The combination of cisplatin-based chemotherapy and radiotherapy has proven to be an effective treatment for invasive bladder cancer in many clinical studies. Intraarterial approaches to chemotherapy have been developed to reduce systemic toxicities and improve the response rate. Internal iliac arterial infusion chemotherapy (IIA) combined with irradiation obtained complete response in more than 80% of invasive bladder cancer. There are only a few published studies on the treatment by IIA with pelvic irradiation for patients with bladder cancer with pelvic lymph node metastasis. 1,2 We reported that IIA with pelvic irradiation is effective for patients with pelvic lymph node metastasis and that more than 50% of the patients achieve an 8-year survival with this treatment. 3 Herein, we report two patients with bladder cancer with N3 pelvic lymph node metastasis who were successfully treated by IIA combined with whole-pelvis irradiation.
Internal Iliac Arterial Infusion Chemotherapy
After 2 hours of hydration with normal saline solution at 500 ml/h and after the patient received 25 g of mannitol, angiographic catheters (no. 5 Fr) were inserted through the contralateral femoral artery to the internal iliac artery; the catheter tip was located inferior to the origin of the superior gluteal artery. Extent of disease, placement of the catheter, and chemoperfusion of the bladder tumors were ensured by angiography. Each course of chemotherapy with cisplatin (CDDP) 30 to 50 mg/m2 or carboplatin (CBDCA) 100 mg/m2, THP (tetra hydropyranyl-doxorubicin) 20 mg/m2, and methotrexate (MTX) 20 mg/m2 were introduced in a few minutes.
Radiotherapy was commenced on the day after IIA chemotherapy with 40 Gy to 50 Gy delivered to the urinary bladder, the surrounding tissue, and the pelvic lymphatics. This was performed as the initial pelvic irradiation through opposing (anteroposterior–posteroanterior) portals extending from the lower margins of the lateral margin extending 1.5 cm beyond the pelvic brim. The dose was delivered in 5 fractions per week by a megavoltage linear accelerator (10 MV) in daily fractions of 2 Gy during 4 to 5 weeks.
Every 3 weeks, 3 to 7 cycles of CDDP 30 to 50 mg/m2, MTX 20 mg/m2, and THP 20 mg/m2 were administered along with 40 Gy to 50 Gy. of whole-pelvis irradiation. For the renal function-impaired patient, IIA was performed with 100 mg/m2 of CBDCA instead of CDDP.
A 73-year-old man (transitional cell carcinoma [TCC], grade III, T3aN3) had a broad-base trigonal bladder tumor and bilateral hydronephrosis caused by obstruction of the ureteral orifices. There was no distant metastasis but computed tomography revealed a 5-cm tumor in the left internal iliac node (Fig. 1A). Bipedal lymphography and fine-needle aspiration biopsy of pelvic lymph nodes revealed one right and three left internal iliac lymph node metastases. The Eastern Cooperative Oncology Group performance status of the patient was grade 0. Two cycles of intravenous MEC (MTX 45 mg/body, epi-doxorubicin 75 m/body, CDDP 150 mg/body) were not effective. Thus, we performed 7 cycles of IIA (CDDP 70 mg/body, THP-doxorubicin 30 mg/body, MTX 30 mg/body) and 40 Gy of irradiation to the whole pelvic space. Based on imaging evaluation of this neoadjuvant treatment, the left internal iliac node had decreased to 2 cm 4 months later, and the trigonal bladder tumor showed complete response by computed tomography (CT) scan, and transurethral whole layer core biopsy 4 revealed no residual bladder tumor. Repeated lymphography and fine-needle aspiration biopsy could not detect malignant cells, and all pelvic lymph nodes were decreased in the size. Computed tomography–guided core biopsy of the enlarged left internal iliac node, which was not visualized by lymphography, was performed twice after the fifth and seventh IIA, and could not detect malignant cells. We selected bladder preservation for this patient. However, pelvic node metastasis developed on the side opposite that of the primary node metastasis 36 months after the completion of the treatment (Fig. 2A) but was successfully treated by five cycles of IIA (CBDCA 150 mg/body, THP-doxorubicin 30 mg/body, MTX 30 mg/body) and 50 Gy of focused irradiation (Fig. 2B). The patient now shows no evidence of disease 60 months after the completion of the initial treatment.
A 76-year-old man had a 7-cm left common iliac lymph node metastasis, 7-cm bladder tumor in the left side wall, and left hydronephrosis. The Eastern Cooperative Oncology Group performance status of the patient was grade 0. He was treated with 5 cycles of IIA (CBDCA 150 mg/body, THP-doxorubicin 30 mg/body, MTX 30 mg/body) and 50 Gy of irradiation and obtained a complete response (Figs. 3 and 4). He now shows no evidence of disease 21 months after the completion of the initial treatment. A side effect of IIA, grade II thrombocytopenia caused by CBDCA, was treated by thrombocyte infusion.
An increased proportion of complete responses was noted when cisplatin-based combination chemotherapy was used, but most reports cited various toxicities when these regimens were used intravenously. 5,6 To reduce the systemic toxicities and improve the response rate, intraarterial chemotherapy had been suggested. 7–9
A meta-analysis indicated that a benefit in survival was obtained if radiotherapy was given concomitantly with chemotherapy. 10 Because of the effectiveness of cisplatin-based chemotherapy in patients with invasive bladder cancer, the often favorable response of the primary tumor to combination chemotherapy, and synergetic effect of chemotherapy and radiotherapy, it is surmised that a combination of chemotherapy and radiotherapy represents an alternative to radical cystectomy. The most effective combination and doses of chemotherapy and sequence of chemotherapy and irradiation have not yet been established. We applied IIA chemotherapy to obtain the peak concentration of drugs at the tumor site for optimal radiosensitization. It has been postulated that cisplatin combinations have an activity greater than cisplatin alone; moreover, concomitant cisplatin and irradiation increase overall pelvic disease control in comparison with noncisplatin-based combination treatment with radiation. We used a combination of cisplatin (or carboplatin), THP-doxorubicin, and methotrexate with radiotherapy to obtain the effect of combination chemotherapy as well as the synergistic effect of cisplatin, THP-doxorubicin, and methotrexate with radiotherapy, because these three are effective against tumors of the urinary tract. 11
Because tumor radiosensitivity is often apparent at more than 40 Gy, the Massachusetts General Hospital and Radiation Therapy Oncology Group included a check cystoscopy after 40 Gy was delivered to select patients for bladder preservation and incomplete responders who had poor prognosis after bladder-sparing surgery. 12
As arterial infusion chemotherapy, 50 mg/m2 to 70 mg/m2 of cisplatin is commonly used. Conversely, for renal-impaired patients, carboplatin is another candidate for arterial infusion. In experimental work using rabbits, 10 mg/kg of carboplatin was reported to be effective as IIA for bladder or cervical cancer. 13,14 In clinical use, 300 mg/m2 to 400 mg/m2 of carboplatin is used. 15,16 However, in our 2 cases, only 100 mg/m2 of carboplatin was sufficient not only for bladder tumors but also for large pelvic lymph node metastasis. Arterial infusion of carboplatin was as effective as cisplatin. Low-dose carboplatin should be examined for IIA.
For N3 bladder cancer, complete response by chemotherapy alone is rare, and those patients did not survive 3 years. 1,2 In our Case 1, although he had recurrent pelvic lymph node metastasis, he now shows no evidence of the disease 5 years after the completion of the initial treatment.
The prognosis of patients with invasive bladder cancer with pelvic lymph node metastasis is poor, and only 30% have been reported to achieve 5- and 10-year survival rates. 1 Few clinical studies have been carried out on pelvic node metastasis treated by IIA and irradiation. We have reported 5- and 8-year survival rates of 76% and 57%, respectively, in 13 patients with multimodality therapy combined with IIA and irradiation. 3
A side effect of IIA, grade II thrombocytopenia, was caused by CBDCA in Case 2. Radiation cystitis and radiation proctitis are common complications of irradiation to urinary bladder. Fortunately, we have experienced no such cases.
IIA combined with pelvic irradiation was effective for large pelvic lymph node metastasis (N3) in the two patients with bladder cancer.
Acknowledgment: The authors thank the doctors of Radiological Department, Tohoku University Hospital, for the radiologic treatment and internal iliac arterial infusion chemotherapy of patients.
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