Diana H. Cauley

Cancer immunotherapy: sipuleucel-T and beyond.

In April 2010, sipuleucel‐T became the first anticancer vaccine approved by the United States Food and Drug Administration. Different from the traditional chemotherapy agents that produce widespread cytotoxicity to kill tumor cells, anticancer vaccines and immunotherapies focus on empowering the immune system to overcome the tumor. The immune system consists of innate and adaptive components. The CD4+ and CD8+ T cells are the most crucial components of the adaptive arm of the immune system that act to mediate antitumor responses. However, T‐cell responses are regulated by intrinsic and extrinsic mechanisms, which may interfere with effective antitumor responses. Many anticancer immunotherapies use tumor‐associated antigens as vaccines in order to stimulate an immune response against tumor cells. Sipuleucel‐T is composed of autologous mononuclear cells incubated with a fusion protein consisting of a common prostate cancer antigen (prostatic acid phosphatase) linked to an adjuvant (granulocyte‐macrophage colony‐stimulating factor). It is postulated that when the vaccine is infused into the patient, the activated antigen‐presenting cells displaying the fusion protein will induce an immune response against the tumor antigen. In a recent randomized, double‐blind, placebo‐controlled, phase III clinical trial, sipuleucel‐T significantly improved median overall survival by 4.1 months in men with metastatic castration‐resistant prostate cancer compared with placebo. Although overall survival was improved, none of the three phase III clinical trials found a significant difference in time to disease progression. This, along with cost and logistic issues, has led to an active discussion. Although sipuleucel‐T was studied in the metastatic setting, its ideal place in therapy is unknown, and clinical trials are being conducted in patients at different stages of disease and in combination with radiation therapy, antiandrogen therapy, and chemotherapy. Various other anticancer vaccines and immunotherapies for other tumor types are currently under investigation and in clinical trials. These immunotherapies were formulated to incorporate tumor‐associated antigens aimed at stimulating effector T‐cell responses or to block regulatory mechanisms that suppress the function of effector T cells. Additional studies will determine how these therapies can best improve clinical outcomes in patients with cancer.

Mammalian target of rapamycin (mTOR) inhibitor‐associated non‐infectious pneumonitis in patients with renal cell cancer: predictors, management, and outcomes

To characterise the incidence, onset, management, predictors, and clinical impact of mammalian target of rapamycin (mTOR) inhibitor‐associated non‐infectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma (mRCC).

mTOR inhibitor associated noninfectious pneumonitis in patients with renal cell cancer: management, predictors, and outcomes

To characterise the incidence, onset, management, predictors, and clinical impact of mammalian target of rapamycin (mTOR) inhibitor‐associated non‐infectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma (mRCC).

Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis

Background Nonseminomatous germ cell tumor of the testis (NSGCT) is largely curable. However, a small group of patients develop refractory disease. We investigated the hypothesis that intratumoral heterogeneity contributes to the emergence of chemoresistance and the development of refractory tumor subtypes. Results Our institutions records for January 2000 through December 2010 included 275 patients whose primary tumor showed pure embryonal carcinoma (pure E); mixed embryonal carcinoma, yolk sac tumor, and teratoma (EYT); or mixed embryonal carcinoma, yolk sac tumor, seminoma, and teratoma (EYST). Patients with EYST had the highest cancer-specific mortality rate (P = .001). They tended to undergo somatic transformation (P = .0007). Two of 5 patients with clinical stage I EYST who had developed recurrence during active surveillance died of their disease. Materials and Methods In this retrospective study, we evaluated consecutive patients who had been diagnosed with the three most common histological phenotypes of NSGCT. Chemoresistance was defined as the presence of teratoma, viable germ cell tumor, or somatic transformation in the residual tumor or the development of progressive or relapsed disease after chemotherapy. In a separate prospective study, we performed next-generation sequencing on tumor samples from 39 patients to identify any actionable genetic mutations. Conclusions Our data suggest that patients with EYST in their primary tumor may harbor a potentially refractory NSGCT phenotype and are at increased risk of dying from disease. Despite intratumoral heterogeneity, improved patient selection and personalized care of distinct tumor subtypes may optimize the clinical outcome of patients with NSGCT.

Proteinuria with first-line therapy of metastatic renal cell cancer.

Background Vascular endothelial growth factor receptor inhibitors, mammalian target of rapamycin inhibitors, and tyrosine kinase inhibitors are approved for metastatic renal cell cancer. Proteinuria can occur, but there is limited data regarding the incidence, monitoring, and management in metastatic renal cell cancer patients. Objective Our primary objective was to describe the incidence and severity of proteinuria in metastatic renal cell cancer patients treated in the first-line setting with pazopanib, bevacizumab, or everolimus. Methods We conducted a retrospective review of patients with metastatic renal cell cancer enrolled from January 2011–April 2013 in a phase II trial. Baseline and toxicity data were extracted from the electronic medical record. Descriptive statistics were used. Results In all, 129 patients were eligible for analysis. The overall incidence of proteinuria was 81%, with most events being Grade 1 or 2. The incidence of proteinuria was 80% (n = 35) for pazopanib, 64% (n = 25) for bevacizumab, and 96% (n = 44) for everolimus. At peak proteinuria, 80% (n = 28), 64% (n = 16), and 80% (n = 35) of patients on pazopanib, bevacizumab, and everolimus, respectively, were managed with continued monitoring at the same dose. The overall incidence of Grades 3 and 4 events was 24% (n = 6) and found in the bevacizumab group. Conclusion A high incidence of proteinuria with minor severity within each class was demonstrated. It may be reasonable to continue therapy at the same dose for Grade 1 or 2 proteinuria. Treatment modification or discontinuation of therapy may be warranted with Grade 3 or 4 proteinuria.

Safety of Same-day Pegfilgrastim Administration in Metastatic Castration-resistant Prostate Cancer Treated With Cabazitaxel With or Without Carboplatin

Micro‐Abstract Although myeloid growth factors are commonly used to treat metastatic castration‐resistant prostate cancer, the optimal timing of administration has not been well studied. We demonstrate that same‐day pegfilgrastim administration after cabazitaxel treatment with or without carboplatin in patients with metastatic castration‐resistant prostate cancer is feasible. Furthermore, we observed that the rate of urinary tract inflammation was higher than that reported anecdotally. Introduction: Although myeloid growth factors are commonly used to treat metastatic castration‐resistant prostate cancer (mCRPC), the optimal timing of administration has not been well studied. We assessed the effects of same‐day pegfilgrastim, a neutrophil stimulator, after cabazitaxel treatment with or without carboplatin in patients with mCRPC. We also evaluated the frequency of urinary tract inflammation during treatment. Patients and Methods: Between September 2010 and September 2014, 151 consecutive patients with mCRPC underwent cabazitaxel treatment with or without the addition of carboplatin at a single institution. We assessed absolute neutrophil count recovery, incidence of neutropenia, neutropenic fever, antibiotic usage, treatment delays or discontinuation, dose reduction, and hospitalization with pegfilgrastim administration. Radiologists blinded to therapy reviewed computed tomography scans to detect urinary tract inflammation. Results: The median patient age was 69 years (range, 41‐88 years); 78% of patients were white, and 54% had a Gleason score ≥ 9. Median overall survival was 9 months (95% confidence interval, 8‐11 months). One patient (< 1%) had neutropenia; 38 patients (25%) had infection. During cycle 1, a significantly higher proportion of patients receiving pegfilgrastim after 24 hours developed infection than did those receiving pegfilgrastim the same day (26% vs. 6%; P = .01). Conclusion: Same‐day pegfilgrastim administration after cabazitaxel treatment with or without carboplatin in patients with mCRPC is feasible. The urinary tract inflammation rate (21%) was higher than that reported anecdotally. Results need to be prospectively validated.

Outcomes of Adults With Ewing Sarcoma Family of Tumors (esft) of the Kidney: A Single-institution Experience

Background: Ewing sarcoma family of tumors (ESFT) of the kidney are exceedingly rare. Given the rarity of this neoplasm and the complexity associated with its management, information regarding treatment and outcome is warranted. Materials and Methods: We conducted a retrospective study of patients with ESFT of the kidney who were treated at MDACC between January 1, 2001 and January 1, 2011. Descriptive statistics were used. Results: Thirteen patients were identified (median age, 33 y; male:female 11:2). Common presenting symptoms were back pain, flank pain, and hematuria. Six patients had metastatic disease at presentation. Initial diagnostic biopsy was performed in 6 patients. Immunohistochemistry showed strong positivity for CD99 (mic2) and cytogenetic analysis demonstrated evidence of EWSR1 fusion gene in 8 cases. Nine patients underwent nephrectomy. Frequently used chemotherapy regimens consisted of vincristine, doxorubicin, and ifosfamide. Median overall survival was 17.2 months. Three patients were alive at the time of analysis, at 2, 7, and 11 years from diagnosis (the latter without evidence of disease). Conclusions: Renal ESFT carry a guarded prognosis with limited response to therapy and short median overall survival. For patients with metastatic disease, diagnostic biopsy and sarcoma-based chemotherapy regimens are recommended as upfront therapeutic strategy. The role of nephrectomy in the metastatic setting is unclear. Future studies with novel therapies are needed.

Neuroendocrine Tumors of the Kidney: A Single Institution Experience

BACKGROUND Renal NETs, comprised of carcinoid tumors and small cell carcinomas, are a rare group of neoplasms. The rarity of these tumors pose a diagnostic and therapeutic challenge. Our purpose was to characterize the cases treated at a tertiary cancer center and to evaluate patient outcomes with the available treatment modalities. PATIENTS AND METHODS This was a retrospective study of patients with renal NETs seen at The University of Texas M.D. Anderson Cancer Center between January 1, 2001, and January 1, 2011. Patient and tumor data were analyzed using descriptive statistical methods. RESULTS Three cases of carcinoid tumors and 6 cases of small cell carcinoma were identified. The median age at diagnosis was 53 years for patients with carcinoid and 65 years for patients with small cell carcinoma. The most common presenting symptoms were back pain, flank pain, and hematuria. The morphological appearance of the tumor cells and their immunohistochemical reactivity for neuroendocrine markers and cytokeratin helped establish the diagnosis. Nephrectomy was the mainstay of treatment for carcinoid tumors, yielding good long-term results, even in the presence of metastases. Surgery and chemotherapy were used for small cell carcinoma of the kidney. The median overall survival for patients with small cell carcinoma of the kidney was 17.3 months. CONCLUSION Renal carcinoid tumors are indolent and are associated with prolonged survival, and small cell carcinomas of the kidney are aggressive tumors with relatively short overall survival. Although palliative in nature, cytotoxic chemotherapy is the mainstay of therapy and is best given before surgery.

Everolimus (E) and temsirolimus (T) associated pneumonitis (P) in patients with metastatic renal cell cancer (mRCC): A single-center experience.

401 Background: P is a known adverse effect (AE) of mammalian target-of-rapamycin inhibitors, with a literature reported incidence of 25-45%. The goal of this review was to characterize the incidence, timing, management, and overall survival (OS) of pts treated at our center. METHODS Retrospective review of 332 patients (pts) with complete, evaluable records, who received E and/or T between 6/1/2007 and 10/1/2010. Clinical correlation was made in conjunction with serial radiologic imaging studies. RESULTS P occurred in 25.2 of E and 8.1 % of T pts. 10.7 of E and 11.1 % of T pts reported no symptoms (sx). 60.7 and 72.2 % reported cough, 67.9 and 61.1 % dyspnea, 17.9 and 5.6 % fever, and 67.9 and 88.9 % fatigue, with E and T, respectively. The median # of sx/pt was 2 and 3; 42.9 and 50 % received steroids, 35.7 and 22.2 % received antibiotics, 21.4 and 27.8 % had a pulmonary consult, and 10.7 and 16.7 % received oxygen, with E and T, respectively. Providers discontinued tx in 75 and 38.9%, continued tx in 17.9 and 27.8%, continued at reduced dose in 0 and 5.6%, held and later dose reduced in 7.1 and 16.7%, and held then resumed at same dose in 0 and 11.1% of pts, with E and T, respectively. The median NCI-CTC P grade was 2 (range 1-3) in both groups. No patients died from P. CONCLUSIONS A higher incidence of P was observed in pts treated with E than T. The finding of improved OS in pts who develop P with E is intriguing and should be further investigated. [Table: see text].

Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: predictors, management, and outcomes: mTOR inhibitor-associated non-infectious pneumonitis in patients with RCC

To characterise the incidence, onset, management, predictors, and clinical impact of mammalian target of rapamycin (mTOR) inhibitor‐associated non‐infectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma (mRCC).