Uzair B. Chaudhary

Long-term experience with management of renal cell carcinoma involving the inferior vena cava

OBJECTIVES To evaluate the long-term outcome and prognosis and influence of patient and tumor characteristics and therapeutic interventions on patients with renal cell carcinoma (RCC) extending to the inferior vena cava (IVC). METHODS The data of 75 patients (51 men and 24 women; age range 27 to 92 years) with RCC and involvement of the IVC, including 49 without and 26 with metastatic disease, treated between July 1973 and December 1998 were reviewed. The clinical presentation, laboratory and imaging investigations, extent and level of caval involvement, operative details, and estimated blood loss, as well as the postoperative course, morbidity, and actuarial and disease-free survival were analyzed. RESULTS Seventy-five patients between 27 and 92 years old with RCC involving the IVC were studied. Of the 54 operative patients, 48 had no metastasis and 6 had metastatic disease; 32 had IVC tumor extension to the infrahepatic or low retrohepatic IVC, 7 had high intrahepatic IVC extension, and 15 had right atrial extension. In 7 patients, tumor had invaded the IVC wall. Partial IVC wall excision was done in 4 patients and resection of a complete segment of the IVC in 3 patients. Tube graft to replace a segment of the IVC was used in 2 patients. Patients with intracardiac extension were initially treated with cardiopulmonary bypass. Subsequently, profound hypothermia and circulatory arrest were also used. Three patients died in the postoperative period: two with and one without metastatic disease. The follow-up period ranged between 25 and 144 months. Of the 48 patients without evidence of metastasis at surgery, the perioperative mortality rate was 2%. Twenty-two patients (47%) were alive without evidence of metastases, 4% developed solitary metastasis, and 36% eventually developed multiple metastases. CONCLUSIONS Our long-term experience confirms that of other investigators that nonmetastatic RCC with extension into the IVC is a potentially curable condition provided complete removal can be achieved. The level of extension of the tumor thrombus dictates the surgical techniques used for successful removal of the tumor thrombus. The treatment of patients with caval involvement and metastatic disease at presentation needs to be carefully individualized. Those with extensive multiorgan metastases continued to do poorly irrespective of the therapeutic approach chosen.

Long-Term Complications of Chemotherapy for Germ Cell Tumours

Testicular cancer is the most common solid tumour among young males aged 15–35 years. Cisplatin-based combination chemotherapy has changed the outlook of this disease. Disseminated testicular cancer, once uniformly fatal, now has a cure rate of more than 80% with combination chemotherapy. Systematic randomised trials have shown that cisplatin, etoposide and bleomycin (PEB) combination chemotherapy remains the mainstay of treatment. While there is a high cure rate with chemotherapy in patients with this disease, some long-term complications from chemotherapy have now been recognised, including secondary leukaemia, therapy-related solid tumours, nephrotoxicity, neurotoxicity, pulmonary toxicity, vascular toxicity and infertility.Etoposide, a DNA topoisomerase II inhibitor, is a significant risk factor for developing leukaemia; the risk appears to be correlated with the total dose given. Patients receiving cisplatin-based combination chemotherapy for testicular cancer also appear to have a higher relative risk for developing second non-germ cell malignancies; the greatest risks for therapy-related solid tumours were seen with a combination of radiation therapy plus chemotherapy.Long-term vascular toxicities associated with chemotherapy include Raynaud’s phenomenon, acute myocardial infarction and cerebrovascular events. Bleomycin is thought to be the most important drug in the pathogenesis of Raynaud’s phenomenon, while cisplatin is the most likely agent involved in myocardial infarction.Peripheral neuropathy is the most common form of neurotoxicity observed with cisplatin-based chemotherapy. Risk factors for the development of neural damage include a high cumulative dose of cisplatin, the use of vinblastine and the concomitant development of Raynaud’s phenomenon. Cisplatin is also well known to cause significant nephrotoxicity.Approximately 25% of patients present with azoospermia after undergoing combination chemotherapy with a follow up of 2–5 years.Physician awareness of complications associated with chemotherapy is vital to maximise efficacy, minimise toxicity, and preserve quality of life after treatment. Sperm cryopreservation should be considered for patients who desire children. Close monitoring during therapy allows for the early diagnosis of complications, and close follow up of patients after the completion of therapy is necessary to monitor for relapse and development of long-term complications such as myelodysplastic syndrome and leukaemia. Despite these complications, given the potential for cure rates in this young group of patients, the benefits far outweigh the risks.

Intermittent androgen deprivation: Update of cycling characteristics in patients without clinically apparent metastatic prostate cancer

OBJECTIVES To update the cycling characteristics and patterns of treatment in patients receiving intermittent androgen deprivation (IAD) for clinically localized and recurrent prostate cancer. METHODS We report our experience with 61 patients treated with IAD. Thirty-four patients had received no prior treatment, and 27 had developed recurrent disease after previous local therapy. No patient had clinically apparent metastatic disease before the initiation of therapy. The mean and median serum prostate-specific antigen (PSA) level before treatment was 25.3 ng/mL and 16.0 ng/mL, respectively (range 0.5 to 190 ng/mL). For each cycle, androgen deprivation was continued until PSA became undetectable or a nadir level was reached. Patients were then observed without treatment, and therapy was reinstituted after the serum PSA value reached a predetermined level. Patients were no longer eligible to cycle off treatment when their serum PSA increased despite ongoing androgen deprivation or if any objective evidence of disease progression was present on imaging studies. RESULTS Follow-up ranged from 7 to 60 months (mean 30) from the start of treatment. Patients received from one to five treatment cycles (median two), with a median cycle length of 14 months. The median nadir serum PSA level during androgen deprivation was 0.01 ng/mL and was reached within an average of 6 months (range 4 to 9) after beginning treatment. Patients spent an average of 45% of the time not receiving therapy, but the time off therapy decreased as the number of treatment cycles increased. Five patients (8.1%) demonstrated progressive disease, with a median time to progression of 48 months. When examining the cycling characteristics of these patients, no consistent pattern of failure emerged. CONCLUSIONS IAD appears to be a viable treatment option in select patients with localized prostate cancer. With each consecutive cycle, the amount of time the patient was not receiving therapy decreased, despite achieving a low nadir PSA. Longer follow-up with more patients failing IAD will be required before clear patterns of failure emerge in these patients.

Results of a phase II trial of gemcitabine plus doxorubicin in patients with recurrent head and neck cancers: Serum C 18-ceramide as a novel biomarker for monitoring response

Purpose: Here we report a phase II clinical trial, which was designed to test a novel hypothesis that treatment with gemcitabine (GEM)/doxorubicin (DOX) would be efficacious via reconstitution of C18-ceramide signaling in head and neck squamous cell carcinoma (HNSCC) patients for whom first-line platinum-based therapy failed. Experimental Design: Patients received GEM (1,000 mg/m2) and DOX (25 mg/m2) on days 1 and 8, every 21 days, until disease progression. After completion of 2 treatment cycles, patients were assessed radiographically, and serum samples were taken for sphingolipid measurements. Results: We enrolled 18 patients in the trial, who were evaluable for toxicity, and 17 for response. The most common toxicity was neutropenia, observed in 9 of 18 patients, and there were no major nonhematologic toxicities. Of the 17 patients, 5 patients had progressive disease (PD), 1 had complete response (CR), 3 exhibited partial response (PR), and 8 had stable disease (SD). The median progression-free survival was 1.6 months (95% CI: 1.4–4.2) with a median survival of 5.6 months (95% CI: 3.8–18.2). Remarkably, serum sphingolipid analysis revealed significant differences in patterns of C18-ceramide elevation in patients with CR/PR/SD in comparison with patients with PD, indicating the reconstitution of tumor suppressor ceramide generation by GEM/DOX treatment. Conclusions: Our data suggest that the GEM/DOX combination could represent an effective treatment for some patients with recurrent or metastatic HNSCC, and that serum C18-ceramide elevation might be a novel serum biomarker of chemotherapy response. Clin Cancer Res; 17(18); 6097–105. ©2011 AACR.

Chemotherapeutic and targeted biological agents for metastatic bladder cancer: A comprehensive review

The American Cancer Society estimates that 73 510 new cases of bladder cancer will be diagnosed and 15 000 deaths will result this year. The paper summarizes the clinical evidence for the use of platinum‐based, non‐platinum‐based and new targeted biological agents, while reporting the future directions in the treatment of metastatic bladder cancer. For cisplatin‐base regimens, the combination of methotrexate, vinblastine, doxorubicin and cisplatin (M‐VAC) has been the mainstream treatment for both advanced and metastatic bladder cancers. It showed significant improvement in the complete response rate and overall survival time in comparison with single‐agent cisplatin. For cisplatin‐ineligible patients, namely patients with renal impairment, symptomatic cardiac disease and poor performance status, alternative therapies consisting of paclitaxel, gemcitabine and carboplatin were shown to be of benefit. Pemetrexed and vinflunine have also shown effectiveness, with small but demonstrable overall survival benefits. Gemcitabine‐based doublet therapies (combined with paclitaxel, docetaxel, irinotecan, oxaliplatin or epirubicin) have all been shown to be effective and well‐tolerated. Several new targeted therapies, such as gefetinib, sorafenib and lapatinib, have received attention in recent years; however, their effectiveness as single agents in a relapse setting have not been optimal and more studies are warranted.

TOXICITY AND SURVIVAL OUTCOMES OF HYPERFRACTIONATED SPLIT-COURSE REIRRADIATION AND DAILY CONCURRENT CHEMOTHERAPY IN LOCOREGIONALLY RECURRENT, PREVIOUSLY IRRADIATED HEAD AND NECK CANCERS

Reirradiation of locoregionally recurrent, previously irradiated head/neck cancer may be considered in situations of unresectability, medical inoperability, or adverse pathologic features found at salvage resection.

Testicular Lymphoma: An Update for Clinicians

Testicular lymphoma is a lethal disease with a median survival of approximately 12 to 24 months. It is the most common testicular malignancy in men older than 60 years of age. Testicular lymphoma has a predilection for widespread dissemination to unusual sites, including the central nervous system, contralateral testis, Waldeyer’s ring, skin, and lung. Doxorubicin based chemotherapy with prophylactic intrathecal chemotherapy and radiation to the contralateral testis seems most promising. This review article will focus on the presentation, pathology, patterns of relapse and challenges in improving the outcome of this disease.

Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial

BackgroundCOX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-κB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors.MethodsPatients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily.ResultsNo dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease.ConclusionThe combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated.Trial registration numberNCT00290680.

FERTILITY AFTER CHEMOTHERAPY FOR TESTICULAR CANCER

Disseminated testicular cancer has largely become curable with cisplatin-based chemotherapy. The prospect of fertility after treatment is an important consideration for both patients and clinicians. While there may be an irreversible impairment of spermatogenesis at a cumulative cisplatin dose of greater than 400 mg/m 2, a low sperm count does not necessarily appear to prevent fatherhood. This review summarizes currently available data on the effects of chemotherapy on male fertility and steps that can be taken to preserve fertility in this patient population.

A phase II study of gemcitabine and irinotecan in patients with locally advanced or metastatic bladder cancer.

Background:The objectives of the current study were to evaluate the safety and efficacy of gemcitabine and irinotecan (Irinogem) in patients with metastatic bladder cancer. Irinotecan and gemcitabine are newer-generation chemotherapeutic agents with different mechanisms of action, nonoverlapping toxicity profiles, and synergistic activity in vitro. Methods:Sixteen patients have been enrolled, of which 13 are evaluable for response. The median age is 68.5 years (range, 52 to 82 y). According to the Bajorin prognostic model for metastatic bladder cancer, 8 patients were classified as “low risk” and 8 as “intermediate risk.” Gemcitabine 1000 mg/m2 and irinotecan 100 mg/m2 were administered on days 1 and 8 of each 3-week cycle. All patients had histologically proven transitional cell cancer of the bladder with bidimensionally measurable disease. All but 2 patients were chemotherapy naive at enrollment. Results:The median number of cycles administered was 4. Among the 13 patients evaluable for efficacy, objective radiographic response was documented in 8 patients (2 complete and 6 partial responses), 4 had stable disease, and 1 progressed on therapy. Median progression-free survival was 8.78 months (95% confidence interval, 5.98-15.38) and median overall survival was 13.51 months (95% confidence interval, 8.02-21.93). Toxicity evaluated in all 16 patients was modest: 2 episodes of febrile neutropenia, grades 3 to 4 neutropenia in 4 patients, grades 3 to 4 diarrhea in 2 patients, grades 3 to 4 fatigue in 1 patient, grades 3 to 4 nausea/vomiting in 2 patients, grades 3 to 4 neurological toxicity in 1 patient, and no grades 3 to 4 thrombocytopenia. No toxic deaths were noted. One patient discontinued therapy due to grade 4 fatigue, 1 due to stroke, 1 due to grade 4 colitis, 1 due to progressive disease, and 1 declined to participate in the trial after receiving the first cycle of therapy. Conclusions:The results of the current study suggested that the combination of Irinogem was an effective treatment for patients with metastatic bladder cancer, with manageable toxicities. The study was closed early due to delays in accrual and loss of funding. Hence, the study lacks adequate power to make definite conclusions. Further studies in multi-institutional setting in patients with normal and compromised renal function are warranted.