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The M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) regimen was used to treat 25 patients with transitional cell carcinoma of the urothelial tract. Treatment consisted of monthly cycles of 30 mg. per m.2 methotrexate, followed 24 hours later by 3 mg. per m.2 vinblastine, 30 mg. per m.2 doxorubicin and 70 mg. per m.2 cisplatin, and concluded with repeat vinblastine and methotrexate on days 15 and 22. Significant tumor regression was noted in 71 per cent of the patients. Complete clinical remission was observed in 12 of 24 patients (50 per cent, 95 per cent confidence limits 30 to 70 per cent) with bidimensionally measurable indicator lesions, 6 of whom had pathological confirmation. After surgical exploration 4 patients required downstaging to a partial remission. The median duration of response has not yet been reached at 9.5 plus months, range 4.5 plus to 16 plus. Five patients (21 per cent) had a partial clinical remission for 4 to 8 plus months, 1 had a minor response for 4 months and 1 had stable disease for 11 months. All metastatic sites responded, including bone (6 of 8 cases), liver (3 of 5), locoregional (12 of 17) and intravesical (6 of 7) disease. Toxicity included moderately severe myelosuppression that resulted in nadir sepsis in 4 patients and a drug-related death in 1, mild to moderate anorexia, vomiting, alopecia and renal dysfunction. These preliminary results suggest that treatment with methotrexate, vinblastine, doxorubicin and cisplatin is extremely effective against locoregional and disseminated urothelial tract tumors, with the expectation (95 per cent confidence limits) of inducing objective tumor regression in 53 to 89 per cent of the cases.

Gallium nitrate, an agent known to inhibit bone resorption, was evaluated in patients with bidimensionally measurable hormone-refractory prostatic cancer. The starting dose was 200 mg/m2 iv by continuous infusion over 7 days. Two patients (10%; 95% confidence limits, 0%-22%) achieved short partial remissions of 1 and 6+ months, while seven of 23 (30%; 95% confidence limits, 14%-52%) showed a diminution of bone pain. Serial indices of bone turnover including serum calcium, phosphorus, and urinary hydroxyproline excretion showed a significant decrease at the completion of the infusion which returned to baseline prior to the next cycle. The data suggest the effect on bone was too short to produce consistent improvement. Reasons for the dissociation of pain relief and antitumor activity are discussed.

Elliptinium, 100 mg/m2 i.v. weekly, was administered to 14 patients with advanced renal cancer and 4 with breast cancer. There were no responses in 11 adequately treated patients. An unexpectedly high incidence of xerostomia, allergic, and hemolytic reactions were observed, which resulted in cessation of the trial. Recent data suggest polymer formation occurs with reconstituted elliptinium, and further trials are warranted when a new formulation is available.

Methylglyoxal-bis(guanylhydrazone) (MGBG), an inhibitor of polyamine synthesis, was administered to 35 patients with hormone-resistant advanced adenocarcinoma of the prostate in doses of 500 or 600 mg/m2 per week intravenously. Of 31 patients with bidimensional measurable soft-tissue lesions, 25 had an adequate trial, defined as four or more doses. Six (24%; 95% confidence limits, 8% to 32%) patients achieved a partial remission (greater than or equal to 50% reduction in tumor size) in soft-tissue disease. Response was noted to start after one to two doses and persisted for a median of three months (range, 1 to 4 months). Toxicity was tolerable, and significant myelosuppression was not observed. The lack of response in osseous metastases may be secondary to the short duration of remission or to the presence or inducibility of the enzyme ornithine decarboxylase in bone. Since some animal prostatic cancer tumor models are sensitive to cytotoxic drugs that produce polyamine inhibition, clinical trials of MGBG combined with other inhibitors of the polyamine pathway should be explored.

A phase-II trial of 4-demethoxydaunorubicin (4-DMDR) was performed in 21 patients with advanced renal cell carcinoma. The drug had demonstrated a broader spectrum of activity with less cardiotoxicity in preclinical evaluation than the parent compound daunorubicin. The starting dose was 12.5 mg/m2, with escalations to 15 and 17.5 mg/m2 in the absence of toxicity. Myelosuppression was the primary toxicity and cardiac toxicity was not seen in four patients who received four or more doses of DMDR. No responses were seen in 19 adequately treated patients, including 14 who had received no prior therapy.

Of 133 patients with advanced urothelial tract cancer given methotrexate (MTX), vinblastine (VBL), Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (DDP) (M-VAC regimen), significant tumor regression occurred in 72% +/- 8% of 121 with transitional cell carcinoma (TCC) evaluable for response. Complete remission (CR) was achieved in 36% +/- 9% of patients, of whom 11% required the addition of surgical resection of residual disease. Although 68% of CR patients have relapsed, CR median survival will exceed 38 months compared with 11 months for partial (36%) and minor (6%) responders, and 8 months for nonresponders: 2-year and 3-year survivals were 68% and 55%, respectively, versus 0% to 7% for the remaining patients. Sixteen percent of responders developed brain lesions, half of whom had no systemic relapse at the time of progression. Three patients with non-TCC histologies did not respond. In 32 patients who had pathologic restaging, the clinical (T) understaging (T less than pathologic [P] restaging) error was 35%. Although all metastatic sites showed evidence of tumor regression, CR was noted more frequently in lung, in intraabdominal lymph nodes and masses, and in bone (24% to 35%); the rate for hepatic lesions was 15%. There were 52% of 21 N3-4M0 patients who achieved CR versus 33% of 100 with N0-+M+ lesions. Toxicity was significant with 4 (3%) drug-related deaths, 25% incidence of nadir sepsis, 58% greater than or equal to 3+ myelosuppression, and 49% with mucositis. Responsiveness of metastasis in various sites, patterns of relapse, and the usefulness of the new CR response criteria are reported, as is the current status of cisplatin and methotrexate combination regimens.

In 23 patients with known transitional cell carcinoma of the bladder, 58 serial transabdominal sonograms were obtained, providing 35 cases in which interval change could be evaluated by sonography. Results were correlated with cystoscopy or surgery. Sonography accurately gauged change in 29 instances (83%), of which 13 showed increase, four decrease, and 12 stability of tumor. Errors in assessing interval change occurred when surgery between sonograms caused secondary bladder deformity or patchy edema of the bladder wall; these were misinterpreted as tumor growth. When smooth bladder thickening was present, sonography could not differentiate flat tumor from edema. In no case in which the bladder wall was normal on sonography was tumor found. In four cases sonography was a more accurate indicator of depth of tumor than cystoscopy was. These results suggest that sonography is a useful adjunct to cystoscopy and may be a dependable means of decreasing the frequency of invasive procedures to evaluate the extent of bladder disease. The use of these two techniques together may improve the accuracy achieved by using cystoscopy alone.

Transabdominal ultrasonography of the bladder was performed in 25 examinations on 20 patients being treated for bladder carcinoma. The presence or absence of tumor was accurately gauged in all 20 patients. As compared to cystoscopy, tumor staging was less accurate. Eleven of 15 patients with tumor present were accurately staged. Edema, intravesicular clot, and tumor calcification caused overstaging of tumors. Poor bladder distensibility limited examinations. Three patients were followed up with serial examinations, and sonography accurately determined the response to therapy.

The standard therapy for muscle-infiltrating tumors of the bladder remains radical cystectomy with or without radiation. Caution should be exercised about recommending newer regimens outside of clinical trials. However, combination chemotherapy programs can produce dramatic and durable remissions in a significant percentage of patients with advanced urothelial tract malignancies.

Fifty-seven patients with advanced measurable urothelial tract cancer, 52 of whom had an adequate trial, were treated weekly with 3 to 4 mg. per m.2 vinblastine and 30 to 40 mg. per m.2 methotrexate. Of 3 patients with unidimensional parameters 2 showed improvement lasting 16 and 27 months, which was documented by serial cystoscopic examinations. An additional 2 patients had measurable disease that could have been encompassed in a preoperative radiotherapy field. Both patients are free of disease at more than 12 and 14 months, respectively. Of the 47 patients with bidimensionally measurable parameters 19 (40 per cent) achieved a complete or partial remission lasting a median of 8 months, with a range of 1 to 24 months. Of 25 patients with intra-abdominal or pelvic disease 7 achieved a complete or partial remission and 5 also had a minor remission. Of note, 18 of 38 patients who had received no prior chemotherapy achieved a remission versus 1 of 9 who had been treated previously (p equals 0.06). Responders frequently obtained another remission with subsequent chemotherapy (4 of 9 versus 0 of 16, p equals 0.03). Responders lived 14 months versus 8 months for nonresponders (p equals 0.02). Four responders had brain metastases compared to none of 28 nonresponders. The combination of vinblastine and methotrexate is a well tolerated, effective outpatient regimen for patients with urothelial tract cancers.

A stratified, random-assignment trial of 442 cancer patients was conducted to evaluate medical, psychosocial, and financial outcomes of day hospital treatment as an alternative to inpatient care for certain cancer patients. Eligible patients required: a 4- to 8-hour treatment plan, including chemotherapy and other long-term intravenous (i.v.) treatment; a stable cardiovascular status; mental competence; no skilled overnight nursing; and a helper to assist with home care. Patients were ineligible if standard outpatient treatment was possible. No statistically significant (p less than 0.05) differences were found between the Adult Day Hospital (ADH) and Inpatient care in medical or psychosocial outcomes over the 60-day study period. The major difference was in medical costs--approximately one-third lower for ADH patients (p less than 0.001) than for the Inpatient group. The study demonstrates that day hospital care of medical oncology patients is clinically equivalent to Inpatient care, causes no negative psychosocial effects, and costs less than Inpatient care. Findings support the trend toward dehospitalization of medical treatment.

A total of 11 patients with stage T2-4N0M0 extravesical tumors (prostate, prostatic urethra, urethra and ureter) received 1 to 4 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin. Of 10 evaluable patients 4 (40 per cent) had downstaging to T0 disease with a clinical complete remission observed in 3 of 5 (60 per cent) with transitional cell tumors of the prostate and prostatic urethra. Four patients with urethral tumors of mixed or nontransitional histology failed to achieve a complete remission. The disease was staged pathologically in 4 patients: 1 had a partial remission and 3 had progression (all 4 had residual disease). Because therapy with methotrexate, vinblastine, doxorubicin and cisplatin induced only significant tumor regression of transitional cell elements of extravesical tumors and because it was ineffective against mixed histological tumors and in preventing new stage Tis lesions, surgical resection of such lesions is required.

A randomized trial of thymosin fraction V (60 mg/m2 s.c. twice weekly) given during induction chemotherapy and radiation therapy was performed in 91 patients with small cell carcinoma of the lung. Induction chemotherapy consisted of four cycles of an alternating combination of drugs (cyclophosphamide/Adriamycin/vincristine and cisplatin/etoposide). Radiation to the primary complex was given to patients with limited disease. All patients received prophylactic cranial irradiation. There were 35 patients with limited disease (18 randomized to thymosin and 17 to no thymosin) and 56 with extensive disease (28 thymosin and 28 no thymosin). Pretreatment immunological parameters were comparable between the two groups. For limited disease patients the overall response rate was 100%, including 66% (21 of 32) complete responders. The median duration of response was 19 mo (range, 5-57 mo) and survival 21 mo (range, 4 days to 57 mo). The 3-yr survival was 32%. For ED patients the overall response rate was 95% with 29% (13 of 48) complete. The median duration of response was 10 mo and the median duration of survival 12 mo with 13% alive at 2 yr. A comparison of the thymosin-versus no thymosin-treated patients revealed no difference in response rate, response duration, or survival whether analyzed as a whole or by extent of disease. An analysis based on pretreatment immune function and total white blood cell and absolute lymphocyte count revealed no difference in the survival distributions. No differences in the pattern of toxicity were observed between the thymosin- versus no thymosin-treated patients. The addition of thymosin fraction V during induction chemotherapy and consolidation radiotherapy did not alter outcome.

Of 92 patients who received methotrexate, vinblastine, doxorubicin and cisplatin complete and partial remissions were observed in 69 +/- 10 per cent of 83 adequately treated measurable and evaluable patients with advanced stages (N+M0 and N0M+) transitional cell urothelial cancer. Complete remission was achieved in 37 +/- 10 per cent of the patients clinically, pathologically and after surgical resection of residual disease. With 17 of 31 complete responders (55 per cent) surviving for 26+ to 49+ months, the estimated probability of survival at 2 and 3 years was 71 and 55 per cent, respectively. Partial remission occurred in 31 +/- 10 per cent of the patients, while 8 per cent had a minor response and 23 per cent had progression with median survivals of 11, 11 and 7 months, respectively. Whereas all metastatic sites responded, including the bone and liver, complete tumor regression was observed more frequently with nodal, pulmonary and local-regional lesions. Brain metastases occurred within 6 to 42 months in 18 per cent of the responders, half of whom never had systemic relapse. Of the remaining 9 patients 2 with nontransitional cell histological tumors did not respond, 5 (5 per cent) were inadequately treated and 2 were excluded from response data because of inevaluable disease parameters but they were free of disease at 16+ and 31+ months. Toxicity was significant, with 20 per cent of the patients experiencing nadir sepsis, 4 per cent a drug-related death, 31 per cent +1 renal toxicity and 41 per cent +1 mucositis. The applications and advantages of the newly proposed international response criteria for bladder cancer are discussed in reference to 25 patients who underwent surgical re-staging, indicating that the disease was understaged clinically in 24 per cent (T less than P), as well as in reference to attainment of true (pathological) complete remission and to other urothelial tract trials. While this therapy seems to have limited antitumor activity against nontransitional cell histological cancer, stage Tis disease and later development of de novo lesions, the regimen is efficacious in selected patients with advanced urothelial tract transitional cell carcinoma.

Deaza-aminopterin is a folate analog which is transported more rapidly than methotrexate into cells and appears to be more active than methotrexate against human and animal tumor in vitro. Fifteen patients with advanced urothelial tract cancer were given deaza-aminopterin 30-37.5 mg/m2 IV QW. In responding patients drug was given QOW after 4-6 consecutive doses. Doses were escalated or de-escalated by 7.5 mg/m2 depending on toxicity. Twelve patients had received prior chemotherapy which included methotrexate in nine. Three patients achieved a partial remission lasting 1, 3, and 3 months respectively: all responders had previously failed methotrexate after an initial response to a methotrexate containing regimen. None of the six patients who were methotrexate naive responded to deaza-aminopterin; 3 subsequently received methotrexate without response. Mild mucositis was universal and in 5 was severe. Six patients had an increase in liver transaminases probably secondary to anti-folate hepatotoxicity. Other toxicities included diarrhea, nausea, skin rash and fever. Further studies are needed to define the precise efficacy of deaza-aminopterin in patients with urothelial tract cancers.

10-Deazaaminopterin, a derivative of aminopterin with enhanced cellular uptake relative to methotrexate, was given to fourteen patients with advanced measurable hypernephroma. The dose-limiting toxicity was mucositis. Abnormalities in liver function were seen in 8 patients. No responses were seen in 13 adequately treated patients including 10 who had received no prior chemotherapy. The unique transport of this new group of compounds is discussed.

Etoposide, a semisynthetic derivative of podophyllotoxin, was evaluated concurrently in vitro against a human derived hormone-resistant cell line, PC-3, and in vivo in bidimensionally measurable hormone-resistant human prostatic cancer. In vitro, a dose-response relationship was observed, with 74% inhibition at 10 micrograms/ml (1 h incubation) and greater than 99% inhibition at 90 micrograms/ml, both in the range of clinically achievable concentrations. In vivo, 1 PR (5%, 95% confidence limits 0-12%) of 18+ months was observed in 20 adequately treated patients. The results confirm the limited role of etoposide in hormone-refractory disease and the need for new model systems for evaluation of potential chemotherapeutic compounds in this disease.

A Phase II disease-oriented drug trial using flutamide (4'-nitro-3'trifluoro-methylisobutyranilide) 250 mg by mouth three times a day was undertaken in 28 patients with advanced, bidimensionally measurable renal cell carcinoma. Of 25 adequately treated cases, 1 (4%, 95% confidence limits 0-12%) had a partial remission lasting 9+ months, and 2 had stabilization of disease lasting 6 and 15 months, respectively. Flutamide demonstrated no significant antitumor activity in patients with disseminated renal cell carcinoma. Including patients entered in this study, 62 specimens were evaluated for steroid binding sites using a fluorescent method: 33 of 62 specimens assayed showed no hormone-binding sites, and only 12 cases had androgen binding. Of the 12 of 23 patients receiving flutamide who were biopsied and had an adequate sample for steroid-binding site determination, estrogen binding was demonstrated in 6, androgen binding in 3, and progesterone binding in 4. Since this study did not obtain a sufficient number of cases with androgen-binding positivity, the possible efficacy of flutamide in such cases cannot be excluded.

Recently developed combination chemotherapy programs have now produced durable complete remissions in a significant percentage of patients with advanced urothelial tract malignancies. For advanced disease, efforts must still be directed at developing new agents but must also focus on understanding drug resistance. Some tumors appear to be resistant de novo; others respond for a period of time before a resistant population emerges. Clearly multiple factors come into play. In some cases, pharmacologic factors such as bioavailability metabolism, or toxicities predominate. In other cases, specific genes expressing surface proteins such as the p-glycoprotein identified in resistant ovarian tumors have been implicated. In the 1980s, it is no longer adequate to define tumors simply by pathologic inspection. As demonstrated by Russell and co-workers xenografts of phenotypically similar transitional cell tumors in nude mice demonstrated marked heterogeneity with respect to flow cytometric DNA analysis and immunocytochemistry. With the recent adoption of flow cytometric techniques, both from bladder washings and paraffin sections, insight into the biologic behavior of individual tumors may soon be possible. Blood group antigen expression and monoclonal antibodies to tumor-associated antigens may also help in this regard. For primary tumors, attention is now being focused on protocols aimed at bladder preservation. In some cases, radiation therapy alone can produce long-term survival, despite muscle infiltrating disease. Complete remissions have also been described with chemotherapy alone. The interaction of chemotherapy and radiation therapy has only recently begun to be investigated. In these trials, complete local control must still be the primary goal. Standard criteria for staging and response evaluation, including pathologic documentation of remission status, are crucial. To demonstrate a beneficial effect of therapy, long-term randomized trials will be required. The goal of individualized therapies may soon be possible, which will ideally translate into increased clinical benefit for patients with urothelial tract tumors.

Between 1986 and 1987 patients with hormone refractory metastatic adenocarcinoma of the prostate were treated with hemiskeletal irradiation. One group of 15 patients was treated with a fractionated regimen of 2500-3000 cGy in 9 to 10 fractions. A second group of 14 patients received a single dose of 600 cGy or 800 cGy depending upon whether the upper or lower hemiskeleton was irradiated. Both groups were similar with respect to their initial Karnofsky performance status and extent of disease. With the exception of one patient in the single dose group, all patients treated achieved complete or partial relief shortly after completion of their respective courses of therapy. Of the patients treated with single dose therapy, 10 of 14 (71%) ultimately needed retreatment in the region initially irradiated because of recurrent bone pain or spinal cord compression. In contrast, only 2 of 15 (13%) of the patients receiving the fractionated treatment course needed retreatment (p = .001). Although the median survival of both groups from the time of initial treatments was similar (10 and 11 months), the median duration for palliation was greater for those patients receiving the fractionated regimen as compared with single dose therapy (8.5 months vs 2.8 months). The incidence of treatment related toxicity was similar for both groups. We conclude that fractionated hemiskeletal radiation is a more effective means of palliation when compared to single dose therapy.

A phase-II trial of the second-generation platinum analog 1,2-diaminocyclohexane (4-carboxyphthalato) platinum (II) (DACCP) was performed in 33 patients with non-small cell lung cancer. The compound was studied because of its lack of cross resistance in vitro and decreased nephrotoxicity in both preclinical testing and in a phase-I trial. The starting dose was 640 mg/m2 IV every 3 weeks, with escalations to 720 mg/m2 in the absence of toxicity. Myelosuppression and nephrotoxicity were uncommon. Allergic reactions and neurotoxicity were seen in five and three patients, respectively. Of 28 patients evaluable for response, one partial remission of 3 months' duration was noted in a patient who had previously responded but subsequently progressed during cisplatin and vindesine medication. No responses were seen in 11 adequately treated patients who had received no prior therapy. DACCP has only minimal activity in non-small cell lung cancer. No further studies are planned in this disease.

A phase II trial with bisantrene was performed simultaneously against urothelial tumors in nude mice and in patients with metastatic transitional cell carcinoma. The starting dose was 260 mg/m2, intravenously, every 3 weeks. No responses were seen in the in vivo animal study or in 13 treated patients.

Tumors in bone are usually metastatic, with breast, prostate, and lung tumors accounting for more than 80 percent of clinically manifest lesions. Untreated, such metastases can produce the symptoms that most concern cancer patients--pain, pathologic fractures, and paralysis through epidural cord compression. Recent advances in the understanding of the metastatic cascade and the regulation of bone formation and resorption provide unique therapeutic approaches for prevention and treatment of these lesions. This article reviews the prevalence, distribution, diagnosis, and treatment of metastatic cancer in the skeleton, as well as the processes involved in the development of such metastases, the local mediators responsible for some of the destructive changes in bone, and their pathologic results. In addition to considering some of the conventional therapeutic approaches, a rationale for the use of bone resorption inhibitors, such as the diphosphonates (bisphosphonates), is presented for the prevention and amelioration of the pathologic consequences of skeletal metastases.

Of 50 patients with bladder cancer given 1 to 5 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin in a pilot phase I and II study 63 per cent of 41 with pure transitional cell stage T2-4 lesions responded. While significant downstaging occurred by transurethral resection of the bladder in 70 per cent and by cytology in 60 per cent of the patients, the final T response rate by all noninvasive clinical staging procedures, including sonography and computerized tomography, revealed complete remission in 24 per cent and partial remission in 39 per cent. Of 30 patients who underwent pathological staging 33 per cent achieved stage P0 and 17 per cent stage Tis disease or P less than T. Despite extensive re-evaluation by transurethral resection of the bladder and other noninvasive staging procedures, a clinical staging error (T versus P) of 38 per cent was observed. Of the other 9 patients 4 with mixed nontransitional cell histological findings at presentation never achieved complete remission, although 3 had resolution of all transitional cell elements and 5 (10 per cent) were inevaluable. The toxicity of the regimen was generally acceptable but 6 per cent of the patients required hospitalization for neutropenic fever. While this active regimen can clinically (T) and pathologically (P) induce downstaging in a significant number of patients with primary bladder tumors, this pilot study has raised serious questions concerning the design of future nonrandomized and randomized neoadjuvant studies.