Bladder Cancer

Radiation therapy (RT) and immunotherapy of cancer both date back more than 100 years, and yet, because radiation was often considered immunosuppressive, there had been little enthusiasm for combining them until recently. Immunotherapy has an established role in the treatment of some cancers-superficial bladder cancer treated with bacillus Calmette-Guérin (BCG), renal cell carcinoma and melanoma treated with interferon and interluekin (IL)-2 (Proleukin), and breast cancer and lymphoma treated with monoclonal antibodies such as trastuzumab (Herceptin) and rituximab (Rituxan), which partly function through antibody-dependent cellular cytotoxicity.

Along with various imaging modalities, serologic tumor markers such as CA 15-3 and CA 27.29 have been used for decades to monitor treatment response in patients with metastatic breast cancer (MBC). Despite the frequent use of these markers, they lack high sensitivity and specificity for breast cancer progression. The prognostic significance of these markers remains indeterminate because of the conflicting outcome of many clinical trials. The circulating tumor cell (CTC) test has recently been studied in clinical trials in patients with MBC. Some of the studies showed that high levels of CTCs are correlated with poor survival in MBC. An intergroup trial is underway to determine the implication of changing treatment based on the CTC level. This article will discuss the current data on these markers, with special emphasis on the CTC test. The potential clinical utility of these markers will also be discussed.

Eating a concentrated extract of freeze-dried broccoli sprouts might inhibit bladder cancer by delivering a protective factor right where the bladder is most at risk.

Occult distant micrometastasis at the time of radical cystectomy leads predominantly to distant failures in patients with locally advanced muscle-invasive transitional cell carcinoma of the bladder. Cisplatin-based combination chemotherapy enhances survival in patients with metastatic urothelial cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power. However, randomized clinical trials have demonstrated a survival benefit for neoadjvuant cisplatin-based combination chemotherapy, which should be considered a standard of care. In addition, neoadjuvant therapy may assist in the rapid development of novel systemic therapy regimens, since pathologic complete remission appears to be a powerful prognostic factor for long-term outcomes. Patients who are either unfit for or refuse radical cystectomy may benefit from neoadjuvant chemotherapy with or without radiation to enable bladder preservation.

Occult distant micrometastasis at the time of radical cystectomy leads predominantly to distant failures in patients with locally advanced muscle-invasive transitional cell carcinoma of the bladder. Cisplatin-based combination chemotherapy enhances survival in patients with metastatic urothelial cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power. However, randomized clinical trials have demonstrated a survival benefit for neoadjvuant cisplatin-based combination chemotherapy, which should be considered a standard of care. In addition, neoadjuvant therapy may assist in the rapid development of novel systemic therapy regimens, since pathologic complete remission appears to be a powerful prognostic factor for long-term outcomes. Patients who are either unfit for or refuse radical cystectomy may benefit from neoadjuvant chemotherapy with or without radiation to enable bladder preservation.

Occult distant micrometastasis at the time of radical cystectomy leads predominantly to distant failures in patients with locally advanced muscle-invasive transitional cell carcinoma of the bladder. Cisplatin-based combination chemotherapy enhances survival in patients with metastatic urothelial cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power. However, randomized clinical trials have demonstrated a survival benefit for neoadjvuant cisplatin-based combination chemotherapy, which should be considered a standard of care. In addition, neoadjuvant therapy may assist in the rapid development of novel systemic therapy regimens, since pathologic complete remission appears to be a powerful prognostic factor for long-term outcomes. Patients who are either unfit for or refuse radical cystectomy may benefit from neoadjuvant chemotherapy with or without radiation to enable bladder preservation.

Results from Oncolytics Biotech's phase I trial of Reolysin, its oncolytic reovirus, show stable disease in 7 of 32 patients with advanced or metastatic solid tumors refractory to standard therapy or for which no curative standard therapy exists. Dr. Timothy Yap of The Institute of Cancer Research, Sutton, UK, presented the study at the 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

At-home hematuria screening appears to lessen the frequency of invasive bladder cancer and reduce bladder-cancer-specific mortality, according to results of a study

High-grade urothelial cancer ofthe bladder is not only relativelycommon but unfortunately,is frequently lethal. These tumorsare often diagnosed when thetumors have already invaded the wallof the bladder. Even when they arediagnosed at a time when they areconfined to the mucosa or lamina propria,patients may not respond to abladder-preservation approach. Oftena radical cystectomy with urinary diversionis either not offered at all or notconsidered until the cancer has invadeddeep into the muscularis propria andlocal treatment fails.

Bladder cancer is the fifth most common cancer diagnosed in theUnited States. Prognosis for this disease is dependent on both tumorstage and grade. Radical cystectomy has been the standard treatmentfor muscle-invasive local disease; however, combined-modality approacheswith the use of chemotherapy are gaining momentum withdata suggesting survival improvement. Patients with metastatic diseasehave poor long-term survival rates despite systemic multiagent chemotherapy.A variety of agents, including newer cytotoxic drugs and biologicallytargeted agents, are under investigation to determine the mosteffective regimen. The special needs of specific patient populations,such as the elderly, those with a suboptimal performance status, andpatients with medical comorbidities have gained more attention.Progress in the treatment of this disease is dependent on supportingongoing and future clinical trials.

Drs. Henry, MacVicar, and Hussainprovide a timely reviewof the current management ofmuscle-invasive and metastaticurothelial cancer. The emerging roleof neoadjuvant chemotherapy and thepromise of novel, less toxic targetedtherapies are of particular interest inthe treatment of a disease in whichoutcomes remain poor for locally advancedand metastatic involvementdespite an aggressive multimodalityapproach.[1] We wish to briefly commenton three issues raised by theauthors: (1) the role of surgery in themanagement of invasive disease,(2) the indiscriminate use of neoadjuvantchemotherapy for clinically localizeddisease, and (3) the currentstatus of bladder-sparing approaches.

Optimal therapy for locally advancedbladder cancer aimsto prevent local recurrence,reduce the probability of distant metastasis,and improve survival. Radicalcystectomy coupled with a pelviclymph node dissection is the mainstaytreatment of locally invasive bladdercancer, curing the majority ofpatients with organ-confined bladdertumors, about half with extravesicaldisease, and a significant minoritywith lymph node metastases. Althoughradical cystectomy providesgood local and regional control of invasivebladder cancer, the recurrencefreeand overall survival rates are stillonly 63%–72% and 59%–66%, respectively,among all patients. Themajor predictors for disease-specificsurvival of patients following radicalcystectomy for bladder cancer are thepathologic stage of the primary tumorand status of lymph nodes at time ofcystectomy. Freedom from recurrenceat 5 years after cystectomy is 63%–72% for patients with organ-confineddisease and only 25%-37% for non-organ-confined disease.

It is estimated that, in 1995, about 50,500 new cases of urinary bladder cancer will be diagnosed and that 11,200 patients will die of the diease. The most common malignant tumor of the urinary tract, bladder cancer accounts for 6.5% of all cancers annually. It is the fifth most common cancer among American men [1], and approximately three quarters of all cases occur in men.

The most effective form of therapyfor muscle-invasive bladdercancer is radical surgery andurinary diversion. Numerous clinicalseries demonstrate stage-for-stage 5-and 10-year survival data that are betterthan that seen for other treatmentmodalities.[1] The widespread applicationof continent urinary diversionover the past 2 decades has furtheredthe acceptance of radical surgery, asit provides for the lost function ofvolitional storage and emptying ofurine. Even patients who undergo astandard ileal loop diversion generallytolerate it well and adapt to thealtered body image.[2]

Drs. Fernando and Sandler havewritten a thorough review thathas documented why a bladder-conserving therapy can now bemore widely accepted treatment for patientswith muscle-invading bladdercancer. They have shown that this treatmentapproach, while selective, doeshave a high likelihood of eradicatingthe primary tumor, preserving good organfunction, and not compromisingpatient survival. These successful approacheshave evolved over the past 25years following initial reports of theeffectiveness of cisplatin against transitionalcell carcinoma and then reportsof added efficacy when cisplatinis given concurrently with radiation.

This is a timely review on thecurrent status of selective bladderpreservation for muscleinvasivebladder cancer. Although controversial,the concept is extremely attractiveto patients, and evidence fromretrospective and/or small series demonstrateits efficacy. Most of these trials,however, have included highlyselected patients. Unfortunately, thereare few, if any, ongoing randomizedcontrolled trials comparing radical cystectomyto bladder-preserving protocols.Although the overall 5-yearsurvival rate for radical cystectomy andtrimodality therapy is approximately50%, patients with pure T2 disease frequentlyachieve 5-year survival ratesapproaching 70%.[1-3] While it is clearlybeyond the scope of this editorial togo into an in-depth analysis of all thestudies reported to date, several significantquestions remain.

While organ preservation with nonextirpative surgery, radiotherapy,and frequently, chemotherapy has become a favored strategy in thetreatment of many cancers, bladder preservation for patients with invasivedisease remains controversial. The standard treatment for muscleinvasivebladder cancer in the United States is still radical cystectomywith pelvic lymph node dissection. An alternative to cystectomy ismultimodality bladder preservation with thorough transurethral resection,chemotherapy, and radiation therapy. This review will addressissues raised by a multimodality approach for the treatment of invasivebladder cancer.

Currently, the four-drug combination of methotrexate, vinblastine,doxorubicin (Adriamycin), and cisplatin (MVAC) or the two-drug combinationof gemcitabine and cisplatin (GC) represents the standard ofcare for patients with locally advanced and metastatic transitional cellcarcinoma of the urothelium. Recently, there has been a plethora ofdata from other chemotherapeutic regimens. Promising new agents,such as the multitargeted antifolate pemetrexed (Alimta), and new drugcombinations have demonstrated increased efficacy and/or decreasedtoxicity compared with current regimens. Currently, data are availablefrom three phase II studies utilizing pemetrexed or the combination ofpemetrexed/gemcitabine (Gemzar) in patients with locally advanced andmetastatic transitional cell carcinoma of the urothelium. Further investigationof combinations of pemetrexed and other active drugs inthe treatment of patients with locally advanced and metastatic diseaseis warranted.

Pemetrexed (Alimta) is an antifolate that is effective in the inhibitionof multiple enzyme targets including thymidylate synthase,dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase.The compound has been evaluated in several phase I trials, bothas single agent and in combination with other cytotoxic agents. Theinitial schedule selected for further investigation in phase II trials waspemetrexed 600 mg/m2 as a 10-minute infusion on day 1 every 21 days.During the subsequent phase II development, the dose of pemetrexedwas adjusted to 500 mg/m2 due to bone marrow and gastrointestinaltoxicities. The adjusted dose of pemetrexed was well tolerated throughoutthe late-phase drug development program. Preclinical evidencesuggests that pemetrexed has additive or synergistic activity when combinedwith many other clinically important anticancer agents, includinggemcitabine (Gemzar), fluorouracil, carboplatin (Paraplatin),oxaliplatin (Eloxatin), paclitaxel, and vinorelbine (Navelbine). Doselimitingtoxicities in these studies were primarily hematologic, and therewas no evidence of cumulative hematologic toxicity. During the drugdevelopment program it was discovered that supplementation with folicacid and vitamin B12 profoundly increased the tolerability ofpemetrexed. The studies discussed in this review demonstrate thatpemetrexed is well tolerated as a single agent and will be an importantcontribution to combination chemotherapy regimens.

The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.

NEWTON, Massachusetts-Matritech Inc has launched its new point-of-care diagnostic test for bladder cancer-NMP22 BladderChek. Cytogen Corporation (Princeton, New Jersey) will distribute the product.

BETHESDA, Maryland-The National Cancer Institute’s Kidney/Bladder Cancer Progress Review Group has released 13 priority recommendations intended to serve as a national plan to guide research in the two diseases over the next 5 years. The recommendations cover basic and translational research, cancer control, and cancer treatment, and range from understanding the biologic mechanisms underlying the two diseases to developing innovative strategies to eradicate them.

NEWTON, Mass-Matritech Inc. has received clearance from the US Food and Drug Administration to market NMP22 BladderChek for monitoring patients with a history of bladder cancer.

In less than a decade, docetaxel (Taxotere) has progressed from initial studies in anthracycline-refractory metastatic breast cancer to several large, phase III randomized trials evaluating its efficacy as adjuvant, neoadjuvant, and first-line therapy for metastatic breast cancer, non-small-cell lung cancer (NSCLC), and ovarian cancer. In other tumor types, including prostate, head and neck, gastric, and bladder cancer, ongoing phase III trials are comparing docetaxel-containing regimens to previously established regimens. For the seven tumor types reviewed in this supplement, phase III study information for docetaxel or docetaxel-based combinations are presented. Impressive results have been consistently demonstrated in the trials reported to date.

The multistep process of carcinogenesis, which can take many years, provides many opportunities for intervention to inhibit disease progression. Effective chemoprevention agents may reduce the risk of cancer by inhibiting the initiation stage of carcinoma through induction of apoptosis or DNA repair in cells harboring mutations, or they may act to prevent promotion of tumor growth. Similarly, chemoprevention may entail blocking cancer progression to an invasive phenotype.

Among the most exciting new anticancer products presented at the 2001 ASCO meeting were new drugs that block the epidermal growth factor receptor (EGFR). About 30% to 90% of carcinomas express high levels of EGFR. These include, among others, head and neck cancer, lung cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, and bladder cancer.

Fenretinide (N-4-hydroxyphenyl-retinamide, or 4-HPR) is a semisynthetic retinoid that was initially developed as a low-dose chemopreventative agent.[1-3] Unlike other naturally occurring retinoids such as all-trans, 13-cis, and 9-cis retinoic acids, fenretinide does not induce systemic catabolism that interferes with the maintenance of effective plasma levels during long-term use. This characteristic, combined with the agent’s low toxicity and its ability to block aspects of carcinogenesis, provided the rationale for the development of fenretinide in lower doses as a chemoprevention agent for breast, prostate, and bladder cancer.

Conventional histopathologic evaluation of bladder cancer, encompassing tumor grade and stage, is inadequate to accurately predict the behavior of most bladder tumors. Intense research efforts are under way to identify and

ANAHEIM, California-A phase III Intergroup trial has provided strong evidence that neoadjuvant MVAC-methotrexate, vinblastine, doxorubicin (Adriamycin), cisplatin (Platinol)-provides a survival benefit in patients with locally advanced bladder cancer, David Crawford, MD, said at the American Urological Association (AUA) annual meeting (abstract 1069).

Conventional histopathologic evaluation of bladder cancer, encompassing tumor grade and stage, is inadequate to accurately predict the behavior of most bladder tumors. Intense research efforts are under way to identify and