John R. Daniels

The Role of Adjuvant Chemotherapy Following Cystectomy for Invasive Bladder Cancer: A Prospective Comparative Trial

We assigned 91 patients with deeply invasive, pathological stage P3, P4 or N+ and Mo transitional cell carcinoma of the bladder (with or without squamous or glandular differentiation) to adjuvant chemotherapy or to observation after radical cystectomy and pelvic lymph node dissection. For most patients chemotherapy was planned as 4 courses at 28-day intervals of 100 mg./M.2 cisplatin, 60 mg./M.2 doxorubicin and 600 mg./M.2 cyclophosphamide. A significant delay was shown in the time to progression (p = 0.0010) with 70% of the patients assigned to chemotherapy free of disease at 3 years compared to 46% in the observation group. Median survival time for patients in the chemotherapy group was 4.3 years compared to 2.4 years in the observation group (p = 0.0062). In addition to treatment groups, important prognostic factors included age, gender and lymph node status. The number of involved lymph nodes was the single most important variable. We recommend adjuvant chemotherapy for patients with invasive transitional cell carcinoma after definitive surgical resection.

Reassessment of the Role of Adjunctive Surgical Therapy in the Treatment of Advanced Germ Cell Tumors

We treated 30 patients for stage B3 or B3C germ cell tumors between December 1978 and December 1983. After initial, high dose, platinum-based combination chemotherapy, all patients underwent adjunctive resection of all clinically evident residual disease. Residual malignant elements were found in the retroperitoneum in 35 per cent of 26 nonseminomatous germ cell tumor patients and in 40 per cent of those with residual lesions beyond the retroperitoneum following chemotherapy. After additional chemotherapy, including platinum plus etoposide for patients with residual malignant elements, 80 and 75 per cent of those with stages B3 and B3C disease, respectively, achieved a complete sustained remission at a mean followup of 30 to 38 months, respectively. The strongest predictors of ultimate treatment failure were the presence of extensive pulmonary disease at presentation and the finding of residual malignant elements in resected lesions. Of 4 patients with seminoma 3 achieved sustained complete remission, while 1 died of recurrent embryonal carcinoma. These data support the role of adjunctive resection of clinically evident residual lesions following initial platinum-based chemotherapy in advanced metastatic germ cell tumors, and demonstrate the efficacy of additional platinum-etoposide-based chemotherapy in the 35 to 40 per cent of patients who harbor residual malignant disease in resected lesions.

Chemotherapy of small-cell carcinoma of lung: a randomized comparison of alternating and sequential combination chemotherapy programs.

One hundred forty-seven eligible patients with small-cell carcinoma of the lung (SCCL) have been randomized to receive alternating (A) or sequential (S) combination chemotherapy. Initial treatment was with three cycles of VAM (A) or two cycles of POCC (S). VAM consists of VP16-213 200 mg/m2 intravenously (IV) day 1, Adriamycin (Adria Laboratories, Columbus, Ohio) 50 mg/m2 IV day 1, and methotrexate 30 mg/m2 IV day 1 repeated at 21-day intervals. POCC consists of cyclophosphamide 600 mg/m2 IV days 1 and 8, vincristine 1.5 mg/m2 (maximum, 2 mg) IV days 1 and 8, CCNU 60 mg/m2 po day 1, and procarbazine 100 mg/m2 po days 2 through 15. After initial treatment, all patients received whole brain radiation therapy (3,000 rad/10 fractions/2 wk). Patients with limited disease in addition received irradiation encompassing the tumor, hilar, mediastinal, and supraclavicular regions (5,000 rad/25 fractions/5 wk). After radiation, patients on arm A received POCC alternating with VAM; patients on arm S received POCC until progression when they were to be treated with VAM. The alternating arm was superior with respect to rate of complete remission (CR), median disease-free survival (MDFS), and median survival (MS). The advantage of alternating therapy was not as clearly demonstrated in the limited disease groups when interposition of involved field radiation delayed the initiation of the alternating schedule. In limited disease alone, comparing arm A with arm S, no statistically significant differences were noted. The CR rate was 42% v 54%, MDFS was 14 v 10 months, and MS was 16 v 10 months. In extensive disease, the CR rate was 44% v 20% (P = .03), MDFS was 6 v 4 months (P = .003), and MS was 10 v 7 months (P = .001). Improved treatment outcome in SCCL is achieved when combination chemotherapy regimens of similar effectiveness are administered in an alternating rather than sequential schedule.

Patterns of failure in small cell carcinoma of the lung

The initial sites and frequencies of disease progression in 97 patients with small cell carcinoma of the lung treated in a Northern California Oncology protocol were analyzed. Among the extensive disease complete responders (25 patients), the chest was the most frequent initial relapse site (18 patients), followed by the liver (nine patients) and bone (six patients). For those patients who had a partial or no response to treatment, the chest was the most frequent site of persistent disease and the majority progressed in the chest initially. The addition of chest irradiation (5000 rad/5 weeks) to patients with limited disease significantly reduced the incidence of relapse (25%) and prolonged the disease‐free interval in the chest in the complete responders, but did not affect the failure pattern in partial and nonresponders. All patients received prophylactic cranial irradiation and three limited disease patients (10%) and three extensive disease patients (4%) progressed in the brain. Cancer 50:1857‐1863, 1982.

Reduced mammographic density with use of a gonadotropin-releasing hormone agonist - Based chemoprevention regimen in BRCA1 carriers

Purpose: Women with a BRCA1 mutation (BRCA1mut) need risk reduction options beyond mastectomy and oophorectomy. We evaluated the efficacy, safety, and tolerability of hormonal chemoprevention with a gonadotropin-releasing hormone agonist (GnRHA) with low-dose add-back steroids in BRCA1mut carriers. Experimental Design: The 12-month open label clinical trial used the GnRHA deslorelin, ultra-low-dose estradiol (E2), and replacement testosterone, administered via daily intranasal spray in premenopausal women with a BRCA1mut, and intermittent oral medroxyprogesterone acetate. The end points included mammographic percent density, bone mineral density, endometrial hyperplasia, symptom inventory, and quality of life (Medical Outcomes SF-36 survey). Results: Six of eight BRCA1mut women (mean age, 30.3 years; range, 25-36 years) completed the study. Mammographic percent density was significantly reduced at 12 months (median absolute mammographic percent density decrease, 8.3%; P = 0.043), representing a 29.2% median reduction in mammographic percent density. Bone mineral density remained within reference limits for all participants; there were no cases of atypical endometrial hyperplasia and menses resumed within a median of 67 days (range, 35-110 days) after last drug treatment day. The treatment was well tolerated; hypoestrogenic side effects were minimal and transient; and there were no significant changes in quality of life. Conclusions: The GnRHA deslorelin, with low-dose add-back steroids, was well tolerated and significantly decreased mammographic percent density in BRCA1mut carriers. This regimen may reduce breast cancer risk and improve the usefulness of mammographic surveillance by reducing density. This is the first demonstration, to our knowledge, of a direct reduction of mammographic densities in young BRCA1mut carriers.

Current status of adjuvant chemotherapy after radical cystectomy for deeply invasive bladder cancer

Between March, 1976, and December, 1982, 70 of 157 patients (45%) undergoing single-stage radical cystectomy with pelvic lymphadenectomy and urinary diversion with the intent to cure invasive bladder cancer were found to have pathologic Stage P3B, P4 and/or N + disease. Thirty-four of the 70 patients received adjuvant prophylactic chemotherapy after cystectomy and 36 patients were followed expectantly. From 1976 through 1977 adjuvant chemotherapy consisted of cyclophosphamide 1 Gm/M2 each month for six months; from 1978 through June, 1980, adjuvant chemotherapy consisted of cis-platinum 100 mg/M2 each month for four months with the exception of 1 patient treated more aggressively with combination chemotherapy (CISCA). Since July, 1980, a prospective study has been utilized in which patients were randomized into two groups, Group A receiving combination chemotherapy and Group B followed up expectantly; adjuvant chemotherapy appears to result in a slight delay in time to relapse but no influence in overall survival was observed.

Chemosensitivity of human neoplasms with in vitro clone formation

SummaryWe analyze experience with 600 specimens for in vitro chemosensitivity assessment of human neoplasms utilizing a soft agar colony-forming technique. Good test reproducibility is demonstrated. Disaggregation with collagenase enhances yield and does not alter chemosensitivity profiles. Therapeutic exposure to chemotherapy prior to biopsy reduces in vitro sensitivity to the specific agents used in vitro. The cyclophosphamide derivatives 4-hydroperoxycyclophosphamide (4-HC) and phosphoramide mustard are active in vitro, and produce comparable rank order sensitivities among tested tumors. There is marked reduction of in vitro 4-HC sensitivity in patients with prior therapeutic cyclophosphamide exposure, supporting the use of this derivative in test systems. Rank order of test results among specimens is compared at 0.1 μg and 10 μg drug/ml. Substantial differences in rank order at these two dose levels are demonstrated, indicating that the in vitro test dose selected is an important variable.

Unusual antiproliferative effects of transforming growth factors-β 1 andβ 2 against primary cells from human tumors

Transforming growth factorsβ 1 andβ2 (TGF-β1 andβ2), tested in a clonogenic assay against primary cells from human tumors, suppress proliferation to different extents. In nineteen of twenty-six cell cultures, proliferation was < 50% of control with factor at 0.04 or 0.4 nM. Of these, TGF-β 2 was more active than TGF-β1 in fourteen; and TGF-β1 was more active than TGF-β2 in five. In seven of the nineteen, proliferation was 0% with one or the other factor. In contrast, cisplatin was much less effective in inhibiting proliferation of some of the same cells even at 1,000 or more times the molar concentration of the factors. Surprisingly, when TGF-β 1 and TGF-β2 were combined at equal concentrations, the antiproliferative effect of one was cancelled or markedly inhibited by the other.

Treatment of Endometriosis with the GnRHa Deslorelin and Add-Back Estradiol and Supplementary Testosterone.

Background. This randomized, multicenter, open-label clinical trial was intended to generate pilot data on the efficacy and safety of the gonadotropin-releasing hormone agonist (GnRHa) deslorelin (D) with low-dose estradiol ± testosterone (E2  ± T) add-back for endometriosis-related pelvic pain. Methods. Women with pelvic pain and laparoscopically confirmed endometriosis were treated with a six-month course of daily intranasal D with concurrent administration of either transdermal E2, intranasal E2, or intranasal E2  + T. Efficacy data included evaluation of dyspareunia, dysmenorrhea, pelvic pain, tenderness, and induration. Cognition and quality of life were also assessed. Safety parameters included assessment of endometrial hyperplasia, bone mineral density (BMD), and hot flashes. Results. Endometriosis symptoms and signs scores decreased in all treatment arms from a baseline average of 7.4 to 2.5 after 3 months of treatment and 3.4 after 6 months. BMD changes and incidence of hot flashes were minimal, and no endometrial hyperplasia was observed. Patient-reported outcomes showed significant improvement across multiple domains. Conclusions. Daily intranasal D with low dose E2  ± T add-back resulted in significant reduction in severity of endometriosis symptoms and signs with few safety signals and minimal hypoestrogenic symptoms that would be expected with the use of a GnRHa alone.

Subselective intra-arterial chemotherapy infusion in the treatment of hepatocellular carcinoma.

Intra-arterial delivery of chemotherapy is a well-established dominant treatment for hepatocellular carcinoma (HCC). This approach takes advantage of differential blood supply to the cancer, which is arterial, and to the liver, which is predominantly portal. Randomized trials demonstrating survival benefit have used transarterial chemoembolization (TACE) with arrest of blood flow and arterial obstruction to increase efficiency of drug delivery. Treatment-associated morbidity is significant but usually justified by the patient benefit. A number of alternative embolic particles have been explored to address efficacy and toxicity deficiencies of the original technology. In this article we list those materials. We then develop evidence that sub-selective arterial infusion therapy without embolic agents provides equivalent efficacy with less treatment morbidity.