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Bladder Cancer

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November 2nd 2004

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.


CME Content


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.

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).

ANAHEIM, California-In patients with superficial bladder cancer, it is possible to optimize treatment with mitomycin (Mutamycin) by enhancing the drug concentration in urine, according to the results of a multicenter study presented at the American Urological Association annual meeting (abstract 776).

BOSTON-A combination of transurethral resection (TUR) and radiochemotherapy with cisplatin (Platinol) and fluorouracil (5-FU) produced the most promising results in a German study of bladder-sparing protocols for patients with invasive bladder cancer.

CARPINTERIA, Calif-A newly available fluorescent-based immunocytologic test to detect superficial bladder cancer, ImmunoCyt, used in conjunction with urinary cytology, will likely reduce the need for periodic cystoscopies in patients with transitional cell bladder cancer and enhance the early detection of recurrent disease.

Researchers who conducted a large, randomized clinical trial across Europe, Great Britain, and Canada found that in order to improve safety and reduce toxicity, advanced bladder cancer patients can be treated with a combination of gemcitabine (Gemzar) and cisplatin (Platinol). This combination (known as GC) did not extend survival, but it was much less toxic than the currently used combination, MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], and cisplatin).