Timothy Gilligan

Unexpected Association between Induction of Immunity to the Universal Tumor Antigen CYP1B1 and Response to Next Therapy

Purpose: The carcinogen activator cytochrome P450 1B1 (CYP1B1) is expressed on almost all human tumors with rare expression on normal tissues. Anti-CYP1B1–specific T cells kill CYP1B1-expressing tumors, providing the rationale to examine CYP1B1 as a target for immunotherapy. Experimental Design: ZYC300, a plasmid DNA of CYP1B1 encapsulated in biodegradable poly-dl-lactide-coglycolide microparticles, was used in a phase I clinical trial to treat 17 patients with advanced stage, progressive cancer. ZYC300 was administered i.m. at a fixed dose of 400 μg every other week for up to 12 doses. Results: Thirteen patients received six vaccinations and five received all 12 doses. No significant adverse events were observed. Six patients developed immunity to CYP1B1, three of whom developed disease stabilization. All but 1 of 11 patients who did not develop immunity to CYP1B1 progressed and did not respond to salvage therapy. Five patients who developed immunity to CYP1B1 required salvage therapy for progressive metastatic disease and showed marked response to their next treatment regimen, most of which lasted longer than 1 year. Conclusions: The association between immunity to CYP1B1 and response to next salvage therapy was not expected. Because six of the seven patients who had clinical benefit regardless of the nature of salvage therapy had developed immunity to CYP1B1, it seems highly unlikely that this occurred by chance alone. Regardless of the mechanism(s) that induced tumor regression, these findings force us to rethink how the generation of antitumor immunity might be integrated into the treatment of cancer.

American Society of Clinical Oncology Clinical Practice Guideline on Uses of Serum Tumor Markers in Adult Males With Germ Cell Tumors

PURPOSE To provide recommendations on appropriate uses for serum markers of germ cell tumors (GCTs). METHODS Searches of MEDLINE and EMBASE identified relevant studies published in English. Primary outcomes included marker accuracy to predict the impact of decisions on outcomes. Secondary outcomes included proportions of patients with elevated markers and statistical tests of elevations as prognostic factors. An expert panel developed consensus guidelines based on data from 82 reports. RESULTS No studies directly compared outcomes of decisions with versus without marker assays. The search identified few prospective studies and no randomized controlled trials; most were retrospective series. Lacking data on primary outcomes, most Panel recommendations are based on secondary outcomes (relapse rates and time to relapse). RECOMMENDATIONS The Panel recommended against using markers to screen for GCTs, to decide whether orchiectomy is indicated, or to select treatment for patients with cancer of unknown primary. To stage patients with testicular nonseminomas, the Panel recommended measuring three markers (alpha-fetoprotein [AFP], human chorionic gonadotropin [hCG], and lactate dehydrogenase [LDH]) before and after orchiectomy and before chemotherapy for those with extragonadal nonseminomas. They also recommended measuring AFP and hCG shortly before retroperitoneal lymph node dissection and at the start of each chemotherapy cycle for nonseminoma, and periodically to monitor for relapse. The Panel recommended measuring postorchiectomy hCG and LDH for patients with seminoma and preorchiectomy elevations. They recommended against using markers to guide or monitor treatment for seminoma or to detect relapse in those treated for stage I. However, they recommended measuring hCG and AFP to monitor for relapse in patients treated for advanced seminoma.

Chemotherapy for prostate cancer

Androgen deprivation therapy remains the mainstay of therapy for patients with advanced prostate cancer and for selected patients with localized prostate cancer. Androgen deprivation therapy is the model of target-based therapies in this disease. Although it is clear that other target-based therapies need to be developed, cytotoxic chemotherapy is emerging as an effective form of treatment for men with prostate cancer. The early studies combining mitoxantrone plus a corticosteroid demonstrated that chemotherapy could be given to men with symptomatic hormone-refractory prostate cancer with minimal toxicity, and significant palliation could be provided. Since then, it has been recognized that estramustine, when combined with a variety of microtubular inhibitors, is very active in hormone-refractory prostate cancer. Doublets combining estramustine plus a taxane seem to be the most active. Although it appears that estramustine may add some activity to taxanes, the mechanism of its activity is uncertain, and its overall value is similarly questioned, particularly in light of its significant toxicity. Regimens that omit estramustine are being explored (ie, either taxane alone or taxane plus biologic agents). In addition, triplet therapy (combining estramustine plus a taxane plus a third drug, such as carboplatin or etoposide) is being explored. Finally, the utility of chemotherapy is beginning to be explored in the context of earlier disease in the neoadjuvant, adjuvant, or serologically relapsing group of patients. Data from these studies are just beginning to be gathered.

Social disparities and prostate cancer: mapping the gaps in our knowledge

To evaluate the current state of our knowledge regarding social disparities and prostate cancer and to map the domains where substantial knowledge has been acquired as well as those where little is known, with the purpose of identifying important areas for future research.A Medline research was conducted to identify published papers regarding social disparities in prostate cancer since 1990. The results of this review are presented in a social disparities and prostate cancer grid designed to highlight which domains of social disparities have been researched and which neglected.The major social disparity in prostate cancer concerns the extremely high prostate cancer incidence and mortality seen among black Americans. This is also the area where the most research has been performed. Low socioeconomic position is associated with poorer prostate cancer outcomes but not with higher prostate cancer incidence. It remains poorly defined to what extent racial/ethnic differences in prostate cancer result from differences in socioeconomic position (SEP). Understanding the causes of the high prostate cancer mortality seen among black men remains the major challenge in the area of social disparities and prostate cancer.

Guideline on Muscle-Invasive and Metastatic Bladder Cancer (European Association of Urology guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement

PURPOSE To endorse the European Association of Urology guideline on muscle-invasive (MIBC) and metastatic bladder cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS The guideline on MIBC and metastatic bladder cancer was reviewed for developmental rigor by methodologists. The ASCO Endorsement Panel then reviewed the content and recommendations. RESULTS The ASCO Endorsement Panel determined that the recommendations from the European Association of Urology guideline on MIBC and metastatic bladder cancer, published online in March 2015, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses the guideline on MIBC and metastatic bladder cancer and has added qualifying statements, including highlighting the use of chemoradiotherapy for select patients with MIBC and recommending a preference for clinical trials in the treatment of metastatic disease in the second-line setting. RECOMMENDATIONS Multidisciplinary care for patients with MIBC and metastatic bladder cancer is critical. The standard treatment of MIBC (cT2-T4a N0M0) is neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy. In cisplatin-ineligible patients, radical cystectomy alone is recommended. Adjuvant cisplatin-based chemotherapy may be offered to high-risk patients who have not received neoadjuvant therapy. Chemoradiotherapy may be offered as an alternative to cystectomy in appropriately selected patients with MIBC and in some patients for whom cystectomy is not an option. Metastatic disease should be treated with cisplatin-containing combination chemotherapy or with carboplatin combination chemotherapy or single agents in patients ineligible for cisplatin.Additional information is available at http://www.asco.org/endorsements/MIBC and www.asco.org/guidelineswiki.

Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab

Bevacizumab and sunitinib are standard initial therapy in metastatic renal cell carcinoma (mRCC). Despite common use, the safety and activity of sorafenib in bevacizumab‐ or sunitinib‐refractory mRCC have not been prospectively investigated.

Pathological evidence of necrosis in recurrent renal mass following treatment with sunitinib

Abstract:  Sunitinib is a highly potent, selective vascular endothelial growth factor‐receptor types 1 to 3, platelet‐derived growth factor (PDGF)‐R‐α, and PDGF‐R‐ß. Preclinical data suggest that sunitinib (SU11248) has antitumor activity that may result from both inhibition of angiogenesis and direct antiproliferative effects on certain tumor cell types. Sunitinib resulted in tumor shrinkage in 80% of patients who had failed treatment with Bevacizumab and 13% of patients demonstrated an objective Response Evaluation Criteria in solid Tumors (RECIST) in a study presented at the 2006 American Society of Clinical Oncology (ASCO) meeting. We report the first published pathological evidence of sunitinibs effect on recurrent renal cell carcinoma. This was seen in a patient with renal cell carcinoma who developed a renal fossa recurrence 2 years following radical nephrectomy. Tumor shrinkage was evident in the nephrectomy bed after treatment with sunitinib. The pathology of the resected retroperitoneal mass and its implications are discussed.

Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular cancer

Testicular cancer (TC) is the most common neoplasm in males aged 15-40 years. The majority of patients have no evidence of metastases at diagnosis and thus have clinical stage I (CSI) disease [Oldenburg J, Fossa SD, Nuver J et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi125-vi132; de Wit R, Fizazi K. Controversies in the management of clinical stage I testis cancer. J Clin Oncol 2006; 24: 5482-5492.]. Management of CSI TC is controversial and options include surveillance and active treatment. Different forms of adjuvant therapy exist, including either one or two cycles of carboplatin chemotherapy or radiotherapy for seminoma and either one or two cycles of cisplatin-based chemotherapy or retroperitoneal lymph node dissection for non-seminoma. Long-term disease-specific survival is ∼99% with any of these approaches, including surveillance. While surveillance allows most patients to avoid additional treatment, adjuvant therapy markedly lowers the relapse rate. Weighing the net benefits of surveillance against those of adjuvant treatment depends on prioritizing competing aims such as avoiding unnecessary treatment, avoiding more burdensome treatment with salvage chemotherapy and minimizing the anxiety, stress and life disruption associated with relapse. Unbiased information about the advantages and disadvantages of surveillance and adjuvant treatment is a prerequisite for informed consent by the patient. In a clinical scenario like CSI TC, where different disease-management options produce indistinguishable long-term survival rates, patient values, priorities and preferences should be taken into account. In this review, we provide an overview about risk factors for relapse, potential benefits and harms of adjuvant chemotherapy and active surveillance and a rationale for involving patients in individualized decision making about their treatment rather than adopting a uniform recommendation for all.

A Phase II Study of Pazopanib in Patients with Localized Renal Cell Carcinoma to Optimize Preservation of Renal Parenchyma

PURPOSE Preservation of renal function is prioritized during surgical management of localized renal cell carcinoma. VEGF targeted agents can downsize tumors in metastatic renal cell carcinoma and may do the same in localized renal cell carcinoma, allowing for optimal preservation of renal parenchyma associated with partial nephrectomy. MATERIALS AND METHODS Localized clear cell renal cell carcinoma patients meeting 1 or both of the following criteria were enrolled in a prospective phase II trial, including radical or partial nephrectomy likely to yield a glomerular filtration rate of less than 30 ml/minute/1.73 m(2), or partial nephrectomy high risk due to high complexity (R.E.N.A.L. 10 to 12) or tumor adjacent to hilar vessels. Pazopanib (800 mg once daily) was administered for 8 to 16 weeks with repeat imaging at completion of therapy, followed by surgery. RESULTS A total of 25 patients enrolled with a median tumor size of 7.3 cm and a median R.E.N.A.L. score of 11. Of index lesions 80% were high complexity and 56% of patients had a solitary kidney. Patients received a median of 8 weeks of pazopanib. The median interval from treatment start to surgery was 10.6 weeks. R.E.N.A.L. score decreased in 71% of tumors and 92% of patients experienced a reduction in tumor volume. Six of 13 patients for whom partial nephrectomy was not possible at baseline were able to undergo partial nephrectomy after treatment. The mean parenchymal volume that could be saved with surgery increased from an estimated 107 to 173 cc (p = 0.0015). In 5 patients a urine leak developed, which was managed conservatively, and 7 received a transfusion, of whom 1 required embolization. CONCLUSIONS Neoadjuvant pazopanib resulted in downsizing localized renal cell carcinoma, allowing for improved preservation of renal parenchyma and enabling partial nephrectomy in a select subset of patients who would otherwise require radical nephrectomy.

Defining the Optimal Treatment for Clinical Stage I Nonseminomatous Germ Cell Testicular Cancer Using Decision Analysis

PURPOSE There is equipoise regarding the optimal treatment of clinical stage (CS) I nonseminomatous germ cell testicular cancer (NSGCT). Formal mechanisms that enable patients to consider cancer outcomes, treatment-related morbidity, and personal preferences are needed to facilitate decision making between retroperitoneal lymph node dissection (RPLND), primary chemotherapy, and surveillance. METHODS Decision analysis was performed using a Markov model that incorporated likelihoods of survival, treatment-related morbidity, and utilities for seven undesired post-treatment health states to estimate the quality-adjusted survival (QAS) for each treatment option. Utilities were obtained from 24 hypothetical NSGCT patients using a visual analog (rating) scale and standard gamble. Results Overall, QAS associated with each treatment was high and differences in QAS were small. Surveillance was the preferred intervention for patients with a risk of relapse less than 33% and 37% using the rating scale and standard-gamble method of utility assessment, respectively. Active treatment was favored over surveillance for patients with relapse risk on surveillance greater than 33% and 37% by the rating scale (RPLND preferred) and standard-gamble methods (primary chemotherapy preferred), respectively. Substantial differences in average utilities were seen depending on the method used. By the rating scale, patients substantially devalued life in six of seven undesired health states but they were surprisingly tolerant of treatment-related morbidity using standard gamble. CONCLUSION A decision model has been developed for CS I NSGCT that estimates QAS for RPLND, primary chemotherapy, and surveillance by considering cancer outcomes, morbidity, and patient preferences. Surveillance was the preferred intervention for all except those patients at high risk for relapse.