlled trials.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic and Predictive Factors in Patients with Advanced Penile Cancer Receiving Salvage (2nd or Later Line) Systemic Treatment: A Retrospective, Multi-Center Study

et al. 2016

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Introduction and objectives: Metastatic penile squamous cell carcinoma (PSCC) is associated with dismal outcomes with median overall survival (OS) of 6–12 months in the first-line and <6 months in the salvage setting. Given the rarity of this disease, randomized trials are difficult. Prognostic risk models may assist in rational drug development by comparing observed outcomes in nonrandomized phase II studies and retrospective data vs. predicted outcomes based on baseline prognostic factors in the context of historically used agents. In this retrospective study, we constructed a prognostic model in the salvage setting of PSCC patients receiving second or later line systemic treatment, and also explored differences in outcomes based on type of treatment.Materials and methods: We performed a chart review to identify patients with locally advanced unresectable or metastatic PSCC who received second or later line systemic treatment in centers from North America and Europe. The primary outcome was OS from initiation of treatment, with secondary outcomes being progression-free survival (PFS) and response rate (RR). OS was estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify prognostic factors for outcomes using univariable and multivariable models.Results: Sixty-five patients were eligible. Seventeen of 63 evaluable patients had a response (27.0%, 95% confidence interval [CI] = 16.6–39.7%) and median OS and PFS were 20 (95% CI = 20–21) and 12 (95% CI = 12, 16) weeks, respectively. Visceral metastasis (VM) and hemoglobin (Hb) ≤ 10 gm/dl were consistently significant poor prognostic factors for both OS and PFS, and Hb was also prognostic for response. The 28 patients with neither risk factor had a median OS (95% CI) of 24 (20–40) weeks and 1-year (95% CI) OS of 13.7% (4.4–42.7%), while the 37 patients with 1 or 2 risk factors had median OS (95% CI) of 20 (16–20) weeks and 1-year (95% CI) OS of 6.7% (1.8–24.9%). Cetuximab-including regimens were associated with a trend for improved RR compared to other agents (Odds ratio = 5.05, 95% CI = 0.84–30.37, p = 0.077). Taxanes vs. non-taxane, and combination vs. single agent therapy was not associated with improved outcomes. The study is limited by its modest sample size.Conclusion: This is the first prognostic classification proposed for patients receiving salvage systemic therapy for advanced PSCC. The presence of VM and Hb ≤ 10 gm/dl was associated with poor OS and PFS. Cetuximab appeared to be associated with better RR. This prognostic model may assist in salvage therapy drug development for this orphan disease by improving interpretation of outcomes seen in nonrandomized data.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Prognostic and Predictive Factors in Patients with Advanced Penile Cancer Receiving Salvage (2nd or Later Line) Systemic Treatment: A Retrospective, Multi-Center Study

et al. 2016

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“…Hence, clinical trials with an objective of seeking signals of biologic and anti-tumor activity when using inhibitors of these pathways require attention. In this context, it is known that cisplatin-based chemotherapy appears to be the most optimal first-line regimen, which accords with the presence of defects in DNA damage repair engendered by BRCA alterations [2]. Additionally PARP inhibitors may warrant evaluation in those with somatic BRCA alterations.…”

Section: Discussionmentioning

confidence: 99%

Kinase analysis of penile squamous cell carcinoma on multiple platforms to identify potential therapeutic targets

Yang

Willey

Mehta³

et al. 2017

Oncotarget

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Penile squamous cell carcinoma (PSCC) is an orphan malignancy with poorly understood biology and suboptimal systemic therapy. Given that kinases may be drivers and readily actionable, we performed comprehensive multiplatform analysis of kinases in PSCC tumor and normal tissue. Fresh frozen tumors were collected from 11 patients with PSCC. After macrodissection to demarcate tumor from normal tissue, the samples underwent multiplatform analysis of kinases. Next Generation Sequencing (NGS) of 517 kinase genes was performed using Agilent Kinome capture and run on the Illumina MiSeq at PE150bp. The NanoString nCounter® platform analyzed the expression of 519 kinase genes. Kinase activity of tissue lysates was measured using PamStation®12 high-content phospho-peptide substrate microarray system. Network mapping was done with GeneGo MetaCore™ and upstream kinase prediction was performed with BioNavigator and the Kinexus database. Ingenuity pathway analysis was performed to integrate elevated kinase activity and gene over-expression with coexisting missense mutations at DNA level. Top pathways upregulated in both the kinase activity and gene expression platforms were PTEN, STAT3, GNRH, IL-8 and B cell receptor signaling. Potentially relevant missense mutations were seen in 176 kinase genes, with the top altered pathways overlapping with gene overexpression being GNRH, NF-kB and STAT3 signaling. ERBB2, ERBB3 and SYK were altered on NGS and also exhibited elevated kinase activity. To summarize, multiplatform comprehensive analysis of kinases discovered potential drivers of PSCC and actionable therapeutic targets. Translational studies are necessary to validate the functional relevance of our data to make advances in this rare malignancy.

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“…In patients with bulky or fixed inguinal lymph node metastasis or distant metastasis, neoadjuvant chemotherapy followed by surgery is also recommended. Cisplatin-based chemotherapy regimens have been shown to improve outcomes in patients with advanced-stage disease compared to non-cisplatin-based chemotherapy regimens [2,11]. Furthermore, taxanes can enhance the efficacy of the regimen [2,12].…”

Section: Discussionmentioning

confidence: 99%

Cisplatin, Methotrexate and Bleomycin for Advanced Recurrent or Metastatic Penile Squamous Cell Carcinoma

Yumura¹,

Kasuga²,

Kawahara³

et al. 2017

Andrology

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Objective: This study aimed to evaluate the efficacy and toxicity of cisplatin, methotrexate, and bleomycin (CMB) chemotherapy in patients with advanced, recurrent, or metastatic penile squamous cell carcinoma (PSCC). Methods:The CMB regimen was administered to 12 patients with advanced (n=7), recurrent (n=4), or metastatic Results:Of the 7 patients with advanced disease who received the CMB regimen as neoadjuvant and/or adjuvant treatment, 5 survived, 1 died of local recurrence and lung metastasis, and 1 died of interstitial pneumonia. Three of the 5 patients with recurrent or metastatic disease died of PSCC. One patient died of interstitial pneumonia due to CMB. Only 1 patient with inguinal lymph node metastasis after penectomy who underwent adjuvant CMB regimen had survived. Eight patients who were disease free survived longer than those who still had the disease. No adverse hematological effects of Grade 3 or higher were observed. Conclusion:The CMB regimen might be effective for advanced PSCC, but not for recurrent or metastatic PSCC. Two patients died of interstitial pneumonitis due to chemotherapy. Hence, we believe that the CMB regimen should not be used as a first-line treatment option in patients with advanced-stage or metastatic PSCC.

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Prognostic risk stratification derived from individual patient level data for men with advanced penile squamous cell carcinoma receiving first-line systemic therapy

Cited by 33 publications

References 29 publications

Prognostic and Predictive Factors in Patients with Advanced Penile Cancer Receiving Salvage (2nd or Later Line) Systemic Treatment: A Retrospective, Multi-Center Study

Prognostic and Predictive Factors in Patients with Advanced Penile Cancer Receiving Salvage (2nd or Later Line) Systemic Treatment: A Retrospective, Multi-Center Study

Kinase analysis of penile squamous cell carcinoma on multiple platforms to identify potential therapeutic targets

Cisplatin, Methotrexate and Bleomycin for Advanced Recurrent or Metastatic Penile Squamous Cell Carcinoma

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