Bladder Cancer

The review by Rampersaud and colleagues provides an excellent summary of the scientific rationale for using hyperthermia to treat cancer and of the current status of combinations of hyperthermia and chemotherapy or radiotherapy. In view of the demonstrated efficacy of the combination of intravescial hyperthermia and mitomycin C (MMC) therapy in preventing the progression and recurrence of non–muscle-invading bladder cancer (NMIBC) in several clinical trials, Rampersaud and colleagues advocate additional studies to further optimize the delivery of hyperthermia and to delineate its clinical utility in this disease.

Modern cancer care is characterized by a focus on organ-sparing multi-modal treatments. In the case of non–muscle-invasive bladder cancer this is particularly true; treatment is focused on reducing the frequency of low-risk recurrences and preventing high-risk progression. Deep regional hyperthermia is an oncologic therapeutic modality that can help achieve these two goals. The combination of hyperthermia with chemotherapy and radiotherapy has improved patient outcomes in several tumor types. In this review, we highlight the biology of therapeutic fever-range hyperthermia, discuss how hyperthermia is administered and dosed, demonstrate how heat can be added to other treatment regimens, and summarize the data supporting the role of hyperthermia in the management of bladder cancer.

Bladder cancer is the fourth most common cancer (excluding skin cancer) in the United States and ranks eighth as a cause of death from cancer among men; there will be an estimated 70,530 new cases and 14,680 cancer-related deaths in the United States in 2010.[1] Of new cases, 70% to 80% present with non–muscle-invasive bladder cancer (NMIBC). Despite endoscopic and intravesical treatments with curative intent, 50% to 70% of these cancers recur, usually within 5 years, and 10% to 30% progress to muscle-invasive disease, in the majority of cases as high-grade lesions.[2,3] Bladder cancer poses a significant economic burden due to the cost of the lifetime need for surveillance, the need to treat recurrent tumors, and the cost of complications associated with treatment. Medicare estimates have ranked bladder cancer treatment the seventh costliest among cancers, with a 5-year net cost of approximately one billion dollars.[4]

Extramedullary disease in plasma cell disorders can occur as a solitary plasmacytoma or can involve multiple sites with vastly different clinical outcomes. The article by Khaliq et al reports an unusual case of solitary extramedullary plasmacytoma (SEP) of the bladder in which the patient had a favorable outcome with lenalidomide/dexamethasone after failing first-line treatment with radiotherapy. In this context it is interesting to compare clinical outcomes of this entity to two other clinical variants of myeloma: solitary plasmacytoma of bone (SPB), and multiple myeloma with extramedullary plasmacytomas (MM/EP).

Plasmacytoma is a rare B-lymphocyte neoplastic disorder that usually presents as the generalized disease multiple myeloma. Less than 5% of the cases present as a solitary mass of monoclonal plasma cells in the bone or soft tissue. Although solitary extramedullary plasmacytoma (SEP) may arise in any organ, it rarely involves the urinary bladder. A 67-year-old male without a history of multiple myeloma presented with urinary frequency and nocturia; he was later diagnosed with SEP of the bladder. The patient was initially treated with a course of radiation therapy without symptomatic improvement; therefore a chemotherapy regimen consisting of lenalidomide and dexamethasone was subsequently given for six cycles. SEP usually carries a better prognosis and higher cure rate than solitary plasmacytoma of bone, as SEP is radiation sensitive. The role of adjuvant chemotherapy in the treatment of SEP that is resistant to radiation therapy is not clear, since most of the recommendations have been derived from the experience of head and neck SEP. The literature also lacks recommendations for choice of a chemotherapy regimen and surveillance of isolated bladder plasmacytoma. Here we present the first case of a radiation-resistant solitary plasmacytoma of the bladder that was successfully treated with lenalidomide and dexamethasone with successful clinical remission.

The authors on “Solitary Extramedullary Plasmacytoma of the Bladder” have provided a quick and accurate diagnosis, work-up, and treatment of this solitary extramedullary plasmacytoma. Solitary extramedullary plamacytomas are rare, and account for only 3% of all plasma cell malignancies. Of the 3% of plasma cell malignancies that are diagnosed, the bladder is one of the least common locations. The rarity of the tumor frequently makes the process of making a correct diagnosis difficult.[1] After making the diagnosis with immunohistochemistry, a bone marrow biopsy must be performed to rule out multiple myeloma. Additionally, a body and skeletal survey must show no evidence of additional disease or lytic lesions in order to confirm localized disease. In this case, these procedures were performed accurately and in a timely fashion.

Adding gemcitabine (Gemzar) to concurrent radiotherapy and cisplatinum in invasive bladder cancer could preserve the organ even when the tumor has invaded the muscle.

A 56-year-old woman was referred to our institution for a left nephroureterectomy after the diagnoses of a nonfunctioning left kidney and noninvasive papillary urothelial carcinoma of the distal left ureter (Ta grade 1). Following the procedure, surveillance cystoscopy and computed tomography (CT) scan of the abdomen and pelvis demonstrated a large bladder tumor with pan-urothelial extension.

Polymedco, Inc, announced the availability of the BTA Stat test-a point of care technology for the early detection of recurrent bladder cancer. This method uses monoclonal antibodies to detect the presence of bladder tumor–associated antigen in urine. It is a single-step, rapid immunochromatographic assay for bladder tumor-associated antigen in voided urine.

The patient is a 39-year-old man who presents with pelvic lymphadenopathy. He has a history of ureteral reflux disease, recurrent nephrolithiasis, right nephrectomy, ileal loop diversion of the left ureter, and radical cystectomy for “bladder cancer,” which he underwent 3 years ago. The lymphadenopathy was discovered incidentally during recent imaging.

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.