Integrating chemohormonal therapy and surgery in known or suspected lymph node metastatic prostate cancer.

BACKGROUND: Prostate cancer persisting in the primary site after systemic therapy may contribute to emergence of resistance and progression. We previously demonstrated molecular characteristics of lethal cancer in the prostatectomy specimens of patients presenting with lymph node metastasis after chemohormonal treatment. Here we report the post-treatment outcomes of these patients and assess whether a link exists between surgery and treatment-free/cancer-free survival. METHODS: Patients with either clinically detected lymph node metastasis or primaries at high risk for nodal dissemination were treated with androgen ablation and docetaxel. Those responding with PSA concentration <1 ng ml(-1) were recommended surgery 1 year from enrollment. ADT was withheld postoperatively. The rate of survival without biochemical progression 1 year after surgery was measured to screen for efficacy. RESULTS: Forty patients were enrolled and 39 were evaluable. Three patients (7.7%) declined surgery. Of the remaining 36, 4 patients experienced disease progression during treatment and 4 more did not reach PSA <1. Twenty-six patients (67%) completed surgery, and 13 (33%) were also progression-free 1 year postoperatively (8 with undetectable PSA). With a median follow-up of 61 months, time to treatment failure was 27 months in the patients undergoing surgery. The most frequent patterns of first disease recurrence were biochemical (10 patients) and systemic (5). CONCLUSIONS: Half of the patients undergoing surgery were off treatment and progression-free 1 year following completion of all therapy. These results suggest that integration of surgery is feasible and may be superior to systemic therapy alone for selected prostate cancer patients presenting with nodal metastasis.

Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with pazopanib after disease progression with other targeted therapies.

AIM: The multi-tyrosine kinase inhibitor pazopanib prolongs progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory metastatic clear-cell renal cell carcinoma (ccRCC). Outcomes and safety data with pazopanib after targeted therapy (TT) are limited. METHODS: We retrospectively evaluated records of consecutive patients with metastatic ccRCC who had progressive disease (PD) after TT and received pazopanib from November 2009 through November 2011. Tumour response was assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumours (RECIST). PFS and overall survival (OS) were estimated by Kaplan-Meier methods. RESULTS: Ninety-three patients were identified. Median number of prior TTs was 2 (range, 1-5). There were 68 events (PD or death). Among 85 evaluable patients, 13 (15%) had a partial response. Median PFS was 6.5 months (95% CI: 4.5-9.7); median OS was 18.1 months (95% CI: 10.26-NA). Common adverse events (AEs) included fatigue (44%), elevated transaminases (35%), diarrhoea (30%), hypothyroidism (18%), nausea/vomiting (17%), anorexia (14%) and hypertension exacerbation (14%); 91% of AEs were grade 1/2. Eleven patients (12%) discontinued therapy due to AEs. There were no treatment-related deaths. CONCLUDING STATEMENT: Pazopanib demonstrated efficacy in patients with metastatic ccRCC after PD with other TTs. Toxicity overall was mild/moderate and manageable.

Penile cancer: current therapy and future directions.

Background Penile cancer (PC) is a rare cancer in western countries, but is more common in parts of the developing world. Due to its rarity and the consequent lack of randomized trials, current therapy is based on retrospective studies and small prospective trials. Design Studies of PC therapy were searched in PubMed and abstracts at major conferences. Results PC is generally an aggressive malignancy characterized by early locoregional lymph node (LN) spread and later metastases in distant sites. Given the strong predictive value of LN involvement for overall survival, evaluating regional LNs is critical. Advanced LN involvement is increasingly being treated with multimodality therapy incorporating chemotherapy and/or radiation. A single superior cisplatin-based regimen has not been defined. Further advances may occur with a better collaboration on an international scale and comprehensive understanding of tumor biology. To this end, the preventive role of circumcision and understanding of the oncogenic roles of Human Papilloma Virus-16, and smoking may yield advances. Preliminary data suggest a role for agents targeting epidermal growth factor receptor and angiogenesis. Conclusion Advances in therapy for PC will require efficient trial designs, synergistic collaboration, incentives to industry and the efforts of patient advocacy groups and venture philanthropists.

Outcome of patients with metastatic renal cell carcinoma treated with targeted therapy without cytoreductive nephrectomy.

BACKGROUND: Cytoreductive nephrectomy (CN) became a standard procedure in metastatic renal cell carcinoma (mRCC) in the immunotherapy era. Historically, median overall survival (OS) of patients treated with interferon alpha (IFN-α) without CN was 7.8 months. Median OS in patients treated with targeted therapy (TT) without CN is unknown. PATIENTS AND METHODS: We retrospectively reviewed records of patients with mRCC who received TT without CN. Kaplan-Meier methods and Cox regression analysis were used to estimate median OS and identify poor prognostic factors. RESULTS: One hundred and eighty-eight patients were identified. Most patients had intermediate-risk (54.8%) or poor-risk (44.1%) disease. Median OS for all patients was 10.4 months [95% confidence interval (CI) 8.1-12.5]. By multivariable analysis, elevated baseline lactate dehydrogenase and corrected calcium, performance status of two or more, retroperitoneal nodal metastasis, thrombocytosis, current smoking, two or more metastatic sites, and lymphopenia were independent risk factors for inferior OS. Patients with four or more factors had increased risk of death (hazard ratio 8.83, 95% CI 5.02-15.5, P < 0.001) and 5.5-month median OS. Nineteen patients (10.0%) survived for 2+ years. CONCLUSIONS: These data highlight the improved OS of patients with mRCC treated with TT without CN, compared with historical IFN-α treatment, and may guide the design of trials investigating the role of CN in the TT era.

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings.

The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 x 10(6) U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen.

Review of metastatic bladder cancer.

Bladder cancer is a major cause of new cancer diagnosis throughout the world. The standard therapy for muscle-invasive bladder cancer is radical cystectomy, while superficial bladder cancer can often be managed with serial resections or intravesical therapy. The 5-year overall survival for patients undergoing radical cystectomy is only about 50%, with the majority of deaths due to metastatic bladder cancer. For these patients and for those who have metastases at diagnosis, chemotherapy with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin is still the standard treatment. Gemcitabine, taxanes, ifosfamide, and pemetrexed have also demonstrated activity in bladder cancer, allowing the development of less toxic chemotherapy regimens that are the subject of ongoing clinical research. Recent insights into the biology of bladder cancer, the introduction of new chemotherapy regimens, and randomized trials of perioperative chemo-therapy have significantly improved the outlook for patients with metastatic bladder cancer. Molecular markers appear to correlate with prognosis after cystectomy, but require further clinical validation and have not replaced pathologic staging for the purpose of making adjuvant treatment decisions. Recent advances in the fields of tumor genetics, angiogenesis, and tumor immunology have been applied in the ongoing development of novel treatment strategies for this challenging disease.

Alternating dose-dense chemotherapy in patients with high volume disseminated non-seminomatous germ cell tumours.

Only about half of patients with a poor-prognosis non-seminomatous germ-cell tumours can achieve a cure. The aim of this phase II study was to assess the efficacy and toxicity of a dose-dense alternating chemotherapy regimen in this subset of patients. High volume non-seminomatous germ-cell tumours was defined as follows: at least two sites of non pulmonary metastases, an extragonadal primary tumour, a serum human chorionic gonadotropin level higher than 10 000 mIU x ml(-1), or a alpha-foetoprotein level higher than 2000 mIU ml(-1). Patients who fulfilled these criteria were treated with the so-called BOP-CISCA-POMB-ACE regimen (bleomycin, vincristine, and cisplatin; cisplatin, cyclophosphamide, and doxorubicin; cisplatin, vincristine, methotrexate, and bleomycin; etoposide, dactinomycin, and cyclophosphamide) plus granulocyte colony-stimulating factor. A total of 58 patients were enrolled. Patients were retrospectively classified according to the International Germ-Cell Cancer Consensus Group classification; 38 patients (66%) had poor-prognosis disease and 19 patients (33%) had intermediate-prognosis. Patients received a median of 2.5 courses (range 0.25 to five courses) of the BOP-CISCA-POMB-ACE regimen. Forty-two patients (72.4%) had a complete response to therapy. With a median follow-up time of 31 months, the 3-year progression-free survival rate was 71% (95% confidence interval, 60 to 84%) and the 3-year overall survival rate was 73% (95% confidence interval: 62 to 86%). The 3-year PFS rates were 83% (95% confidence interval: 68 to 100%) in the intermediate-prognosis group and 65% (95% confidence interval: 51 to 82%) in the poor-prognosis group. Early side effects included mainly grade 4 haematologic toxicity (neutropaenia in 79% of patients, thrombocytopaenia in 69%, anaemia in 22%), grade 4 stomatitis (19%), and four early deaths (7% of patients), at least partially related to toxicity. The dose-dense BOP-CISCA-POMB-ACE regimen is highly active in patients with non-seminomatous germ-cell tumours classified as intermediate-prognosis or poor-prognosis according to the International Germ-Cell Cancer Consensus Group. Because outcomes with this regimen compare favourably with outcome after standard therapy, dose-dense chemotherapy should be further investigated in this subset of patients.

Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial.

BACKGROUND: Prostate carcinoma is linked to osteoblastic metastasis. We therefore investigated the value of bone-targeted consolidation therapy in selected patients with advanced androgen-independent carcinoma of the prostate. METHODS: 103 patients received induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. After two or three cycles of induction chemotherapy, we randomly assigned 72 patients who were clinically stable or responders to receive doxorubicin with or without strontium-89 (Sr-89) every week for 6 weeks. FINDINGS: Overall 62 of the 103 (60%, 95% CI 50-70) patients had a 50% or greater reduction in serum prostate-specific antigen concentration that was maintained for at least 8 weeks, and 43 (42%, 32-52) had an 80% or greater reduction. 49 (52%) patients with bone pain at registration had complete resolution of pain. After follow-up of 67 patients until death, the estimated median survival for all 103 patients was 17.5 months (range 0.5-37.7). For the 36 patients randomly assigned to receive Sr-89 and doxorubicin, the median survival time was 27.7 months (4.9-37.7), and for the 36 who received doxorubicin alone it was 16.8 months (4.4-34.2) (p=0.0014). The hazard ratio was 2.76 (95% CI 1.44-5.29). INTERPRETATION: Bone-targeted consolidation therapy consisting of one dose of Sr-89 plus doxorubicin once a week for 6 weeks, when given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival.

Gene therapy for bladder cancer.

Tumor-suppressor genes can be transferred into tumor cells in vivo using a replication-defective adenoviral vector. P53 mutations are frequent in bladder cancer, and adenovirus-mediated p53 gene transfer is growth-inhibitory to bladder cancer cells in vitro. The vector Ad5CMV-P53, which contains human wild-type p53, is being administered intravesically to patients with bladder cancer in a phase I clinical trial. The results of this study will provide the basis for phase II and phase III trials in which gene therapy will be integrated with existing therapies for improved local control and opportunities for bladder preservation.

Humanized M195 monoclonal antibody conjugated to recombinant gelonin: an anti-CD33 immunotoxin with antileukemic activity.

The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33pos cell lines HL60, OCI/AML2, and OCI/ AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33neg cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8% of cells by flow cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin. Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has antileukemic activity and should be considered for clinical testing in Phase I trials.

Phase I study of suramin combined with doxorubicin in the treatment of androgen-independent prostate cancer.

In this study, we determined the maximum tolerated plasma concentration of suramin (within the predetermined study target range) when combined with doxorubicin in the treatment of androgen-independent prostate cancer. Twenty-four patients received suramin dosages based on proportional adjustment of the steady-state plasma suramin concentration to achieve the targeted plasma concentrations of 50-100, 101-150, 151-200, or 201-250 microg/ml. Doxorubicin (20 mg/m2) was administered i.v. over 24 h at weekly intervals. Suramin was given i.v. over 2 h twice weekly. Patients received treatment until dose-limiting toxicity or disease progression. Side effects similar to those reported for suramin and doxorubicin administered as individual agents were observed. Dose-limiting motor neuropathy developed in three patients (13%). Twelve of 24 evaluable patients (50%; 95% confidence interval, 28-71%) and 6 of 10 evaluable patients (60%; 95% confidence interval, 26-88%) had a >50% decrease of prostate-specific antigen and measurable lesions, respectively. The maximum tolerated plasma level of suramin when combined with doxorubicin was 151-200 microg/ml. Future studies on suramin combined with doxorubicin or other agents could be performed using a fixed dosing scheme with a targeted suramin steady-state plasma concentration of 200 microg/ml.

Phase II trial of alternating weekly chemohormonal therapy for patients with androgen-independent prostate cancer.

Two distinct regimens of weekly chemotherapy for hormone-refractory prostate cancer were combined in an alternating schedule and tested in a Phase II trial to determine efficacy and toxic effects. Forty-six patients with hormone-refractory prostate cancer and rising prostate-specific antigen (PSA) levels entered the trial. Therapy consisted of doxorubicin (20 mg/m2/week) plus oral ketoconazole (400 mg three times a day) given at weeks 1, 3, and 5 and vinblastine (5 mg/m2/week) plus oral estramustine (140 mg three times a day) given at weeks 2, 4, and 6. No therapy was given at weeks 7 and 8. Replacement doses of hydrocortisone were administered throughout treatment to counteract potential adrenal insufficiency secondary to the ketoconazole. In 67% of patients (31 of 46), the PSA declined by 50% or greater for a minimum duration of 8 weeks (95% confidence interval, 52-80%). Among the 16 patients with measurable soft tissue disease, there were 12 responses (75%; 95% confidence interval, 47-92%). The median duration of response was 8. 4 months (1.8-14.9). The median survival for the entire group was 19 months. The median survival of PSA responders has not been reached, whereas that of nonresponders was 13 months (P = 0.010). Seventy-six percent of symptomatic patients noted improvement. Hematological toxicity was modest and was managed without growth factors. Peripheral edema (49%) and deep venous thrombosis (18%) were the most common nonhematological toxicities. The alternating weekly regimen of chemohormonal therapy is active for hormone-refractory prostate cancer, providing a high rate of symptom control, soft tissue response, and PSA decline.

Recombinant human retinoblastoma protein inhibits cancer cell growth.

Aberrant expression of the tumor suppressor gene RB1 is associated with a variety of solid tumors and hematopoietic neoplasms. Certain cancer cell lines in which the protein encoded by RB1 (p110RB) is absent have been reported to show decreased growth rate, clonogenicity, or tumorigenicity following insertion of a transcriptionally active RB1 gene. We asked whether these RB-deficient cells could be growth inhibited by direct exposure to purified p110RB. We report a decrease in uptake of tritiated thymidine by 5637 bladder carcinoma cells (RB-negative) when purified recombinant p110RB is added to culture media. Internalization of the protein by cells and translocation to the nucleus are demonstrated by immunohistochemistry, FACS, and detection of radiolabeled protein in subcellular fractions. Next, we chose a well-described leukemia cell culture model to investigate the potential effect of recombinant p110RB in clinical disease. We observed dose-related decreases in cell number of colony formation in vitro in 8 of 20 acute myelogenous leukemia samples, 7 of which did show endogenous p110RB detectable by immunohistochemistry. Histological appearance following exposure to p110RB shows cytoplasmic vacuolization and nuclear lobulation of degenerating cells. We conclude that purified p110RB added to culture media is internalized by cells, translocated to the nucleus, and exerts a growth-inhibitory effect on certain cancer cell types.

Polymyositis associated with chronic myelogenous leukemia.

A 53-year-old man with chronic myelogenous leukemia developed progressive proximal muscle weakness with electromyographic and histologic features consistent with polymyositis. Although the association of polymyositis with solid tumors is well recognized, an association with hematologic malignancies has not been firmly established. A survey of the world medical literature reveals one previously reported case of polymyositis and one of dermatomyositis associated with chronic myelogenous leukemia. We conclude that polymyositis does occur in association with chronic myelogenous leukemia. Recognition of this association is important, since treatment of polymyositis can be successful.

Primary small noncleaved cell lymphoma of kidney.

The kidney is the second most common site for metastasis of lymphoma though it remains asymptomatic and is not commonly detected with cross-sectional imaging studies. Primary renal lymphoma is a very rare lesion whose existence is controversial. The lymphoma reported here presented as a solitary renal mass without any other evidence of disease. Lymphoma should be included in the differential diagnosis for solitary renal masses even though the usual presentation is bilateral. Renal involvement with lymphoma requires a thorough search for extrarenal disease.

Interphase FISH and morphologic analysis of AML.

Interphase cytogenetic analysis of peripheral white blood cells from a patient with acute myelogenous leukemia (AML) who was previously diagnosed with trisomy 8 was performed for the purpose of documenting clonal response to intensive chemotherapy. DNA in situ hybridization was performed using a probe specific for chromosome 8 alpha-satellite DNA sequences. Cells were stained with Wright stain prior to interphase analysis and photographed to allow correlation of cell morphology with abnormal karyotype. Prior to chemotherapy, the patient's leukocyte differential contained 8% blasts; interphase analysis revealed 23% trisomy 8 cells, including mature granulocytes. Forty days after the start of chemotherapy, at which point the patient had attained clinical remission, interphase analysis revealed only 2% cells with three signals, which was not statistically significant when compared with our own series of controls. The use of interphase FISH analysis in this case provides additional evidence that some leukemic blasts may be capable of limited differentiation in vivo and also suggests a differential sensitivity to chemotherapy between cytogenetically normal and abnormal hematopoietic precursor cells.