The standard method of treatment for patients with locally invasive bladder cancer has still been a total cystectomy, which decrease the quality of life due to the urinary diversion and postoperative impotence. Reconstruction of the bladder using tissue from the intestinal tract has been applied in some cases, and total cystectomy with nerve conservation in order to avoid postoperative impotence has been reported (1). However, these techniques require a long operation time and are invasive, and are therefore not indicated for many patients because most cases of bladder cancer occur in individuals in their 60s-70s.　IN addition, the 5-year survival rates of patients with pT2, pT3a, pT3b, and pT4 bladder cancer are 63-83%, 50-69%, 15-29%, and 21-22%, respectively (2). About 50% of all patients with T2-T4 invasive bladder cancer die within 5 years despite of the decrease in QOL (3-10).　

Trimodality therapy involving radical transurethral resection, chemotherapy and radiation therapy has long been attempted as an alternative approach for patients who require cystectomy. The Radiation Therapy Oncology Group (RTOG) has completed six prospective protocols entering 415 patients with T2-T4a muscle-invasive bladder cancer who were candidates for cystectomy. However, none of the protocols achieved a 5-year survival rate of more than 60% (11-17). Moreover, the 5 year bladder intact survival rates were less than 50% in most of studies (16-19). Improvement of the survival rate with bladder preservation may require a new method, which allows to deliver a higher dosage of anticancer agent specifically into the tumor, without causing systemic side effects.

We have therefore developed a novel bladder preservation therapy [referred to thereafter as the “OMC (Osaka Medical College) regimen”] involving balloon-occluded arterial infusion (BOAI) of an anticancer agent and concurrent hemodialysis (HD). This allows the anticancer agent to accumulate at a high concentration at the site of the tumor while ensuring that the systemic concentration remains low, and this is then followed by radiation therapy.

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The most pertinent issue related to this therapy is why it achieves better outcomes than cystectomy (Fig 1). Using a rat BOAI-CDDP model, we are now investigating the mechanisms responsible for the better outcomes achieved by the OMC-regimen in comparison with total cystectomy. We have found that BOAI allows delivery of an extremely high concentration of anticancer agent to the bladder and surrounding pelvic region, as well as to the pelvic and para-aortic lymphatic tissues. Enhanced radiosensitivity of the cancer cells due to the BOAI-induced high concentration of cisplatin in the bladder, as well as in the lymphatic tissues, may also have contributed significantly to the good outcomes achieved. In addition, the severe hypoxia in the target region resulting from BOAI may play a role in the marked anti-tumor effect, as several basic studies have demonstrated that hypoxia greatly enhances the effectiveness of cisplatin.

The other advantage of the OMC-regimen is a significant reduction of systemic side effects. Cisplatin exerts its anti-tumor activity via the non-protein-bound form, whose concentration falls steeply after administration: its half-life is normally less than 60 minutes, and its concentration falls to below the detection limit 4 hours after administration. The most important point of the OMC-regimen is the removal of non-protein-bound Pt immediately after administration of cisplatin by performing HD via the bilateral common iliac veins, thus accomplishing efficient drainage of cisplatin immediately after passage through the tumor. HD is specifically efficient for cisplatin elimination, since the molecular weight of protein-unbound cisplatin is approximately 300, similar to that of creatinine. Moreover, the anatomic structure and blood supply of the bladder may largely account for the efficient drainage of cisplatin achieved with this approach. As the urinary bladder is situated at the base of the pelvis, the relatively close circuit formed by the internal iliac artery, bladder, and common iliac veins may contribute to efficient drainage of the anticancer agent, thus increasing the elimination efficiency without influencing the systemic circulation. Indeed, we found that >95% of free Pt was efficiently eliminated by HD during BOAI of cisplatin, thus providing optimal conditions for effective local accumulation of Pt in the tumor, with minimal systemic toxicity, allowing even a 91-year-old patient to complete the regimen.

Thus, the OMC-regimen, which delivers an extremely high concentration of anticancer agent to the site of a tumor without causing systemic adverse effects, can be regarded as a curative therapy for elderly patients, not only those for whom total cystectomy is indicated, but also those of whom total cystectomy is not feasible because of age, performance status or other reasons and who are considered physically incapable of tolerating the chemotherapeutic regimens that are usually applied clinically. It is noteworthy that this therapy will improve the feasibility of radical cure without the need for cystectomy in patients for whom such surgery would otherwise be necessary, and also facilitate potential cure in patients whose condition would normally rule out this likelihood and for whom, otherwise, merely palliative treatment would seem the only option.