Jorge Ramos

Clinical Correlates of Benefit From Radium-223 Therapy in Metastatic Castration Resistant Prostate Cancer

We sought to identify potential clinical variables associated with outcomes after radium‐223 therapy in routine practice.

Characterizing the Morbidity of Postchemotherapy Retroperitoneal Lymph Node Dissection for Testis Cancer in a National Cohort of Privately Insured Patients

OBJECTIVE To characterize morbidity of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for testis cancer, we analyze a contemporary national database. PC-RPLND is the standard for residual radiographic masses ≥1 cm (nonseminoma) and positron emission tomography-avid masses ≥3 cm (seminoma). Morbidity for PC-RPLND is greater than primary RPLND, which may be mitigated by performing surgery at a high-volume cancer center. METHODS Current Procedural Terminology and International Classification of Diseases, Ninth Edition codes identified men with testis cancer undergoing PC- or primary RPLND in MarketScan (2007-2012). Multivariable logistic regression assessed factors associated with receiving adjunctive procedures (ie, nephrectomy, vascular reconstruction), prolonged hospitalization, and 90-day readmission. Geographic variables assessed regionalization of PC-RPLND. RESULTS Of 559 men with claims for PC- or primary RPLND (206, 37% PC-RPLND), 19% of PC-RPLND underwent adjunctive procedures (vs 1% among RPLND, P  <  .01). For PC-RPLND, the nephrectomy rate was 10% and the vascular reconstruction rate was 8%. On multivariable analysis, PC-RPLND was associated with undergoing adjunctive procedures (odds ratio 41.9; 95% confidence interval 11.7, 150) and prolonged hospitalization (odds ratio 3.75; 95% confidence interval 1.68, 8.42) compared to primary RPLND. PC-RPLND was not associated with 90-day readmission. Up to 29% of PC-RPLNDs are performed in centers, billing just a single case through MarketScan in the 6 years studied. CONCLUSION PC-RPLND is associated with adjunctive procedures and longer hospitalizations. Given the morbidity of PC-RPLND in this young patient population, efforts are needed to establish quality benchmarks for, reduce the morbidity of, and to accurately discriminate risk during patient discussions prior to this complex, specialized surgery.

The Khorana Score in Predicting Venous Thromboembolism for Patients With Metastatic Urothelial Carcinoma and Variant Histology Treated With Chemotherapy

Background: The Khorana score is a predictive risk model for venous thromboembolism (VTE) in patients with cancer planning to receive chemotherapy. Urothelial carcinoma and variant histologies (UC/VH) were underrepresented in the model. We sought to evaluate whether the Khorana score predicts for VTE in a retrospective multinational data set of patients with metastatic UC/VH. Methods: Patients diagnosed with metastatic UC/VH who received chemotherapy were eligible. Those with incomplete or miscoded data were excluded. Khorana scores were calculated based on the pretreatment data and categorized into high (≥3) or intermediate (1-2) VTE risk. Other patient-, tumor-, and therapy-related factors were also analyzed. The χ2 and logistic regression analyses were used to assess differences in VTE rates based on the clinical characteristics. Subgroup analyses were performed to evaluate the Khorana score and associated variables for early (<3 months) and late (>3 months) VTE. Results: A total of 943 patients were eligible for analysis. The cumulative VTE rate was 9.9%. There was no statistical difference in overall VTE rate between Khorana high- and intermediate-risk groups (P = .16). In the multivariate analysis, nonurothelial histology (odds ratio [OR] = 2.56; P = .002) and the presence of cardiovascular disease (CVD) or CVD risk factors (OR = 2.14; P = .002) were associated with increased VTE risk. In the first 3 months from initiation of chemotherapy, Khorana high risk (OR = 2.08; P = .04) was associated with higher VTE rates. White blood cell (WBC) count (OR = 1.05; P = .04) was the only significant Khorana variable for early VTE. Conclusions: The Khorana score stratifies early but not overall VTE risk in patients with metastatic UC/VH. The WBC count drives the increased early VTE risk seen with the Khorana score.

Venous thromboembolism in metastatic urothelial carcinoma or variant histologies: incidence, associative factors, and effect on survival

Venous thromboembolism (VTE) is common in cancer patients. However, little is known about VTE risk in metastatic urothelial carcinoma or variant histologies (UC/VH). We sought to characterize the incidence, associative factors, including whether various chemotherapy regimens portend different risk, and impact of VTE on survival in metastatic UC/VH patients. Patients diagnosed with metastatic UC/VH from 2000 to 2013 were included in this multicenter retrospective, international study from 29 academic institutions. Cumulative and 6‐month VTE incidence rates were determined. The association of first‐line chemotherapy (divided into six groups) and other baseline characteristics on VTE were analyzed. Each chemotherapy treatment group and statistically significant baseline clinical characteristics were assessed in a multivariate, competing‐risk regression model. VTE patients were matched to non‐VTE patients to determine the impact of VTE on overall survival. In all, 1762 patients were eligible for analysis. There were 144 (8.2%) and 90 (5.1%) events cumulative and within the first 6 months, respectively. VTE rates based on chemotherapy group demonstrated no statistical difference when gemcitabine/cisplatin was used as the comparator. Non‐urotheilal histology (SHR: 2.67; 95% CI: 1.72–4.16, P < 0.001), moderate to severe renal dysfunction (SHR: 2.12; 95% CI: 1.26–3.59, P = 0.005), and cardiovascular disease (CVD) or CVD risk factors (SHR: 2.27; 95% CI: 1.49–3.45, P = 0.001) were associated with increased VTE rates. Overall survival was worse in patients with VTE (median 6.0 m vs. 10.2 m, P < 0.001). Thus, in metastatic UC/VH patients, VTE is common and has a negative impact on survival. We identified multiple associated potential risk factors, although different chemotherapy regimens did not alter risk.

Progress in Understanding What Is Being Statin(ed) in Prostate Cancer.

tation status) on objective response rates with nivolumab, although this difference was not observed in the overall data analysis reported by Larkin et al.1 Furthermore, while there are data to suggest synergy between BRAF-directed therapy and PD-1 blockade (an area of active investigation, although not approved for clinical use), current data do not support clear differences in clinical response rates to PD-1 blockade that can be related to the drug mechanism of action of prior BRAF inhibitor therapy. However, factorsassociatedwithpriorBRAF inhibition,suchasanincreased baseline tumor size after prior therapy, may have an impact on response rates to PD-1 blockade, as previously described.2 Overall, the results do suggest a similar response rate to PD-1 blockade in patients with and without BRAF mutant melanoma in this retrospective data analysis including a heterogeneous study population. The results are also consistent with those of priorstudiesofimmunetherapywithipilimumab3 inwhichBRAF mutation status does not have an impact on objective response rates and are also consistent with a prior report of PD-1 blockade with pembrolizumab in which response rates were similar in the BRAF-mutant and nonmutant patients enrolled in a large clinical trial.4 A prospective randomized clinical study in a uniform study population would be required to confirm that response rates are truly equal in patients with or without BRAF-mutant melanoma, and in patients with and without prior BRAF inhibitor therapy among the BRAF-mutant patients. The results are applicable to patients similar to those eligible for the clinical trials included in the analysis; that is, patients with a good performance status and normal organ function can be considered for treatment with PD-1 blockade with nivolumab regardless of BRAF mutation status. However, clinicians should exercise caution in applying these results to patients who would not meet the trial eligibility criteria of the study population—for example, patients with a poor performance status, because response rates to nivolumab may not be similar in patients with and without BRAF mutations in a nontrial population. BRAF-directed therapy may offer a higher chance of response and clinical benefit in some patients with BRAF-mutant melanoma and should be considered in all patients with BRAF-mutant melanoma. It is clear that patients both with and without BRAFactivating mutations gain benefit from PD-1 blockade, with durable responses observed in both subsets of patients, regardless of prior therapies. Ongoing studies will further define the role of sequencing of BRAF-targeted therapy and PD-1 or CTLA-4 blockade on clinical outcomes. Clinical trials that include PD-1 blockade as well as novel immune therapy combination studies or targeted therapy combination studies can be considered among the first line of therapy options for all patients with advanced melanoma.

Making urothelial carcinomas less immune to immunotherapy.

The success of immune checkpoint inhibitors in advanced urothelial carcinoma provides patients with the prospect for durable objective responses. However, the majority of patients do not respond to immune checkpoint blockade. Several potential predictive biomarkers of response have been evaluated in hopes of better identifying likely responders, though each has been shown to have limitations. Going forward, development of reliable predictive biomarkers is imperative. Likewise, innovative treatment combination approaches to convert non-responders to responders are essential to continue making progress in the field.

Long-Term Survival in Bone-Predominant Metastatic Urothelial Carcinoma

Bladder cancer is the most commonly diagnosed malignancy of the genitourinary tract. In 2013, an estimated 74,690 new cases were diagnosed and there were 15,580 deaths from bladder cancer in the United States.[1] The predominant histologic subtype is urothelial, accounting for 90% of cases in developed countries.[2] Superficial, non-muscle invasive urothelial carcinoma accounts for 70% of new bladder cancer diagnoses.[3] High-risk, typically high grade and T1 lesions, will progress to invade the muscularis propria in 20-25% of patients.[4] The remainder of new diagnoses are either muscle-invasive, locally advanced or metastatic urothelial carcinoma. Approximately 50% of patients with muscle-invasive disease will have a distant recurrence after radical cystectomy.[5] Unfortunately, metastatic urothelial carcinoma portends a very poor prognosis. Treatment with standard first-line chemotherapy regimens such as gemcitabine/cisplatin (GC) or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) leads to a median overall survival of only approximately 15 months.[6, 7] Furthermore, despite better detection modalities and molecular understanding of the disease, there has been no significant improvement in survival over the past twenty years. Interestingly, a small subset of patients with metastatic disease are long-term survivors, with 5-year survival rates of 6.8%.[7], but there is limited data describing which patient- or tumor-related features associate with long-term survival. Here, we present two patients with bone-predominant metastatic urothelial cancer who have had prolonged survival with limited treatment. We also discuss current understanding of prognostic factors in metastatic urothelial carcinoma, and summarize potential future areas of investigation. Case 1 A 65-year-old male with a long-standing smoking history presented with gross hematuria. A computed tomography (CT) scan showed a mass in the left lateral bladder wall and indeterminate size right-sided pelvic lymph nodes. The patient then underwent cystoscopy and transurethral resection of bladder tumor (TURBT) with pathology showing a high-grade urothelial carcinoma with evidence of muscle invasion with focal areas concerning for lymphovascular invasion. The patient then completed 3 cycles of dose-dense MVAC with follow-up imaging showing only some irregular wall thickening in the left bladder wall. He was then, unfortunately, lost to follow-up for several months. Approximately 11 months following initial presentation, the patient re-established care and was found on imaging to have evidence of recurrence in the left lateral bladder wall. This was completely resected and pathology was consistent with the earlier specimen. Following this TURBT, the patient underwent concomitant chemoradiation with low-dose weekly cisplatin and subsequent imaging revealed no evidence of disease. Approximately 21 months from initial diagnosis, he developed severe right shoulder pain with subsequent pathologic fracture. The patient was taken to the operating room for fixation and biopsy with pathology showing metastatic urothelial carcinoma. He was then treated with palliative radiotherapy. Restaging bone scan showed multiple osseous metastases involving both the axial and appendicular skeleton. There was no evidence of liver or lung metastases on CT. He was enrolled on a clinical trial of combination docetaxel and vandetanib for 4 months until restaging imaging showed progression into the soft tissue of the pre-existing bony metastatic lesions in the right ischium and right posterior 5th rib. The patient then received 4 cycles of gemcitabine and paclitaxel before going on a treatment holiday with every 3-6 month surveillance imaging. After 3 years off therapy and almost 6 years since diagnosis, bone scan continued to not show any signs of recurrence (Figure 1). However, surveillance CT imaging revealed new jejunal thickening. He underwent a small bowel resection with pathology confirming recurrence of previously diagnosed urothelial primary with evidence of perineural and lymphovascular invasion. The patient has now been surveyed for 6 months since the surgery, with reimaging every 3 months without any further evidence of disease recurrence. Figure 1 A. Bone scan prior to initiation of chemotherapy with gemcitabine and paclitaxel Case 2 A 74-year-old male presented with superficial, non-muscle invasive urothelial carcinoma and was treated with multiple TURBTs and intravesicular BCG. Three years after initial presentation, he developed hematuria. Cystoscopy with TURBT revealed progression to high-grade muscle-invasive urothelial cancer and evidence of carcinoma in situ but no lymphovascular invasion in the left lateral bladder wall. The patient underwent chemoradiotherapy with weekly paclitaxel at a dose of 50 mg/m2 after declining radical cystectomy. Four months after completing concomitant chemoradiation, the patient presented with neck pain and was noted to have cervical spine metastases at C1, C3, and C4 on CT. A biopsy was consistent with metastatic urothelial cancer. He underwent proton beam radiation therapy to the cervical spine and subsequent spinal fusion. Restaging CT scan revealed prominent peri-aortic and aorto-caval lymph nodes, the largest measuring 1.6 cm in diameter. Bone scan imaging demonstrated new bony metastatic disease in the sternum, ribs, left scapula, and multiple thoracic vertebrae. He then completed 6 cycles of chemotherapy with gemcitabine and cisplatin with complete regression of all suspicious retroperitoneal lymph nodes. He has continued with surveillance imaging every 3-6 months for 2 years without evidence of soft tissue or bony disease progression despite being off all treatment (Figure 2). Figure 2 A. Bone scan prior to initiation of chemotherapy B. Bone scan 20 months after completion of chemotherapy Discussion Our early understanding of prognosis in metastatic bladder cancer is based on long-term follow-up of an intergroup trial comparing cisplatin to MVAC.[8] In this analysis, non-urothelial histology, poor performance status, and the presence of either bone or liver metastases were found to be poor prognostic features.[9] Subsequently, Bajorin et al. also demonstrated that patients with poor performance status and/or the presence of “visceral metastases” had worse outcomes in a cohort of patients treated with MVAC.[10] In this and later studies, “visceral metastases” were grouped and defined as the presence of either liver, lung, and/or bone metastases. Interestingly, though significant in the univariate analysis, liver, lung, and bone metastases were not independently prognostic in the multivariate analysis. Since then, multiple other studies have shown similar results indicating the importance of “visceral metastases” on outcomes in metastatic urothelial cancer.[11-14] However, none of these studies defined bone metastases as an independent predictor of poor outcome. Conversely, in two studies, the presence of liver metastases alone conferred worse outcomes, with bone metastases not influencing survival.[15, 16] Taken together, these studies suggest that the number of sites of metastases and possibly the presence of liver metastases drive the poor prognosis in metastatic urothelial cancer and bone involvement may not negatively affect prognosis. Our report describes two cases of long-term survival in patients with bone-predominant metastatic urothelial cancer. In review of the literature, only one other report of this phenomenon was identified.[17] In that report, a 38 year old patient with biopsy-proven metastatic urothelial cancer only to bone received 6 cycles of carboplatin and gemcitabine with complete radiographic resolution of all sites of disease. He then underwent radical cystoprostatectomy and pelvic lymph node dissection with pathology also demonstrating a complete response in the surgical specimen. After two years, the patient did not have evidence of disease recurrence. Bone is an unrecognized, relatively common site of metastasis of from urothelial carcinoma. Reports estimate the frequency of bone metastases range from 25-47%.[18] However, only 5-15% of patients with urothelial cancer will have bone as the only site of metastatic disease.[18, 19] Neither the prognosis nor mechanism of development of bone-predominant metastatic urothelial cancer have been clearly elucidated. One recent study indicated that older patients had a higher frequency of single-site metastasis, including to bone, based on ICD-9 coding of hospitalized patients.[20] Potentially, as evidenced in this report, bone-predominant disease may be indicative of a good prognosis. One possible mechanism may be that the genetic changes in tumors of patients with bone only or bone predominant metastases may be associated with either a specific treatment-sensitivity or a less aggressive disease phenotype. An example of the former would be case 1, a patient whose disease progressed rapidly after initiating therapy with docetaxel and vandetanib, but had a dramatic and prolonged response to gemcitabine and paclitaxel. Furthermore, recent work suggests that 69% of invasive urothelial bladder carcinomas have targetable genomic alterations, particularly along the PI3K/Akt/mTOR and RTK/MAPK pathways.[21] By utilizing gene sequencing panels to identify and subsequently target these actionable mutations, we may be able to achieve better long term outcomes, not only in bone-predominant disease, but all patients with metastatic urothelial carcinoma.

Venous thromboembolism risk in patients with locoregional urothelial tract tumors

Background Venous thromboembolism (VTE) is common in cancer patients, but there is limited data on patients with urothelial tract tumors (UTT). We previously identified several associative factors for increased VTE rates in patients with metastatic UTT. In this study, we assessed the frequency, associative factors, and impact on survival of VTE in patients with locoregional UTT. Methods Patients with locoregional bladder, upper urinary tract, or urethral cancer were included in this multi‐center study from 29 academic institutions. Patients with < cT2, > N1, or M1 disease at diagnosis were excluded. Patients with incomplete clinical staging or miscoded/missing data were excluded. Cumulative, unadjusted VTE incidence was calculated from time of diagnosis of muscle‐invasive disease, excluding VTEs diagnosed in the metastatic setting. χ2 statistics tested differences in VTE rates across baseline and treatment‐related factors. Significant covariates were incorporated into a multivariate, logistic regression model. Overall survival stratified by VTE was estimated using Kaplan‐Meier methods and evaluated using the log‐rank test. Results A total of 1732 patients were eligible. There were 132 (7.6%) VTEs. On multivariate analysis, non‐urothelial histology (P < .001), clinical Nx stage (P < .001), cardiovascular disease (P = .01), and renal dysfunction (P = .04) were statistically significant baseline factors associated with VTE. Using surgery alone as reference, surgery with perioperative chemotherapy (P = .04) and radiation with concurrent chemotherapy (P = .04) also were significant. Conclusions The VTE incidence of 7.6% in locoregional disease is comparable with our previously reported rate in the metastatic setting (8.2%). Similar to our findings in metastatic UTT, non‐urothelial histology, renal dysfunction, and CVD was associated with increased VTE risk. Micro‐Abstract There is limited data on venous thromboembolism (VTE) risk in patients with locoregional urothelial tract tumors. We performed a multicenter, retrospective study of 1732 patients assessing VTE rate, associative factors, and impact on survival in this population. Our study identified a high VTE rate (7.6%) and several factors associated with increased risk including non‐urothelial histology, renal dysfunction, and cardiovascular disease.

Cardiovascular Mortality in Testicular Nonseminomatous Germ Cell Tumors: Does Statistical Significance Imply Clinical Significance?

Testicular germ-cell tumors (GCTs) represent one of the few solid tumors in which the majority of patients with metastatic disease are cured. In 2015, it is estimated that there will be 8,430 new occurrences and only 380 deaths as a result of testicular cancer. Treatment for testicular GCTs involves radical orchiectomy in almost all patients, regardless of the extent of disease. Subsequent treatment options, which depend on disease stage, include active surveillance, retroperitoneal lymph node dissection (RPLND), and cytotoxic chemotherapy. Radiation therapy is also an option in patients diagnosed with pure seminoma. With the implementation and refinement of cisplatin-based combination chemotherapy in the late 1970s and 1980s, approximately 80% of all patients with metastatic GCTs now are cured. Therefore, understanding the acute and long-term effects associated with treatment for a largely curable disease is important to optimize the care of this patient population. In the article accompanying this editorial, using the SEER database, Fung et al compared the cardiovascular disease (CVD) mortality risk in 15,006 patients with nonseminomatous germ-cell tumors (NSGCTs) who either received chemotherapy as part of their initial treatment plan (n 6,909) or underwent surgery alone (n 8,097) with the CVD mortality risk in the general population. Compared with the general population, there was an increased risk in CVD mortality in patients who were treated with chemotherapy; however, there was no difference in CVD mortality in the surgery-alone group. In total, 54 cardiovascular deaths occurred in the chemotherapy group, and 50 occurred in the surgery-only group. Of interest, the statistically significant increase in CVD mortality in the chemotherapy group compared with the general population was limited to the first year after the diagnosis of testicular NSGCT. In the first year after diagnosis, 11 patients who received chemotherapy for the treatment of testicular NSGCT, versus two patients in the surgery-only group, had a cardiovascular cause of death. Several population-based, observational studies have shown an increased long-term risk of developing CVD in testicular GCT survivors. The most likely explanation for the increased incidence of CVD seen in this patient population is the early development of atherosclerotic disease, possibly secondary to metabolic syndrome. Willemse et al demonstrated a 1.9-fold increased risk of developing metabolic syndrome in testicular GCT survivors and a 2.3-fold higher risk in the subgroup that received chemotherapy compared with healthy men as controls. The mechanism for the development of metabolic syndrome in long-term survivors is not completely understood but may be associated, in part, with hypogonadism that results from cytotoxic chemotherapy. Conversely, Fung et al hypothesize that their novel finding of early CVD mortality may at least partially occur through the direct toxic effect of cisplatin on the vascular system and the resultant endothelial dysfunction. SEER is a large, population-based cancer database that provides extensive information on demographics, tumor characteristics, and initial treatment modalities. The SEER registries also collect and report data on vital status and cause of death, which allow for the study of cancer incidence, survival, and trends in care over time. However, it is important to be aware of some pitfalls when analyses are conducted with the SEER database. First, analyses from SEER are limited by the potential inherent confounders and bias associated with any retrospective analysis. In addition, the heterogeneity and lack of granularity in the SEER-coded causes of death may make the true etiology less clear. In the study by Fung et al, the SEER-coded diseases of heart account for six of the 11 deaths in the chemotherapy group in the first year after testicular NSGCT diagnosis, which suggests an arterial thrombotic event as the cause of death. However, this SEER category also includes the International Classification of Diseases 9th and 10th revisions codes for acute pulmonary embolism, a venous thromboembolic event (VTE). There is abundant evidence that cisplatin increases the risk of VTE in a multitude of malignancies. In testicular GCTs, the estimated thromboembolic (arterial and venous) rate has ranged from 8.4% to 18% in patients who received cisplatin-based chemotherapy. Greater than 80% of the events were VTE in these studies. It is also established that VTE leads to increased mortality in patients with cancer. Because there is a known predominance of VTE associated with cisplatin, the inclusion of pulmonary embolism in the analysis may have contributed significantly to the CVD mortality seen in the chemotherapy group in the study by Fung et al. In addition to the aforementioned six deaths as a result of diseases of heart, the remaining five deaths in the first year resulted from cerebrovascular diseases. This SEER-coded category also is heterogeneous, because it is not possible to discern whether the deaths as a JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 28 OCTOBER 1 2015