Phase I study of taxol using a 5-day intermittent schedule.

Taxol is a plant product derived from the western yew, Taxus brevifolia. We have conducted a phase I clinical study of Taxol used intravenously daily for 5 days at 3-week intervals. The starting dose was 5 mg/m2 daily, and the highest dose used was 40 mg/m2 daily for 5 days. The daily dosage of Taxol was mixed in 250 mL of intravenous fluid and infused over a period of 1 hour. A total of 20 patients with metastatic solid tumors refractory to standard therapy received 45 courses of therapy. Taxol was generally well tolerated and caused no significant nausea or vomiting. A mild degree of diarrhea was reported by six patients, and a moderate degree of stomatitis at the higher dose levels developed in four patients. All patients treated in the dosage range of 20 mg/m2 to 40 mg/m2 experienced nearly complete alopecia. Myelosuppression, predominantly in the form of leukopenia, was the dose-limiting toxicity. The nadir of leukopenia was reached between days 8 and 12 followed by complete recovery between days 15 and 21. Leukopenia was first observed following the Taxol dosage level of 20 mg/m2/d, was moderately severe at the dosage level of 30 mg/m2/d, and was severe at the dosage level of 40 mg/m2/d. No objective tumor regression was observed. A starting dosage level of 30 mg/m2/d for 5 days is recommended for phase II trials using this schedule.

Pelvic lymphadenectomy for staging clinically localized prostate cancer. Indications, complications, and results in 217 cases.

We reviewed the findings of 217 consecutive pelvic lymphadenectomies performed in patients with clinically localized prostatic carcinoma focusing particular attention on the importance of completely removing the hypogastric lymph nodes and on the operative complications associated with a more extensive dissection. Metastatic disease was identified in the lymph nodes of 127 patients (58.6%). The hypogastric nodes were involved in two thirds of the patients with lymph node metastases, and in 29 percent the hypogastric nodes were the only site of metastasis. No increased operative morbidity was documented as a result of extending the level of the pelvic lymphadenectomy to include the lower hypogastric nodes. We conclude that although the lower hypogastric lymph nodes have not been routinely included in most pelvic lymphadenectomies, their removal is important in detecting metastases.

Identifying patients with low-risk clinical stage I nonseminomatous testicular tumors who should be treated by surveillance.

We examined the records of 82 patients with clinical Stage I nonseminomatous germ cell tumors of the testis who, after radical orchiectomy, were treated by surveillance at M.D. Anderson Cancer Center between October, 1981, and March, 1987. Our purpose was to determine whether or not patients with a low risk of relapse can be identified at the time of the initial staging evaluation. In 30 of 82 patients (Group 1), embryonal carcinoma constituted less than 80 percent of the tumor, no vessel invasion was present, and the preorchiectomy serum AFP level was less than 80 ng/dL. No relapses occurred in this group. Fifty-two patients (Group 2) had more than 80 percent embryonal carcinoma or vessel invasion or a serum AFP level higher than 80 ng/dL. Relapse occurred in 24 (46%) of these patients. The difference in the rate of relapse between patients in Group 1 and Group 2 was statistically significant (P less than 0.00001). A separate analysis of teratoma as a predictor of nonrelapse showed that the orchiectomy specimens of 30 of the 82 patients contained more than 50 percent teratoma. Only 1 relapse occurred among 25 patients with more than 50 percent teratoma and no vessel invasion. Our data show that there is a subgroup of patients with clinical Stage I nonseminomatous germ cell tumor who have a very low rate of relapse. We believe these patients can be effectively treated by surveillance and should be spared the morbidity of an unnecessary retroperitoneal lymph node dissection.

Stage B (P2/3A/N0) transitional cell carcinoma of bladder highly curable by radical cystectomy.

Seventy-one patients with pathologic Stage B (P2/3a/N0) transitional cell carcinoma (TCC) of the bladder underwent radical cystectomy alone without preoperative radiotherapy or perioperative chemotherapy between 1983 and 1987 and have been followed a median of fifty months. The five-year actuarial survival and disease-free survival rates were 82 percent and 77 percent, respectively, and only 13 patients (18%) have relapsed. Histologic parameters were evaluated as to prognostic impact; none correlated with disease-free survival rates although the presence of vessel involvement portended a worse disease-free survival rate (68% versus 80%). During this same period, an additional 15 patients underwent radical cystectomy for pathologic Stage B disease but received adjuvant chemotherapy on the basis of vessel invasion. Their disease-free survival rate at five years was 80 percent, comparable to the disease-free survival rate for patients with vessel invasion treated by surgery alone (68%). Although the role of systemic chemotherapy in the management of invasive bladder cancer remains under investigation, it would appear that patients with Stage B TCC are best treated with radical cystectomy alone. Continued analysis of modern surgical results grouped by current pathologic staging criteria is needed to identify patients who have a relatively low risk of relapse and thus little need for additional therapeutic intervention. These results demonstrate that Stage P2/3a/N0 TCC of the bladder is highly curable by surgery.

Will Rogers and the results of radical cystectomy for invasive bladder cancer.

Disease-free survival rates for patients with muscle-invasive bladder cancer treated by radical cystectomy with bilateral pelvic lymphadenectomy with or without adjuvant chemotherapy are 75% to 80% in stage B disease, 60% in stage C disease, and approximately 50% in stage D disease. Vascular invasion is an important prognostic factor in meticulously staged patients. Powerful selection factors, including more accurate clinical and pathologic staging and improved surgery, as well as unspecified selection factors, may contribute to the improved results. In order to evaluate the impact of adjuvant chemotherapy, a randomized, controlled study is necessary.

Prostate specific antigen in patients with clinical stage C prostate cancer: relation to lymph node status and grade.

The preoperatively drawn sera from 84 previously untreated patients who had clinical stage C prostate cancer and underwent staging pelvic lymph node dissections were sent for monoclonal Hybritech analysis to assess the usefulness of prostate specific antigen (PSA) in predicting lymph node status. Of the 84 patients 47 (56%) had positive lymph nodes at surgery. The median PSA value for all patients with nodal metastases was 11.4 ng/.ml., and for those without it was 11.2 ng./ml. Relative to Gleason score, median PSA values were 11.35 for 2-4, 12.2 for 5-7 and 10.9 ng./ml. for 8-10. Within each M.D. Anderson grade median PSA values were 10.15 for grade I, 13.2 for grade II, 12.7 for grade III and 10.5 ng./ml. for grade IV. Simultaneously drawn preoperative frozen serum samples for 28 of these patients were independently analyzed by the Yang radioimmunoassay. Comparing Hybritech and Yang methods revealed strong statistical co-association (correlation coefficient R2 = 97.36, p less than 0.00001) but neither assay was statistically associated with nodal metastasis. Although no PSA level excluded the presence of nodal disease, we suggest that a Hybritech PSA of greater than 30 ng./ml. and a Yang PSA of greater than 50 ng./ml. may serve as a weak adjunctive marker predicting nodal metastasis.

Phase I study of weekly-administered iproplatin [cis-dichloro-trans-dihydroxy-bis-isopropylamine platin (chip, JM9)].

Iproplatin [cis-dichlor-trans-dihydroxy-bis-isopropylamine platinum (CHIP, JM9)] is a new antineoplastic platinum analogue with an octahedral conformation. It has more water solubility than does cisplatin and was found to have less neurotoxicity and nephrotoxicity in experimental animals than cisplatin. Like cisplatin, it has been demonstrated to have a broad spectrum of activity in experimental tumor systems. A phase I study of iproplatin was conducted in 28 patients (12 with melanoma, 8 with sarcoma, 6 with breast cancer, and 2 with colon cancer). All patients had failed prior chemotherapy. Four consecutive doses of iproplatin were administered at weekly intervals followed by a rest period of two weeks for hematologic recovery (one course). One hundred forty-two weekly doses were administered with all patients except three receiving at least one full course. The weekly starting dose of 40 mg/m2 was increased to 120 mg/m2 given over 30 minutes without hydration. Myelosuppression predominantly thrombocytopenia, was the dose-limiting toxicity at weekly doses of greater than or equal to 95 mg/m2 per course. With iproplatin doses 75 mg/m2, 95 mg/m2, and 120 mg/m2, the lowest median granulocyte counts were 2.6 x 10(3)/mm3, 2.2 x 10(3)/mm3, and 1.8 x 10(3)/mm3, respectively. Similarly, at iproplatin doses of 75 mg/m2, 95 mg/m2, and 120 mg/m2, the lowest median platelet counts were 144 x 10(3)/mm3, 99 x 10(3)/mm3, and 31 x 10(3)/mm3, respectively. Mild to moderate nausea and vomiting were observed in the majority of patients. No significant neurotoxicity, nephrotoxicity, or ototoxicity was observed. Objective tumor regression was not observed in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Prompt orchiectomy reduces morbidity and mortality from testicular carcinoma.

The records of 154 patients with non-seminomatous germ cell testicular tumours were reviewed to determine the potential effect of prompt diagnosis and orchiectomy on morbidity and mortality from this disease. Orchiectomy was performed 30 days or less after the onset of testicular symptoms on 65 patients (Group 1) and more than 30 days after the onset of symptoms on 89 patients (Group 2). The initial clinical stages of Group 1 patients were: I, 40 (62%); II, 14 (22%); III, 5 (8%); marker only, 6 (9%). The initial clinical stages for Group 2 patients were: I, 25 (28%); II, 15 (17%); III, 35 (39%); marker only, 14 (16%). The difference between the percentages of Group 1 and Group 2 patients with stage I disease was statistically significant, as was the difference between the percentages of Group 1 and Group 2 patients with stage III disease. One of the Group 1 patients died, whereas 11 of the Group 2 patients died. In 5 of the Group 2 patients who died, orchiectomy had been performed more than 120 days after the onset of testicular symptoms. This study suggests that orchiectomy performed promptly after the onset of testicular symptoms not only helps to reduce mortality from testicular cancer but also has a major effect on its morbidity by reducing the need for systemic chemotherapy or major surgery.

Monoclonal prostate-specific antigen in untreated prostate cancer. Relationship to clinical stage and grade.

The authors evaluated 440 men with clinically staged and untreated prostate cancer with a monoclonal prostate-specific antigen (PSA) assay. The serum PSA value correlated significantly with both the stage and grade of disease (P less than 0.00005). The relationships between PSA and consecutive Stages A, B, C, and D2 (alpha = 0.15) and between progressive Gleason's scores 2 to 4, 5 to 7, and 8 to 10 (alpha = 0.15) were statistically significant. Also statistically significant was the correlation between serum PSA level and intracapsular versus extracapsular disease (P less than 0.00005), although no one value can be used to differentiate reliably between patients in these two categories. The probability of clinically detectable metastasis (Stage D2) is 85% if the serum PSA level is greater than 30; however, 12% of patients without clinical evidence of metastases (Stages A, B, and C) have such a serum PSA value. Despite the statistically significant association between PSA and tumor differentiation and volume as reflected by tumor grade and clinical stage, this marker cannot be used to determine either for an individual patient.