The impact of chemotherapy on the survival of patients with metastatic urothelial tumors.
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Biomedical subjects
Publications and source records attributed to F H Dexeus.
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Preoperative localization of the impalpable undescended testis is necessary to facilitate proper surgical planning. There is an increased incidence of malignant change in the undescended testis; demonstration of malignancy before surgery will significantly alter the treatment. We describe the computed tomographic (CT) and magnetic resonance (MR) findings in 2 patients with malignant change in an intraabdominal testis. The CT scan revealed lesions with areas of low density, 1 of which had focal calcifications; MR revealed lesions of predominantly low or intermediate signal intensity on both long and short TR/TE images, with some areas of very high signal on both sequences. After initial management with chemotherapy, the residual tumor was surgically resected. In neither instance was residual normal testis demonstrated. Both CT and MR are ideal methods of examining malignant transformation of the undescended testis, because of their ability to characterize the internal structure of the organ and, in the case of MR, its capacity for multiplanar imaging. They are almost of equal value except for the ability of CT to identify calcification and of MR to diagnose hemorrhage.
Radiotherapy-associated bladder carcinoma was found in 3.7 percent of 244 cases of advanced urothelial carcinoma. Average age at diagnosis of the bladder tumor was 63.1 years, with a mean of 20.5 years between radiation treatment and diagnosis. All 9 patients presented with gross hematuria. Eight patients had transitional cell carcinoma, 7/8 (87.5%) also had vascular or lymphatic invasion, and 1 was adenocarcinoma. Mean survival was 15.4 months (range 1-40 mos.), with a 55.5 percent one-year disease-free survival after diagnosis. Four patients died of bladder tumor, 4 were alive with no evidence of disease, and 1 was alive with metastasis.
Forty patients with retroperitoneal metastasis from nonseminomatous testicular cancer treated with chemotherapy were retrospectively studied to (1) evaluate the predictive value of mass size as detected by computerized tomography (CT) as an indicator for postchemotherapy surgery and (2) determine the factors that influence relapse. Patients received two further courses of chemotherapy after their serum biomarkers became normal and computed tomography indicated a complete response or presence of a residual but stable mass. We found that patients with initial metastases less than 2 cm had a low frequency (14%) of residual masses after chemotherapy, vs. 59% for those with masses of 2-5 cm and 75% for those with masses of greater than 5 cm (P = 0.03). Of 22 patients with primary embryonal carcinoma, three of seven (43%) with residual masses after chemotherapy had mature teratoma at surgery. Six patients had small (1-2 cm) residual abnormalities that were not removed, and three of these patients relapsed. In conclusion, increasing size of retroperitoneal metastasis by CT scan predicts for increased likelihood of a residual mass after chemotherapy; patients who have a residual mass greater than or equal to 1 cm require retroperitoneal lymphadenectomy after chemotherapy, whether the tumor histology is embryonal carcinoma or teratoma. The role of surgery for patients who have residual retroperitoneal masses less than 1 cm after chemotherapy could not be determined from our study.
We reviewed retrospectively 97 patients treated with cisplatin, cyclophosphamide and doxorubicin chemotherapy at our hospital to evaluate predictive variables for response to chemotherapy and long-term survival free of disease. Histological subtype influenced response: 70 per cent of the patients with pure transitional cell carcinoma achieved an objective response (partial remission 31 per cent and complete remission 39 per cent), whereas 45 per cent of those with mixed tumors achieved response (partial remission 20 per cent and complete remission 25 per cent). Patients with nodal metastases only had an equal over-all response rate to those with visceral metastasis (64 versus 62 per cent) but patients with nodal metastases had a higher complete remission rate (45 versus 20 per cent). A total of 35 patients (36 per cent) achieved a complete response. In 17 of the 35 patients the duration of response was less than 100 weeks and 18 (51 per cent) have survived longer than 100 weeks. Of the 17 patients with a survival free of disease of less than 100 weeks 16 died of recurrent urothelial tumors and 1 died of a second primary tumor. Among the patients with a survival free of disease of longer than 100 weeks only 2 have had recurrent urothelial tumors; 72 per cent of the patients in this category remain free of disease. Patients with pure transitional cell carcinoma were represented in equal frequency among patients achieving a durable complete remission and those with a complete remission of less than 100 weeks. These data demonstrate the ability of cisplatin, cyclophosphamide and doxorubicin combination chemotherapy to achieve a complete remission and long-term survival free of disease among select patients with unresectable urothelial tumors.
A prospective randomized trial tested the hypothesis that interferon and cytotoxic chemotherapy delivered sequentially would be synergistic and would increase the response rate in metastatic renal cell carcinoma. Thirty-six patients were entered and randomized to chemotherapy only (5-fluorouracil, doxorubicin, mitomycin, and cis-platin) vs. interferon alternating with the same chemotherapy. Only 4 of 32 evaluable patients (13%), 2 in each arm, had a major response. Three patients in the alternating arm had minor responses. Complete, partial, and minor responses totaled 7 (22%). All four patients whose only disease was lung metastasis had some evidence of response (p = 0.001). Interferon alternating with chemotherapy did not appear to improve the major response rate over chemotherapy alone. Responses in metastatic renal cell carcinoma appear confined to a favorable subset of patients.
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Twenty-seven patients with locally advanced and inoperable bladder carcinoma (LABCa) were referred for chemotherapy. All were staged by cytoscopy, examination under anesthesia, and computed tomography (CT), and 18 also had bipedal lymphangiography (LAG). In 16 patients (56%), there was agreement between the clinical and the CT staging of the primary bladder tumor. In four of these 16 patients, CT detected lymphadenopathy in three and demonstrated pelvic bone invasion in one. Of the remaining 11 patients, CT underestimated the local extent of the bladder tumor in nine and overestimated in two. Lymphangiography was abnormal in nine patients (50%), in four of whom the abnormality was not seen on CT scan. Among the ten patients with normal LAG, six had abnormal pelvic nodes detected by CT. The LAG affected the overall staging of the tumor in five patients (16.6%). The total incidence of nodal metastasis as seen on CT, LAG, or both was 72%. Although CT and LAG may not add significantly to the clinical staging of the primary tumor in LABCa, they will affect the overall staging of the tumor by detecting lymphadenopathy. Accurate staging of these patients is important because, with aggressive chemotherapy, some of these patients might become candidates for more radical treatment such as surgery or radiotherapy.
We retrospectively reviewed the genetic abnormalities detected clinically in 455 men with advanced germ cell tumors referred for chemotherapy. Of the patients 49 had extragonadal and 406 had testicular germ cell tumors. Of 19 patients with mediastinal germ cell tumors 4 (21 per cent, 3 with teratocarcinoma and 1 with endodermal sinus tumor) had Klinefelter's syndrome. Three of these patients had a 47XXY and 1 had a 48XXYY karyotype. No Klinefelter's syndrome was observed among 30 consecutive patients with retroperitoneal germ cell tumors or among the 406 with testicular tumors. Karyotypes of 35 consecutive patients with testis cancer without evident congenital abnormalities showed normal chromosomal patterns. We found 2 patients with Down's syndrome and testicular tumor, for an incidence of 0.5 per cent (probably significant). We also describe 2 cases of nonseminomatous testicular cancer and Marfan's syndrome (0.5 per cent incidence versus a 5 of 100,000 incidence of Marfan's syndrome in the general population). Apparently, genetic abnormalities are increased in men with germ cell tumors and we discuss the significance of this association.
Adjuvant combination chemotherapy with cyclophosphamide, doxorubicin and cisplatin was administered to 36 patients after cystectomy for bladder cancer. Therapy was tolerated well except for 1 patient who suffered a fatal chemotherapy complication. Indications for adjuvant chemotherapy included vascular invasion of the primary tumor, perivesicular tumor involvement, invasion of adjacent pelvic viscera (vagina and prostate) and nodal metastases. There were 53 concurrently treated patients who did not receive adjuvant chemotherapy despite similar unfavorable pathological indications (high risk control group). Survival rates (61 and 73 per cent, respectively) were not significantly different for those patients treated with adjuvant chemotherapy and an additional group of 158 patients who underwent cystectomy during the study period but who had no adverse pathological findings (low risk control group). Survival rates differed significantly between the low risk (73 per cent) and high risk (38 per cent) control groups (p less than 0.001). Patients with unfavorable histological findings who received adjuvant chemotherapy had a significant survival advantage over the high risk control groups (61 versus 38 per cent, p equals 0.03). These data confirm the predictive value of post-cystectomy pathological findings and suggest that adjuvant chemotherapy with cyclophosphamide, doxorubicin and cisplatin not only prolongs the survival free of disease for patients at high risk for recurrence but it also may ultimately increase the cure fraction of such patients.
Seventy-one patients received adjuvant Cytoxan (cyclophosphamide; Bristol-Myers Co, Evansville, IN), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (CISCA) chemotherapy between March 1981 and March 1986. Patients received adjuvant CISCA chemotherapy if they had pathological findings that were thought to predict for high likelihood of relapse. These included the presence of resected nodal metastases, extravesicular involvement of tumor, lymphatic/vascular permeation of the primary tumor, or pelvic visceral invasion. Sixty-two patients at a similar high risk for recurrence did not receive adjuvant CISCA chemotherapy because they refused, had medical contraindications to therapy, or were not referred for chemotherapy. Two-hundred six patients had a cystectomy performed during the same study period but had none of the poor prognostic features suggesting a high risk for relapse. Sixty-two percent of the patients receiving adjuvant chemotherapy are alive and disease-free for a mean follow-up of 118 weeks (range, 28 to 310 weeks). A survival advantage exists for the adjuvant-treated patients when compared with those with unfavorable pathological findings who did not receive adjuvant chemotherapy (70% v 37%) (P = .00012): no difference exists in long-term disease-free survival for those with favorable pathological findings (long-term disease-free survival 76%) v those who received adjuvant chemotherapy (70%) (P = .33). Adjuvant CISCA chemotherapy prolongs the disease-free survival of some patients following a cystectomy. Patients who benefitted from adjuvant CISCA chemotherapy included those with resected nodal metastases, extra-vesicular involvement of tumor, and direct invasion of the pelvic viscera. Patients not benefitting from adjuvant CISCA chemotherapy in this analysis included those with lymphatic/vascular invasion in their primary tumor as the sole manifestation of high risk for relapse.
Fifty-two patients with advanced seminoma were treated with primary chemotherapy: 44 received cyclophosphamide and weekly cisplatin, and 8 received sequential weekly cisplatin alone. Of the patients treated with chemotherapy alone only 44 achieved a complete remission and 4 were salvaged with further therapy (1 chemotherapy and 3 radiation therapy). These 48 patients (92 per cent) remained free of disease at a followup of 30 to 471 weeks. Six prognostic factors were tested by univariate analysis (chi-square) and only the use of previous chemotherapy predicted for a lower complete remission rate (p equals 0.02). Renal toxicity (greater than 0.4 mg. per dl. increase in serum creatinine) occurred in 2 patients (4 per cent). Neurotoxicity occurred in 16 patients (31 per cent). No fatal toxicity occurred. Cyclophosphamide and weekly cisplatin were well tolerated in patients previously treated with radiation therapy and is the treatment of choice for patients with disseminated seminoma.
We describe 3 patients with metastatic transitional cell carcinoma of the prostate who achieved a complete response with regimens containing cisplatin. Two patients received cyclophosphamide and weekly cisplatin, and 1 was given cyclophosphamide, doxorubicin and cisplatin. All 3 patients had extensive pulmonary metastasis at initiation of chemotherapy. One patient, who also had massive local disease, suffered an isolated brain metastasis 9 months after completion of chemotherapy but he remains in systemic remission 5 months later. Another patient had bilateral brain metastases 3 months after achieving complete remission with chemotherapy, followed 4 months later by systemic relapse. The third patient, who also had bone and bone marrow metastasis, is free of disease 20 months after completion of chemotherapy. In contrast, none of 14 patients with transitional cell carcinoma of the bladder and other sites treated with the same regimens obtained a complete response. Advanced transitional cell carcinoma of the prostate must be recognized promptly, since it is nonresponsive to hormonal manipulation and complete responses have been achieved with cisplatin chemotherapy programs as used in our patients.
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Thirty-eight patients with primary urothelial tumors recurring in the pelvis or nodal presentation were treated with intravenous or intra-arterial cyclophosphamide, doxorubicin and cisplatin chemotherapy. The 38 patients were selected owing to unresectability by local criteria (12 patients) or by virtue of nodal metastases (26 patients). Histologically, the patients either had pure transitional cell carcinoma (29), transformation to a histological subtype of transitional cell carcinoma (7) or pure squamous cell carcinoma (2). An over-all 50 per cent complete remission rate was achieved with an 18 per cent objective pelvic response rate, and 32 per cent failed to respond to chemotherapy. Responses by histological subtype revealed that patients with pure transitional cell carcinoma had a 62 per cent complete remission rate, those with transitional forms had a 14 per cent complete remission rate and none with squamous cell carcinoma responded to chemotherapy. A significant difference in the incidence of responses among patients with transitional carcinoma and those with transition forms was seen (p less than 0.02). Complete remissions were independent of disease site. Nineteen patients achieved a complete remission with a mean duration of 86 weeks and median of 81 weeks (range 33 to 172 weeks). Toxicity of the chemotherapy was moderate with a high incidence of peripheral neuropathy and leukopenic infections. No deaths of chemotherapy were encountered. Patients with locally advanced or metastatic transitional cell carcinoma of the urothelium to lymph nodes can benefit from intravenous and intra-arterial cyclophosphamide, doxorubicin and cisplatin chemotherapy.
Forty-nine patients with histologically proven germ cell tumors arising in extragonadal sites were retrospectively reviewed. Included in the review were an additional seven patients with undifferentiated tumors with a pathologic appearance compatible with that of a germ cell tumor and elevated levels of serum biomarkers (beta subunit of human chorionic gonadotropin [beta-HCG] +/- alpha-fetoprotein [AFP]. Nineteen patients had a pure seminoma arising in an extragonadal site, whereas 30 patients had nonseminomatous germ cell tumors. Seven patients had primary undifferentiated tumors with elevated levels of serum biomarkers. Sixteen (84%) of the 19 patients with pure extragonadal seminomas with normal levels of serum AFP are alive and free of disease. Eighteen of these 19 patients received platinum-containing regimens and four had received prior chemotherapy that failed. Of the patients with nonseminomatous germ cell tumors, 12 (40%) of the 30 are alive and free of disease with vinblastine/bleomycin +/- cisplatin (13 patients) or CISCAII (cisplatin, cyclophosphamide, and doxorubicin) (nine patients) alternating CISCAII/VBIV (eight patients) chemotherapy. None of the seven patients with undifferentiated germ cell tumors are alive and free of disease. Three of the five patients with pure anterior mediastinal endodermal sinus tumors treated with chemotherapy remain alive and free of disease. Of the seven patients with choriocarcinomas arising in extragonadal sites, three are alive and free of disease. A classification for patients with extragonadal germ cell tumors incorporating site of origin, histology, and likelihood of being truly extragonadal is proposed. The implications of this classification are discussed.