Continuous-infusion 5-fluorouracil and cisplatin for advanced/recurrent transitional cell cancer of the bladder: a Southwest Oncology Group trial.

Significant toxicities result from the use of MVAC (methotrexate, vinblastine, adriamycin, cisplatin) for advanced/ recurrent transitional cell carcinoma of the bladder (ARTCCB). An alternative regimen of 5-fluorouracil (5-FU) and cisplatin was evaluated by Southwest Oncology Group (SWOG). Thirty-eight patients with ARTCCB were treated with continuous infusion 5-FU 1,000 mg/m2/days 1-5 and cisplatin 100 mg/day 1, on a every-21-days schedule. There were two complete responses (CR) and eight partial responses (PR) among 36 eligible patients, for an overall response rate of 28% [95% confidence interval (CI) 14-45%]. Median duration of response was 6 months, and median duration of survival was 9 months. No toxic deaths occurred. Grade 4 leukopenia occurred in 5 patients. Other toxicities were mild. Only two documented infections occurred in 5 patients with neutropenia. The response rate of 28% is better than that achieved with cisplatin alone and not dissimilar to the range of response for MVAC. Toxicities were less and tolerable. This regimen will need further evaluation.

Investment in new technology research can save future health care dollars.

OBJECTIVE: To perform a cost analysis of the emerging technology of lymphatic mapping for patients with malignant melanoma. DESIGN: A retrospective, computer-aided chart and financial cost and charge review of consecutive patients with the diagnosis of melanoma registered at a cancer center from December, 1995 to March, 1996. PARTICIPANTS: 73 consecutive patients with the diagnosis of Stage 1 and 2 melanoma (cutaneous disease only) had nodal staging of their disease with either a sentinel node (SLN) biopsy or an elective complete node dissection (ELND). This was determined largely by patient choice and the protocol in operation at the time of the presentation of the patient to the clinic. OUTCOMES MEASURED: There were no deaths in the series. Patient morbidity endpoints included rates of infection, incidence of extremity lymphedema, development of a seroma in the regional nodal basin wound and wound healing. Clinical outcome was measured by the ability to obtain complete nodal staging information with the new lymphatic mapping technology, and recurrence rates in the nodal basin after a negative SLN biopsy. Total charges, direct costs and total costs were calculated from all hospital, OR, pathology and lab charges. Professional fees were included in the analysis. RESULTS: Group 1 patients (50) had melanomas greater than 0.76 mm in thickness treated with a wide local excision (WLE), lymphatic mapping and SLN biopsy under general anesthesia. Five patients (Group 2) had their procedure performed under a straight local anesthesia. Group 3 patients (18) had nodal staging performed with an elective node dissection. In Groups 1 and 2, if the SLN was positive for micrometastases, the patients were taken back to the OR for a complete node dissection. The total charges per patient were $13,835, $6,853 and $19,285, respectively. Significant dollar savings were achieved if the nodal staging could be accomplished with the lymphatic mapping technology (p = 0.001). Morbidity was significantly less in Groups 1 and 2 compared to Group 3. After a mean follow-up of three years, only one patient has recurred in a SLN negative basin. CONCLUSIONS: With 38,300 new cases of melanoma diagnosed each year in the United States, a projected savings of $172 million per year (general anesthesia) and $350 million per year (local anesthesia) could be realized if this new mapping technology could be incorporated into the care of the melanoma patient. Patient morbidity is minimized, nodal staging is complete and patients return to work sooner. Recently approved adjuvant therapy can be applied in a selective fashion, treating only those patients in which a documented benefit has been obtained, saving the health care system more dollars. Initial investment in defining the technology was minimal.

Combination transurethral resection, systemic chemotherapy, and pelvic radiotherapy for invasive (T2-T4) bladder cancer unsuitable for cystectomy: a phase I/II Southwestern Oncology Group study.

OBJECTIVES: Primarily to evaluate the toxicity and, secondarily, the tumor response and patient survival associated with a three-phase combined modality treatment plan for patients with invasive transitional cell carcinoma (TCC) of the bladder (T2-T4,NX-N2, MO) who are medically unsuitable for or who refuse cystectomy. METHODS: Eligible patients initially underwent extensive transurethral resection (TUR) of the primary tumor with the attempt to resect disease totally. Subsequently, they received systemic combination chemotherapy consisting of two cycles of methotrexate, cisplatin, and vinblastine (MCV), followed by cystoscopic re-evaluation of the bladder tumor. Patients then received 6480 cGy radiotherapy to the bladder with concurrent systemic cisplatin. Toxicity, primary tumor response, and overall survival were evaluated. RESULTS: Of 34 eligible patients, 27 patients completed the treatment series. Twenty-two received 80% to 100% of the prescribed doses of MCV and only 2 patients experienced grade 4 hematologic toxicities. The most common toxicities were gastrointestinal (23), hematologic (21), and renal (8). The complete response (CR) rate after all treatment phases was 56% (19 of 34), 10 patients achieving a complete tumor resection of visible tumor at the initial TUR of the bladder (TURB); 3, a CR after MCV; and 6, after radiotherapy and concomitant cisplatin. The median overall survival was 21 months with 6 of 34 (18%) alive at 57 months (range, 36 to 75). Complete resection of tumor by TURB was associated with prolonged overall survival. The bladder was the initial site of recurrence in 85% of patients who had achieved a CR status. CONCLUSIONS: This older age patient group tolerated this combined modality therapy with acceptable toxicities, but the overall survival rate was not improved compared with those reported with radiotherapy alone.

Phase II trial of CHIP for the treatment of advanced, hormonally refractory carcinoma of the prostate. A Southwest Oncology Group Study.

CHIP, a second generation analogue of cisplatin, was subjected to a Phase II trial for the treatment of advanced, hormonally refractory carcinoma of the prostate. Forty-six patients were treated with CHIP 300 mg/m2 intravenously every 4 weeks. Evaluations for tumor response were done after three cycles of therapy. Among 40 evaluable patients there were no complete responses, but there were 6 partial responses for an overall response rate of 15% (95% confidence interval of 5.7 to 29.8%). The median time to response was 2.4 months and the median progression-free survival was 4.1 months. Median survival was 8.4 months. The most common toxicities were hematologic and gastrointestinal. While CHIP can be administered on an outpatient basis, its response rate for prostatic carcinoma appears to be similar to that of cisplatin.

Phase II trial of amonafide in advanced colorectal cancer: a SouthWest Oncology Group study.

Amonafide is a substituted benzisoquinolinedione that exerts its cytotoxicity through effects on macromolecular synthesis and intercalation of DNA. In this trial, 44 patients with advanced colorectal cancer and without prior chemotherapy received amonafide at a starting dose of 300 mg/m2 intravenously over one hour, on a daily x 5 schedule every 3 weeks. Toxicities of grade 3 or above included granulocytopenia, thrombocytopenia, sepsis, anaphylaxis and transient aphasia. Forty-seven % of patients had grade 3 or higher toxicity of any type. There were no complete or partial responses for an overall response rate of 0%, with a 95% confidence interval of 0-9%. The level of toxicity observed on this trial suggests an appropriate dose intensity of amonafide, despite lack of knowledge of patients' acetylator phenotypes.

Phase II trial of chlorozotocin and fluorouracil in islet cell carcinoma: a Southwest Oncology Group study.

PURPOSE: A phase II trial that used fluorouracil (5-FU) and chlorozotocin (CTZ) was performed in patients with metastatic islet cell carcinoma to determine the response rate and toxicity. PATIENTS AND METHODS: Patients received four cycles of induction chemotherapy. Good-risk patients received 5-FU 800 mg/m2/d days 1 to 4 as a continuous intravenous (IV) infusion (CIV) and CTZ 175 mg/m2 IV on day 1. Poor-risk patients (previous radiation to > or = 25% bone marrow-bearing areas; serum bilirubin > or = 5 mg/dL; creatinine > 1.0 mg/dL) received 5-FU 600 mg/m2/d and CTZ 75 mg/m2 in a similar manner. In responding or stable patients, reduced doses of 5-FU and CTZ were continued as maintenance therapy (maximum, 18 months). RESULTS: Forty-seven of 51 patients were eligible, and 44 received chemotherapy. Fourteen of 44 patients had partial responses, with 13 of 36 (36%; 95% confidence interval [CI], 21.0% to 54.0%) good-risk patients and one of eight (12%; 95% CI, 0.3 to 52.6%) poor-risk patients responding. Median survival of all patients was 25 months, and the median response duration was 11 months. Side effects were moderate to severe and included myelosuppression and gastrointestinal toxicity. Thirteen patients developed renal toxicity, which was severe or life-threatening in five. This seemed to be related to the administration of cumulative doses of CTZ > or = 1,500 mg. CONCLUSION: These results demonstrate that the combination of 5-FU and CTZ has activity in islet cell carcinoma, but the occurrence of renal toxicity secondary to CTZ may limit the use of this agent.

VM-26 in colorectal carcinoma: a Southwest Oncology Group study.

In this multi-institutional phase II study, VM-26 or Teniposide was administered to forty-two patients with advanced colorectal cancer. Patients were initially treated at 60 mg/M2 daily for 5 days with dose adjustments depending on toxicity. One complete response and one partial response were observed lasting six and four months respectively. Leukopenia was severe in 40% of patients. No drug related deaths were seen. In this Southwest Oncology Group (SWOG) study, VM-26 appeared to have minimal benefit in advanced colorectal cancer.

Hormonal therapy for locally advanced prostate cancer.

A patient with locally advanced prostate cancer (stages C and D1) has a poor prognosis with a high risk of developing and dying of distant metastases. Hormonal therapy is the major form of systemic therapy for metastatic (stage D2) prostate cancer. The most commonly used forms of hormonal therapy are orchiectomy, diethylstilbestrol, and luteinizing hormone releasing hormone, agonists that prevent the stimulation of tumor cells by testosterone. They produce a 60%-80% symptomatic or objective response rate, but their ability to prolong overall survival remains uncertain. Surgical adrenalectomy, hypophysectomy, and pharmacologic adrenal suppression prevent the clinically less significant adrenal androgen stimulation of tumor cells. Antiandrogens competitively inhibit the interaction between androgens and cytosolic androgen receptors. Complete androgen blockade (luteinizing hormone releasing hormone agonist and antiandrogen) was initially espoused to be superior to single-agent hormonal therapy, but preliminary results from a multigroup randomized trial suggest that it has only a minimal advantage. The benefit of hormonal therapy in stages C and D1 prostate cancer at the time of diagnosis has not been clearly established. Available studies are few, and most often they are uncontrolled or include only small numbers of patients. However, they suggest that the early use of hormonal therapy prolongs disease-free survival but does not prevent ultimate disease progression or prolong overall survival. Hormone receptor assays may be helpful in the selection of patients who would benefit from early hormonal therapy.

Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery.

Seventy patients with muscle-invading bladder carcinoma (clinical stages T2 to T4) who were not candidates for cystectomy were treated with combined cisplatin and full-dose external-beam radiation on a multi-institutional prospective protocol from 1980 through 1985. Thirty-six patients are alive, all but three without evidence of cancer. The complete response rate is 77% in the 62 patients completing planned irradiation and 70% for all patients. Among the complete responders, 73% are currently maintained, and this group has a significantly higher four-year survival than those not having a complete response and those with recurrence of disease--57% vs 11%. The observed high complete response rates in patients in all stages and the high survival rates suggest irradiation plus cisplatin therapy offers an important therapeutic gain over radiation therapy alone for invasive cancer of the bladder. These results encourage further evaluation of combining cisplatin-based, multidrug chemotherapy with irradiation in patients with locally very-advanced bladder tumors who are not suited for surgery.

Cisplatin bolus and 5-FU infusion chemotherapy for non-small cell lung cancer.

Patients with unresectable non-small cell lung cancer were treated with combination chemotherapy: cisplatin (100 mg/m2) on Day 1 and 5-FU (1 g/m2 continuous infusion) on Days 1-5, initially every third week, then every 4-6 weeks. Group 1 consisted of 19 patients without prior therapy and Group 2 consisted of 15 patients with prior therapy. Using standard criteria, seven patients (37%) in Group 1 achieved partial remissions lasting 2 to greater than 31 months (median, 10). Patients with squamous cell carcinoma or good performance status were somewhat more likely to respond. Three patients (20%) in Group 2 achieved partial remissions lasting 5-7 months. Mucositis (grade II in six patients, grade III-IV in seven patients) was the dose-limiting toxicity, especially in Group 2. These responses to cisplatin bolus and 5-FU infusion in patients with non-small cell lung cancer were not greater than those achieved with other cisplatin-containing regimens. However, this combination does have activity and might be effectively combined with radiation therapy as has been done for carcinomas of other sites.

Cisplatin and full dose irradiation for patients with invasive bladder carcinoma: a preliminary report of tolerance and local response.

Twenty-seven patients with invasive bladder carcinoma (clinical stages T2 to T4) who were not candidates for cystectomy were treated by transurethral resection, cis-diamminedichloroplatinum (cisplatin) and full dose radiotherapy according to protocol 8 of the National Bladder Cancer Collaborative Group A. Nausea and vomiting occurred in 74 per cent of the patients but were mild in 41 per cent. Maximum followup was 27 months and during that time 3 significant toxic reactions occurred: renal failure, systemic sepsis and a transient partial small bowel obstruction. Of 17 evaluable patients complete responses of the primary bladder cancer to the treatment were achieved in 11 of 13 with stages cT2 and cT3 cancer and in 2 of 4 with stage cT4 disease. The members of National Bladder Cancer Collaborative Group A have found transurethral resection, cisplatin and full dose external beam radiotherapy practical clinically. Longer followup will be necessary to determine if the observed high initial complete response rate of the tumor indicates real lasting benefit for these patients.

Autologous red blood cell and platelet engulfment in hairy cell leukemia.

Seven cases of hairy cell leukemia (leukemic reticulo-endotheliosis) are presented in which peripheral blood or splenic hairy cells or both were identified engulfing autologous red blood cells or platelets. In 3 patients, approximately 5-15% of their peripheral blood hairy cells were engulfing red cells and platelets. In 2 patients, intercellular junctions were present between processes of hairy cells and were similar to processes occasionally seen connecting Langerhans cells to each other. Also, parallel tubular arrays were identified in the cytoplasm of hairy cells from 2 other patients. We conclude that autologous red blood cell and platelet engulfment is a common finding in hairy cell leukemia.

4,000 RAD preoperative irradiation followed by prompt radical cystectomy for invasive bladder carcinoma: a prospective study of patient tolerance and pathologic downstaging.

The initial National Bladder Cancer Collaborative Group A experience with 4,000 rad adjuvant preoperative radiation therapy followed promptly (within 1 to 28 days) by radical cystectomy and urinary diversion in patients with muscle-invading bladder cancer was monitored prospectively with respect to tolerance of radiation therapy, early postoperative complications and pathologic downstaging. All patients completed the scheduled megavoltage irradiation with, at most, only mild intestinal, urinary or hematologic toxicity. In addition, 86 per cent of the patients completed planned radical cystectomy, with a median interval between radiation therapy and surgery of 13.6 days. No patient died postoperatively. Of the patients 69 per cent recovered with no postoperative complications, while 18 per cent had 1, 9 per cent had 2 and 4 per cent had 3 complications. Pathologic downstaging occurred in 39 per cent of the patients: the disease was downstaged to stage pT0 in 24 per cent and to stage pT1 or pTIS in 15 per cent. Of the patients with an interval of 13 days or less between radiation therapy and surgery the disease was downstaged to stage pT0 in 20 per cent and 63 per cent had no postoperative complications. In patients with an interval of more than 13 days the disease was downstaged in 30 per cent and 76 per cent had no postoperative complications. The results support our rationale for selecting this regimen of adjuvant full dose preoperative radiation therapy, which can shorten the interval between diagnosis and cystectomy, while allowing for the possibility of pathologic downstaging and a radiation dose that is likely to sterilize unresected pelvic micrometastases.

Combined modality therapy for advanced, diffuse lymphocytic and histiocytic lymphomas.

Forty-six previously untreated patients with advanced aggressive non-Hodgkin's (34 poorly differentiated and mixed diffuse, 8 histiocytic and 4 undifferentiated) were treated with a 3 phase combined modality program employing cyclophosphamide (C), hydroxyl-daunomycin (H), vincristine (O), prednisone (P), procarbazine (P) [CHOP(P)] combination chemotherapy in an initial induction phase, radiotherapy and nonmarrow toxic chemotherapy as a second consolidation phase, followed by a third phase of CHOP(P) chemotherapy for four more cycles. Long-term maintenance therapy was not given. High dose involved field radiation in phase II was limited to volumes encompasing less than 50% of the marrow bearing skeleton. The large majority of patients (82%) had such widespread involvement that this limitation precluded the use of local radiation and were treated instead with a mean of 132 rad of fractionated total body irradiation (TBI). Thirty-eight patients (83%) achieved complete remission. Twenty-nine (66%) of the 44 patients evaluable for follow-up, and 22 (61%) of the 36 patients receiving TBI, remain alive in complete remission for observation periods of up to 26 months.

Reduction of fatal graft-versus-host disease by 3H-thymidine suicide of donor cells cultured with host cells.

The effect of the tritiated thymidine (3H-TdR) suicide technique on the ability of donor cells to induce fatal graft-versus-host disease (GVHD) was studied. C57BL/6 (H-2b) spleen cells were stimulated in vitro with irradiated BALB/c (H-2d) Moloney lymphoma cells in mixed culture and 3H-TdR of high-specific activity added to eliminate proliferating cells. The ability of such cells to induce fatal GVHD was assayed by injecting them i.v. into adult BALB/c mice immunosuppressed with cyclophosphamide (180 mg/kg). These cells induced fatal GVHD in fewer mice (52 per cent) than did C57BL/6 cells cultures with BALB/C lymphoma cells but without 3H-TdR (87%) and C57BL/L cells cultured with irradiated C57BL/6 cells with (95 per cent) or without 3H-TdR (86 per cent). Thus, the 3H-TdR suicide technique greatly diminished the ability of cells to induce lethal GVHD.

Induction of increased graft-versus-host disease by mouse spleen cells sensitized in vitro to allogeneic tumor.

The aim of our study was to sensitize cells in vitro, follow their proliferative and cytotoxic responses, and determine their ability to cause lethal graft-versus-host disease (GVHD). C57BL/6 (H2b) spleen cells were incubated with irradiated BALB/C (H2d) Moloney lymphoma cells (LSTRA) in mixed leukocyte culture conditions for 2, 4, or 6 days and then tested. The maximal proliferative response occurred after 4 days. In vitro cytotoxic reactivity against 51Cr-labeled LSTRA was generated by 4 days (76.3+/-3.1% 51Cr released) and 6 days (133.0+/-4.8%) of sensitization but not by 2 days (-0.2+/-1.1%). Induction of fatal GVHD was assayed by injecting graded doses of the C57BL/6 spleen cells i.v. into adult BALB/c mice pretreated with cyclophosphamide, 180 mg/kg. Cells sensitized for 2 days were effective but no more so than were (control) cells cultured with irradiated C57BL/6 spleen cells. However, cells sensitized longer were far more active than the control cells. Cells sensitized for 4 days killed 70 of 88 mice (80%), and those sensitized for 6 days killed 37 of 48 mice (77%), whereas control cells killed only 42 of 90 mice (47%) (P less than 0.005). Thus, cells sensitized in vitro exhibited an increased ability to induce GVHD in vivo, which was temporally associated with the development of cytotoxicity in vitro.