Immuno-chemotherapy in metastatic renal cell carcinoma: long-term results from the rambam and linn medical centers, Haifa, Israel.

Nephrectomy, immuno-chemotherapy and resection of residual disease have been the treatment of choice for patients with metastatic renal cell carcinoma during the past decades. The aim of this study was to report the long-term results of this treatment approach. Sixty-two patients with metastatic renal cell carcinoma participated in a Phase II study. At diagnosis, 32 patients had localized disease, 30 had metastatic disease and 53 underwent nephrectomy. Metastatic sites were lungs, lymph nodes, bones and liver. Immuno-chemotherapy consisted of: interleukin-2, interferon alpha, 5-fluorouracil and vinblastine. All patients were evaluated for toxicity and response to treatment. CR was achieved in 4 patients and PR in 14. Seven patients, with maximum response to immuno-chemotherapy underwent resection of residual tumor and reached CR. Therefore, CR was achieved in 11 patients (18%) with a median survival of +67 months. Flu-like symptoms were the common side effects. Performance status and histology type significantly affected survival. Nephrectomy, immuno-chemotherapy and resection of residual disease are recommended for patients with metastatic renal cell carcinoma.

Quantitative bone single-photon emission computed tomography for prediction of pain relief in metastatic bone disease treated with rhenium-186 etidronate.

PURPOSE: To calculate radiation doses of rhenium-186 ((186)Re) etidronate in painful bone metastases using quantitative bone single-photon emission computed tomography (SPECT) and to determine the threshold dose for predicting pain relief. We also wanted to determine whether technetium-99m ((99m)Tc) methylene diphosphonate (MDP) concentrations predict radiation doses of (186)Re etidronate in painful lesions. MATERIALS AND METHODS: Forty-eight patients with breast and prostate cancer were evaluated. Patients received therapeutic doses of (186)Re etidronate. The area under the pain over time curve (AUPC) was measured for 8 weeks after treatment. Response was calculated as the percentage of change in AUPC. Quantitative bone SPECT (QBS)-measured concentration of (186)Re etidronate was used for calculating radiation doses. Receiver operating characteristics curve analysis determined the radiation dose threshold that best separated responders from nonresponders. SPECT-measured concentration of (186)Re etidronate in the urinary bladder was correlated with its concentration in the voided urine. Concentration of (99m)Tc MDP was compared with radiation doses to painful metastases. RESULTS: The radiation dose threshold was 2.10 Gy. For a decrease of 50% in the AUPC, the positive predictive value (PPV) of this value was 75% and the negative predictive value (NPV) was 88%. For a decrease in pain of 33%, the PPV was 84% and the NPV was 81%. In prostate cancer patients only, the PPV was 81% and the NPV was 92%. The correlation between in vivo/in vitro measured urine concentration was 0.90. The correlation between (99m)Tc MDP concentration and radiation doses of (186)Re etidronate was 0.92. CONCLUSION: QBS-measured radiation doses of (186)Re etidronate in painful metastases are a good predictor of pain relief. Bone SPECT using (99m)Tc MDP predicts radiation doses delivered by (186)Re etidronate.

Whole abdominal irradiation following chemotherapy in advanced ovarian carcinoma.

One hundred and sixteen patients with advanced ovarian carcinoma, who underwent primary cytoreductive surgery, received 6-11 courses of chemotherapy by cis-platin (50 mg/m2) and adriamycin (50 mg/m2) every 21 days. This was followed by second look laparotomy in 66 patients with no clinical evidence of disease. Consolidation abdominal irradiation was administered to 43 patients. Two techniques of irradiation were employed: between 1980-1983 whole abdominal irradiation was used and patients were to receive 3000 cGy in 4 weeks (Schedule I). Due to myelosuppression only 13 of 26 patients (50%) completed the planned dose of radiation. Between 1983-1985 the target volume was divided into upper and lower parts. First, the lower abdomen received 3000 cGy in 3 weeks, and then the upper abdomen received the same dose (Schedule II). Sixteen of seventeen patients (94%) thus treated, completed the planned dose of radiation. The actuarial survival for all 116 patients was 28% of 5 years. Irradiated patients with negative second look laparotomy had a survival probability of 100% at 24 months. Irradiated patients with microscopic disease at second look operation had an actuarial 5-year survival of 66%. Patients with minimal residual disease at second look laparotomy, receiving consolidation abdominal irradiation, had an actuarial survival of 5% only at 36 months. It is concluded that consolidation radiotherapy is effective in patients with negative or microscopic residual disease at second-look laparotomy. In regard to bone marrow tolerance, split field technique of irradiation is preferred.

The effect of low-dose interleukin-2-based immunotherapy on salivary function and composition in patients with metastatic renal cell carcinoma.

One of the side-effects accompanying low-dose recombinant interleukin-2 (rIL-2)-based immunotherapy is salivary hypofunction. We evaluated the functional and compositional whole salivary profile at both resting and stimulated conditions in 10 renal cell carcinoma patients who received prolonged low-dose rIL-2-based immunotherapy. Following the termination of 4 weeks of the combined administration of rIL-2 and recombinant interferon-alpha (rIFN-alpha), we found significant reductions of salivary flow rates at resting condition, accompanied by significant multiple compositional alterations, including increases in calcium, magnesium and phosphate concentrations, and significant reductions in total protein concentration. In contrast, no flow rate reduction was noted under stimulated condition, and the only significant altered compositional component was the phosphate. We recommend salivary-supporting therapies and anticariogenic treatments for patients undergoing low-dose rIL-2-based immunotherapy.

[Treatment of urinary bladder cancer--a retrospective analysis].

Data on 482 stage A-0--D2 bladder cancer patients referred between 1975-86 were analyzed. Prognosticators of survival were stage, histologic subtype and differentiation. 143 patients with disease localized to the pelvis (stage A-0--D1) received definitive radiotherapy with 60 Gy or more, and 25 underwent preoperative irradiation and cystectomy. Later, a group of 56 selected patients with stage B--D1, referred between 1988-1991, received neo-adjuvant MCV chemotherapy (methotrexate, cisplatin and vinblastine) preceding either definitive radiotherapy or surgery. The 2-year overall actuarial survival rates were similar: 63% for radiotherapy only, 72% for cystectomy and 68% for neo-adjuvant chemotherapy; they were also similar when broken down by stage and grade.

[Radiotherapy of localized prostatic carcinoma].

112 patients with localized prostate cancer, clinical stage A2-C, were treated by definitive radiotherapy between 1982-1988. Radiation volume encompassed the prostate, seminal vesicles and pelvic lymph nodes. The 10-year actuarial survival figures were: overall 51%; stage A2 87%; stage B 50%; stage C 36%; well differential tumors 67%; moderately differentiated 50%; poorly differentiated 32%; patients with local tumor control 55%; and patients with minimal local control 36%. It is concluded that external beam irradiation is effective in localized prostatic cancer. Stage and grade are prognosticators of survival.

Correlations of dose and time-dose-fractionation factors (TDF) with treatment results and side effects in cancer of the uterine cervix.

Treatment results and side effects were analyzed for 57 patients with stage IB-IIIA cancer of the uterine cervix who received external beam radiotherapy combined with intracavitary insertion of cesium-137 sources. The total dosage and time-dose-fractionation (TDF) factors were calculated at point A and at points of maximum exposure in the rectum and bladder. The overall 5-year survival was 62%, and 78% of the complete responders were free of disease at 5 years. A total of 12 patients (21%) developed rectal complications. Two patients (4%) had rectal fibrosis and proctitis; seven cases of rectal bleeding occurred (12%), and 3 patients (5%) developed rectovaginal fistulas. There was no correlation between dose and TDF at point A and treatment failure or appearance of rectal complications. However, the occurrence of radiation damage in the rectum was consistently associated with high values of TDF when they were calculated in the region of maximal exposure in the rectum. The results suggest that TDF may be a useful parameter for predicting radiation damage in combined external beam and intracavitary treatment of cervical cancer.

Treatment of muscle invasive bladder cancer. Is there a role for neoadjuvant chemotherapy?

PURPOSE: Because 5-year survival with advanced bladder cancer is still poor, the search for optimal treatment continues as dose the necessity of clarifying goals of treatment. PATIENTS AND METHODS: We compared the outcome of 3 different but widely accepted treatment protocols for bladder cancer in order to find which, if any, was superior, with particular emphasis upon the performance of the newest treatment, neoadjuvant chemotherapy. Data on 224 bladder patients treated at our institution (1975 to 1991) with 1 of the 3 protocols was analyzed. Those protocols were: 1. radiotherapy > 60 Gy (143 patients); 2. low dose radiotherapy followed by cystectomy (25 patients); 3. chemotherapy followed by either definitive radiotherapy or surgery (56 patients). Because the latter group was also a chronologically newer group with a shorter possible follow-up, we compared all treatments on the basis of 2-year survival, using Kaplan-Meier life tables. We briefly reviewed those modalities which are bladder-sparing because of the significance to quality of life of this factor. RESULTS: Two-year survival figures for the patients were: 63% for those who received only radiotherapy; 72% for those undergoing cystectomy: 68% for the group to whom neoadjuvant chemotherapy was administered. The differences were not statistically significant. However, 23% of those patients treated neoadjuvantly were alive with intact bladders at 2 years. CONCLUSION: These results do not suggest that a superior survival advantage is associated with any of these 3 protocols and neoadjuvant chemotherapy, in particular, cannot be seen as conferring a new and important survival advantage. However, neoadjuvant chemotherapy followed by radiotherapy does permit bladder conservation and, given that life span will often be reduced, the importance of helping to keep the remainder of the patient's life as comfortable as possible, can hardly be overestimated.

Serum free/total prostatic-specific antigen in prostate cancer patients treated with LH-RH agonists.

OBJECTIVE: This study is based on promising results using the ratio of free/ total (F/T) prostatic-specific antigen (PSA) for discrimination between benign prostatic hypertrophy and prostate cancer. We tried to determine the value of F/T PSA in different clinical situations at a certain time point during follow-up of luteinizing-hormone-releasing hormone (LH-RH) agonist treatment and to correlate it to T-PSA. PATIENTS AND METHODS: 182 patients followed-up for different periods in the last 3 years were routinely monitored for serum T-PSA. During the last 11 months, F-PSA was also measured together with T-PSA, and the ratio of F/T PSA was calculated. In 26 patients, the ratio of F/T PSA was monitored sequentially in several samples. RESULTS: Although 5 patterns of clinical response to LH-RH agonists were identified according to previous T-PSA, the F/T ratio could significantly (p < 0.05) discriminate between patients responding to treatment in contrast to patients escaping, fluctuating or not responding to hormonal ablation. Those patients responding to hormones showed a higher F/T PSA ratio (36.5 +/- 33.1%) compared to the nonresponding group (12.0 +/- 10.1%). CONCLUSIONS: During individual follow-ups, the pattern of response to LH-RH treatment is reflected by the F/T PSA ratio: while successful treatment causes an F/T PSA increase, relapse is accompanied by a decrease in this ratio. However, the changes in the F/T PSA ratio did not precede the indicative changes in T-PSA. It seems that increased values of F/T PSA ratios are intrinsic features of 'benign' prostatic disease, and the molecular events resulting in different PSA molecules in various clinical situations have to be elucidated.

Multimodal approach (surgery, chemotherapy, and radiotherapy) in the treatment of advanced ovarian carcinoma.

Forty-five patients with advanced ovarian carcinoma without prior chemotherapy were treated with cisplatin-Adriamycin (doxorubicin) combination, 50 mg/m2 intravenously, for 11 cycles. Second-look operation (SLO) was performed in patients without evidence of disease at the end of chemotherapy. Abdominopelvic irradiation was administered to those found to have microscopic or minimal disease (tumor less than 2 cm) at SLO. Forty patients were evaluable. Chemotherapy induced complete response in 56.7% and partial response in 16.7%. In 25% of the reoperated patients, no tumor was found; 30% had microscopic disease; 25% had minimal disease; and 20% had larger tumors. Two-year survival rate was 45%. The residual tumor left at initial operation, the histologic grade, and the response to chemotherapy influenced survival. Toxicity was moderate. There were three treatment-related deaths (one due to sepsis, one due to cardiotoxicity, and one at SLO, respectively). Radiotherapy was poorly tolerated after chemotherapy. The median duration of follow-up was 21.5 months. Further follow-up is needed to study the long-term benefits of this multimodal approach.

T-cell subpopulation in patients with metastatic renal cell carcinoma treated by recombinant interleukin-2, recombinant interferon-alpha, 5-fluorouracil, and vinblastine.

T-cell subpopulations were evaluated in 10 patients with metastatic renal cell carcinoma treated with recombinant interleukin-2, recombinant interferon-alpha, 5-fluorouracil, and vinblastine. T-cell subpopulation was tested by flow cytometry, and the results were compared with healthy control subjects. Mean T-cell values before treatment as compared with control were as follows: CD3, 68 vs. 73%; CD4, 34 vs. 53%; CD8, 38 vs. 31%; CD4/CD8, 1.1 vs. 1.8; CD4CD69, 20 vs. 47%, and CD8CD69, 24 vs. 19%. The difference in CD4, CD4/CD8, and CD4CD69 was statistically significant. After treatment (8 weeks), the values of CD4/CD8 ratio and CD4CD69 increased. Three patients achieved complete response, two partial response, and two had stabilization of the disease. After treatment, the CD4/CD8 ratio increased in complete responders, from 1.1 to 2.0, and CD4CD69 increased in complete and partial responders, from 11 to 37% and 23 to 31%, respectively. In nonresponders, no similar change was observed. In conclusion, increases in CD4/CD8 ratio and CD4CD69 levels in metastatic renal cell carcinoma patients may be associated with response to immunochemotherapy.

Targeting pulmonary metastases of renal cell carcinoma by inhalation of interleukin-2.

INTRODUCTION: Pulmonary metastases of renal cell carcinoma (RCC) are associated with poor prognosis. Inhalation therapy with interleukin-2 (IL-2) is thus an appealing method for palliation. This multicenter study summarizes the national experience of IL-2 inhalation in patients with lung metastases of RCC. PATIENTS AND METHODS: Forty patients (median, 66.5 years of age) with radiologically documented progressing pulmonary metastases were enrolled. All patients had to be able to comply with inhalation technique, and were not candidates for other treatment options. Twenty-eight patients were systemic treatment-naïve. The protocol included three daily inhalations of IL-2 to a total dose of 18 MU. Treatment had to be continued until one of the following occurred: progression; a complete response; a life threatening toxicity; or patient refusal. Response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) system. RESULTS: The disease-control rate reached 57.5%, with a partial response rate of 2.5% and a disease stabilization rate of 55%. Median time to progression was 8.7 months. The main side-effects were cough and weakness. CONCLUSIONS: Inhalation of IL-2 for the treatment of pulmonary metastases in RCC is feasible, tolerable and beneficial in controlling progressive disease for considerable periods of time. The definition of response of biological therapy may need to be re-assessed and modified: stable disease should be regarded as a favorable response.