Therapeutic options for patients with invasive bladder cancer: the Stanford experience.
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Publications and source records attributed to F S Freiha.
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Morphometric reconstruction of 122 consecutive radical prostatectomy specimens were analyzed for cancer volume and grade, seminal vesicle (SV) invasion, lymph node (LN) metastasis, and complete capsular penetration. The mean cancer volume for 91 specimens without SV invasion or LN metastasis was 3.7 cm3; for 14 with only SV invasion, 9.0 cm3; for 17 with LN metastasis, 15.2 cm3; and for 12 with both SV invasion and LN metastasis, 17.8 cm3. The mean cancer volume for 60 specimens without capsular penetration was 2.5 cm3, and for 62 it was 9.0 cm3. Grade of cancer correlated well with tumor volume. We believe that radical prostatectomy for cure should be performed on patients with tumors less than 3.8 cm3 in volume. Methods for accurate assessment of tumor volume before surgery should be given research priorities.
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To compare the clinical usefulness of the serum markers prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), we measured them by radioimmunoassay in 2200 serum samples from 699 patients, 378 of whom had prostatic cancer. PSA was elevated in 122 of 127 patients with newly diagnosed, untreated prostatic cancer, including 7 of 12 patients with unsuspected early disease and all of 115 with more advanced disease. The PSA level increased with advancing clinical stage and was proportional to the estimated volume of the tumor. The PAP concentration was elevated in only 57 of the patients with cancer and correlated less closely with tumor volume. PSA was increased in 86 percent and PAP in 14 percent of the patients with benign prostatic hyperplasia. After radical prostatectomy for cancer, PSA routinely fell to undetectable levels, with a half-life of 2.2 days. If initially elevated, PAP fell to normal levels within 24 hours but always remained detectable. In six patients followed postoperatively by means of repeated measurements, PSA--but not PAP--appeared to be useful in detecting residual and early recurrence of tumor and in monitoring responses to radiation therapy. Prostate massage increased the levels of both PSA and PAP approximately 1.5 to 2 times. Needle biopsy and transurethral resection increased both considerably. We conclude that PSA is more sensitive than PAP in the detection of prostatic cancer and will probably be more useful in monitoring responses and recurrence after therapy. However, since both PSA and PAP may be elevated in benign prostatic hyperplasia, neither marker is specific.
In 46 radical prostatectomy specimens, carcinoma volume and Gleason histologic grade were compared among 21 cancers containing Grade 3 cribriform areas and 25 noncribriform carcinomas. All cribriform cancers but only 44% of the noncribriform cancers were larger than 1.7 ml. Grade 4-5 areas were present in 86% of cribriform cancers and 36% of noncribriform cancers. All 17 cancers larger than 4.0 ml contained Grade 4-5 areas, and 15 of these showed cribriform areas. By contrast, noncribriform Grade 3 areas were found in 45 of 46 carcinomas. In most cases, cribriform carcinoma was predominantly intraductal; cell masses either followed normal duct contours or showed a basal cell layer by routine microscopic study or by immunohistochemical staining for basal cell-specific keratin. Seven cases showed primary origin of cribriform carcinoma within ducts by evolution from intraductal dysplasia, a presumptive premalignant lesion. It was proposed that cribriform carcinoma is equivalent to intraductal Grade 4 cancer, and that many Grade 4 prostate cancers may evolve directly from an identifiable intraductal precursor.
Primary osteogenic sarcoma of the bladder is an extremely rare disease. Fewer than 30 cases of tumors of the bladder containing bone or cartilage have been reported. Only 14 cases of well-documented primary osteogenic sarcoma of the bladder appear in the world's literature. The authors describe the first detailed description of such a patient treated with radiotherapy and chemotherapy as well as provide a review of this rare and interesting entity.
Tumour volume was related to metastasis, seminal vesicle invasion, capsule invasion, and histological differentiation in a series of 100 unselected prostates with carcinoma removed at necropsy and 38 removed at radical prostatectomy. All these variables were highly inter-related. In both series, metastases were associated only with tumours larger than 4 ml, a volume attained by only 13% of the necropsy tumours. Loss of differentiation was strongly correlated with tumour volume, and only tumours of Gleason grade 4 or 5 had metastasised. It was concluded that the natural history of prostate cancer is highly predictable. The capacity to metastasise probably develops only in tumours which have grown much larger than 1 ml and acquired poorly differentiated areas as a manifestation of the phenomenon of tumour progression. The unusually low proportion of metastatic prostate cancer is readily explained by the large proportion of small-volume tumours in this organ.
Two patients with parenchymal brain metastases from adenocarcinoma of the prostate (CaP) are presented. Both patients had the diagnosis made antemortem by biopsy, and tumor immunoreactivity for prostatic phosphatase and prostate specific antigen confirmed prostatic origin. Brain metastases from prostatic adenocarcinoma are unusual, occurring in only 0.2 per cent of all patients with CaP. Patients present with symptoms of motor dysfunction, headache, and seizures. The mean age at presentation of brain metastases from CaP is fifty-nine years old, which is younger than most patients with CaP. The majority of patients die within weeks after diagnosis. Craniotomy with tumor debulking, radiation therapy, and androgen deprivation may be useful in prolonging survival. All reported cases of CaP metastatic to brain have been histologically moderately differentiated or poorly differentiated. The periprostatic venous plexus is considered the most likely route of tumor spread to the brain.
A comparison was made between tumor area estimated on rectal palpation and actual tumor size calculated from the radical prostatectomy specimen in 17 patients with prostatic carcinoma. For each patient a diagram of the rectal examination findings was superimposed onto a histological reconstruction map of the surgical specimen, and relative areas were measured with a computer. In only 1 case was there close correlation between palpated and actual tumor area. Seven patients had actual tumor areas that were more than twice the palpated area. In 5 patients the palpated areas corresponded to foci of capsular involvement, while adjacent large areas of cancer abutting the capsule were not recognized. Discrepancies of this magnitude may result not infrequently in assignment of a clinical stage B1 to tumors that are histologically stage B2.
Thirty-seven patients with hormonally refractory prostatic carcinoma entered a randomized trial comparing doxorubicin and doxorubicin plus cisplatin. All patients had failed prior hormonal treatment. Mean Karnofsky performance status (76% doxorubicin versus 75% combination), percent of patients with prior palliative irradiation (40% doxorubicin versus 35% combination), and hemoglobin levels of less than or equal to 12 g/dl (30% doxorubicin versus 24% combination) were roughly equivalent in the two treatment groups. More patients treated with doxorubicin than the combination treatment had an elevated acid phosphatase level at study entry (90% versus 65%). Measurable bidimensional tumors were present in 13 patients in 16 sites in the doxorubicin arm and in 10 patients in 11 sites in the combination arm. Partial responses were seen in 1 of 13 patients in the doxorubicin arm and 2 (20%) of 10 patients in the combination arm. Improvement in Karnofsky performance status of 20% or greater was rarely observed with either treatment (7% doxorubicin versus 8% combination). Acid phosphatase levels normalized or improved by 50% in 39% of patients who received doxorubicin and 27% of patients who received the combination. The overall response rate by National Prostatic Cancer Project Criteria was 53% for doxorubicin and 59% for doxorubicin plus cisplatin. Myelotoxicity and gastrointestinal toxicity were severe, particularly in the combination arm, and required discontinuation of treatment in some patients who responded to treatment. Moderate renal dysfunction (creatinine value 2.0-3.0 mg/dl) occurred only in the combination arm at an incidence of 23%. Time to progression and survival were similar for the two treatment groups. In this small group of 37 patients, the combination of cisplatin and doxorubicin showed no improvement over doxorubicin alone in response, response duration, or survival, and was difficult to administer in this patient population.
Eighty-one patients with advanced testicular cancer were evaluated for gynecomastia or severe breast tenderness at diagnosis and after platinum-based chemotherapy. The prognostic significance of gynecomastia in these two settings was explored. At presentation, 10% (8 patients) had gynecomastia or breast tenderness and elevated HCG levels. The likelihood of gynecomastia was greater with increasing HCG level (P = 0.002). However, gynecomastia at presentation was a more powerful independent discriminant of poor survival than the initial HCG level by multivariate analysis (P = 0.004). Fifteen percent (12 patients) developed transient gynecomastia after chemotherapy not attributable to other known causes. HCG levels were normal. Endocrine evaluation typically revealed elevated FSH, LH, and estradiol/testosterone ratios. This may have reflected damage to testicular germinal epithelium. All 12 patients are alive without disease in contrast to the 8 patients who had gynecomastia at diagnosis. Therapy decisions should therefore be based on the time of onset of gynecomastia and in the context of appropriate clinical markers and evaluation.
We report the efficacy and toxicity of combined cisplatin, methotrexate and vinblastine for the treatment of metastatic transitional cell carcinoma of the bladder in 50 evaluable patients. Of these 50 patients 17 had not undergone cystectomy and had residual invasive bladder cancer. Of these 17 patients 11 had complete response of the bladder lesions following cisplatin, methotrexate and vinblastine for metastatic disease, including 6 of 12 treated by cisplatin, methotrexate and vinblastine alone, and 5 of 5 treated with cisplatin, methotrexate and vinblastine plus palliative or preoperative pelvic irradiation. Complete response was confirmed in 10 of the 11 patients by endoscopy and biopsy, and in 1 by cystectomy. One patient whose liver metastasis responded to cisplatin, methotrexate and vinblastine had conversion to complete response by cystectomy for persistent bladder cancer. Of these 17 patients 7 are alive, including 5 without disease, 4 to 41 months after treatment. The bladder appears to be responsive to this combination chemotherapy for invasive transitional cell carcinoma. This experience underscores the need for regular pathological re-staging of the bladder cancer in patients receiving chemotherapy.
Endodermal sinus tumor is the most common testicular neoplasm in childhood. The management of children with this neoplasm remains controversial. We have treated prospectively 5 children with stage I endodermal sinus tumor with limited surgery and no adjuvant therapy. The median patient age at diagnosis was 21 months (range 5 to 24 months). All children underwent an inguinal orchiectomy with high ligation of the spermatic cord. Retroperitoneal node dissection was not performed in any case and no child received adjuvant chemotherapy or radiation therapy. All patients were well without evidence of recurrent disease at a median followup of 46 months (range 19 to 72 months). Because these tumors usually are localized at the time of diagnosis, rarely spread to the retroperitoneal nodes and have a biological marker in most cases, and because good salvage chemotherapy is available for patients with relapse, we believe that nonmetastatic testicular endodermal sinus tumors in children can be managed with radical orchiectomy alone. Retroperitoneal node dissection is not necessary and adjuvant therapy is not indicated if markers return to normal. Further treatment should be reserved for the rare child with relapse.
Fifty-eight patients with metastatic transitional cell carcinoma of the urinary tract received cisplatin, methotrexate, and vinblastine (CMV) combination chemotherapy. Complete responses (CRs) were noted in 14 of the 50 (28%) evaluable patients and partial responses (PRs) in 14 patients for an overall response rate of 56% (95% confidence limits of 42% to 70%). The median duration of the 14 CRs was 9 months. Six of the 14 CRs (43%) remain in unmaintained remission from 6 + to 35 + months from onset of treatment. The median survival of evaluable patients receiving CMV was 8 months. Median survival for CRs was 11 months v 7 months for PRs (P less than .05) and 6 months for nonresponders. Renal and hematologic toxicities with this regimen were moderate. CMV is an effective regimen for patients with metastatic transitional cell carcinoma of the bladder. Prolonged disease-free survival may result from a CR to this regimen.
One hundred and forty-six patients with clinically localized carcinoma of the prostate were surgically staged and treated with external beam irradiation to the prostate and to the lymph node-bearing areas. Sixty-four (44%) of these patients had needle biopsy of the prostate 18 months or more following completion of therapy. Thirty-nine (61%) of the biopsies were interpreted as positive and 25 (39%) as negative. Twenty-eight (72%) of the 39 patients with a positive biopsy have subsequently developed metastases as compared to only 6 of 25 (24%) of the patients with a negative biopsy. It is concluded that an apparently positive postirradiation biopsy is likely to indicate active disease and identifies patients at a higher risk for development of metastases. Other details of staging, grading, and outcomes that compare these two groups are discussed.
The histopathological findings of tissue removed from 40 patients with a residual mass after completion of induction chemotherapy with cis-platinum, vinblastine and bleomycin are reviewed. These patients with advanced testicular cancer were treated with chemotherapy until normalization of tumor markers and until there was no further decrease in the size of palpable or radiologically evident masses for 2 successive cycles of chemotherapy. The mean number of chemotherapy cycles preoperatively was 5.2. Residual carcinoma was found in only 1 patient (3 per cent), teratoma in 18 (45 per cent), and fibrotic and/or necrotic masses in 21 (52 per cent). With this tailored treatment regimen in which an operation is performed after maximal chemotherapeutic response, the number of patients with viable residual tumor at operation can be minimized. Complete retroperitoneal lymph node dissection concomitant with resection of the residual mass was performed in 22 of 32 patients with residual masses in the retroperitoneum. The 1 patient with carcinoma in the mass also had carcinoma in several of the lymph nodes, and 4 of the 11 with teratoma in the mass had teratoma in the lymph nodes. Since the histopathological findings of the mass often parallel those of the lymph nodes, and since masses containing only fibrosis and/or necrosis cannot be ascertained with accuracy at operation, a complete retroperitoneal lymph node dissection is recommended in patients with a residual retroperitoneal mass.