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Tumor involvement of the bone marrow in patients with Hodgkin's disease may be suspected in the presence of other manifestations of advanced disease such as fever, lymphopenia, hypoalbuminemia, mixed cellular histologic type, or Stage III or IV disease by other clinical parameters. It occurs more frequently in the older age groups. When anemia, leucopenia, and/or thrombocytopenia are present and are unrelated to recent bone marrow suppressant chemotherapy, marrow involvement is likely to be present. Bone marrow examination, done by multiple trephine biopsies, provides an adequate sampling of tissue and results in a high incidence of detection of involvement by Hodgkin's disease. This manifestation of Hodgkin's disease is associated with a relatively short survival. Aggressive combination chemotherapy is necessary to produce a significant remission.

BACKGROUND A patient with diffuse large cell lymphoma who had a complete response lasting 35 years following a 3-day course of uracil mustard stimulated a recall review of patients treated with this oral alkylating agent. METHODS Records of patients treated with uracil mustard between 1958 and 1970 were reviewed. A current histologic review according to the International Formulation was performed when possible. Total doses of uracil mustard were similar to those of mechlorethamine, although there were variations in the dose schedule. RESULTS Employing criteria used over 25 years ago to evaluate patients' responses, the overall regression rate for 94 non-Hodgkin lymphoma patients was 69.2% (complete response [CR] 23.4%). Of 62 patients with Hodgkin disease, 69.4% responded (CR 9.7%). For 39 patients with chronic lymphatic leukemia, the combined complete and partial response rate was 74% (CR 7.7%). Thrombocytopenia was the primary toxicity. CONCLUSIONS Uracil mustard is an unmarketed, inexpensive oral alkylating agent that has been effective in the treatment of patients with lymphoma, chronic lymphatic leukemia, and thrombocythemia. Perhaps it should be reevaluated. Cancer 1999;85:2265–72. © 1999 American Cancer Society.

BACKGROUND A national survey of the management of Hodgkin's disease patients based on cases in the National Cancer Data Base (NCDB) provides a basis for evaluating the results of educational and therapeutic programs. These patients are believed to have been drawn from all nationalities, native and migrant, and were reported by hospital cancer registries throughout the United States, including large and small community hospitals, university and other teaching hospitals, military and Veterans Administration (VA) hospitals, and National Cancer Institute (NCI)-Designated Centers. METHODS Data submitted voluntarily to the NCDB were used to determine trends in patterns of patient care across time. For the period 1985-1994, data from 35,033 patients with newly diagnosed Hodgkin's disease were analyzed and separated into two time periods, 1985-1989 and 1990-1994. RESULTS Data were analyzed with respect to age, race, histology, stage, treatment, and survival. The majority of patients (83.6%) were white, the age group with the highest incidence was 20-29 years, and nodular sclerosis was the most common histologic type. Staging was reported as a combination of clinical and pathologic stage ("combined stage"). The number of cases of reported stage increased from 51.7% for the years 1985-1989 to 75.7% for the years 1990-1994. Radiation therapy was used primarily to treat patients in Stages I and II, although the overall use of radiotherapy declined by 10% in the later period. The overall observed 5-year survival rate was 83.2%, and the disease specific observed survival rate was 84.9%. Stage for stage, survival was better for younger patients and poorer for older patients. CONCLUSIONS The survey reflects the actual management of Hodgkin's patients disease. The reported cases for 1994 represent 60.6% of the estimated occurrences for that year in the U.S. There has been a significant improvement in the frequency of use of the staging system. A continuing increase in survival for patients with Hodgkin's disease is occurring. This method of studying disease management provides a measure of educational efforts and guides to developmental research. Cancer 1998;83:1041-1047. © 1998 American Cancer Society.

Background. Chemotherapy is most effective when applied during the biologically active stage of tumor cells. According to the authors' previous tumor marker kinetic study, methotrexate plus 5-fluorouracil (MF) was found to yield either a cytolytic effect in an MF-sensitive tumor cell population or a cytostatic effect in an MF-resistant population. In the latter, the suppressive effect was transient and the biologic activity resumed in one week after MF administration. Methods. Based on this marker kinetic study, an alternating chemotherapy program was designed to study its antitumor and side effects. Methotrexate (M) (200 mg/ m 2 ) and 5-fluorouracil (F) (500 mg/m 2 ) were administered intravenously on day 1 followed 24 hours later by leucovorin (L) (10 mg/m 2 orally every 6 hours for 6 doses). Cyclophosphamide (C) 300 (mg/m 2 ), doxorubicin (A) (50 mg/ m 2 ), and vincristine (V) (1 mg/m 2 ) were given on day 8. The MFL/CAV was given every 4 weeks. Results. Forty-nine patients with metastatic breast cancer were enrolled; 41 were eligible. There were 5 complete and 23 partial remissions, producing a total response rate of 68%. In 15 patients with liver metastases, the response rate was 73% and the median survival 13.7 months, results superior to those previously reported for this subgroup of patients. Side effects were manageable. Conclusions. This regimen, which can be given safely in an outpatient setting, yielded encouraging response and survival rates in patients with visceral-dominant disease with poor prognoses

BACKGROUND The success of chemotherapy for Stage III testicular carcinoma warranted its use as an adjuvant therapy for Stage II cancer. The current report reflects the adjuvant program begun at the University of Minnesota using four courses of vinblastine, bleomycin, and cisplatin (VBP) before the onset of the Testicular Cancer Intergroup Study using two courses of chemotherapies. METHODS A review of 78 patients with Stage II nonseminomatous germ cell tumors treated between 1972 and 1986 defined three groups: 19 patients treated between 1972 and 1979 with various adjuvant chemotherapies (termed "other"), 37 patients treated from 1975 to 1986 with VBP adjuvant chemotherapy, and 21 patients who received no therapy during the same era of VBP. The latter group was not offered adjuvant chemotherapy at other institutions or declined therapy. RESULTS Nineteen patients received adjuvant chemotherapy before the cisplatin era. Their survival rate was 42%, including two patients treated with cisplatin-based chemotherapy for recurrence. In the group of 21 patients who did not receive adjuvant therapy, 14 (66.7%) survived. Of these, five had no recurrence and nine were treated for recurrence. In a third group, adjuvant VBP therapy was given to 37 patients, 32 of whom received four full courses. There have been no recurrences, and 36 (97.3%) remain alive; one obese patient with hypertension died of a ruptured aortic aneurysm 12.9 years after the retroperitoneal lymph node dissection. Nodal involvement was more extensive in the VBP group. CONCLUSION Four courses of VBP adjuvant chemotherapy for pathologic Stage II testicular cancer resulted in a 100% cure rate, all patients having been followed up for more than 6 years. Whether two courses are as adequate remains to be determined when long-term follow-up is reported.

Background. The Minnesota Cancer Surveillance System (MCSS) provides information on the occurrence of newly diagnosed cancers among Minnesota residents. Cancer is a major cause of death and morbidity in older persons. Population cancer risk (PCR) was assessed as a measure of the number of cancers that will occur in the lifetime of 1000 persons. Methods. Approximately 98.6% of all cancers diagnosed in residents of Minnesota are reported by pathologists to the MCSS. By statistical methodology an estimate was made of the total number of cancers that will occur in the lifetime of 1000 people (PCR). The calculation assumes people born today will have the 1988–1990 Minnesota cancer incidence and life expectancy rates. Results. Incidence rates for all cancers in Minnesota have been increasing. Life expectancy in Minnesota is greater than in most areas of the United States. Approximately 50% of all cancers occurred in Minnesotans older than 70 years. The overall PCR is 459 cancers per 1000 lifetimes. It is estimated that by the year 2020 more than 100,000 living Minnesotans will have had cancer diagnosed during their lifetime. Conclusion. During the next 20 years, as the Baby Boomer generation in Minnesota moves into the high-risk years for cancer, the number of newly diagnosed cancers will increase disproportionately more than the increase in size of the older population. In view of the projected number of patients with cancer by the year 2020, cancer care will be different from what it is today. Geriatric cancer care will become a significant medical, public health, economic, bioethical, and social issue.

Patterns of care for Hodgkin's disease in the United States were surveyed through voluntary audits of hospitals with cancer programs nonapproved and approved by the Cancer Commission of the American College of Surgeons. Four hundred and seventy-three hospitals reported 6,345 patients diagnosed immediately preceding December 31, 1975. The survival rates varied with age, being better at younger ages and worse in the elderly. By pathologic stage, the younger patients faired better than the elderly in each stage grouping. Histologic type was not a factor in this poor prognosis. Hodgkin's disease in elderly patients has a different biologic behavior than in younger patients.

OBJECTIVE: Prior reports on Hodgkin's disease have suggested a biologic behavior difference between young and old patients. A study of 35,033 patients could confirm that older patients do not do as well as young patients regardless of age. METHODS: The National Cancer Data Base provided data from U.S. tumor registries on 35,033 patients newly diagnosed with Hodgkin's disease from 1985 through 1994. For analysis the patients were divided into two time periods, 1985-1989 and 1990-1994. The earlier period provided survival data to assess the impact of age and stage. RESULTS: The overall disease-specific, 5-year survival rate for the 1985-1989 period was 84.9%. For stages I and II, it reached almost 90%. For both observed survival based on all deaths and disease-specific survival, the duration of survival decreased with increasing age. This decrease with age occurred for all stages of the disease. CONCLUSIONS: The data reflect the actual status of management of Hodgkin's disease in the United States rather than the best attainable results. The decreasing survival with increasing age and in all stages further supports the concept of a difference in biologic behavior of Hodgkin's disease associated with age.

Controversy exists in using carcinoembryonic antigen (CEA) for monitoring the clinical course of breast cancer. In this study, the kinetics of two plasma tumor markers, CEA and CA15-3, immediately after the initiation of chemotherapy were assessed in 30 patients with advanced breast cancer. Four distinct kinetic patterns were seen. Two patterns fitted the expected relationship where the plasma marker increased during tumor progression (nine patients), and declined in tumor regression (five patients). The third pattern was paradoxical in that objective tumor regression in eight patients was associated with an acute surge of these markers followed by a steady decline. The doubling times for both CEA and CA15-3 were immediately shortened four-fold after therapy suggesting tumor cytolysis in treatment responders. Equally paradoxical was the fourth pattern where tumor progression in eight patients was associated with a rapid and transient decline of markers followed by rebounds. Such a rapid decline may be due to a suppression of marker release, as demonstrated in an in vitro study. Adequate knowledge of these putative paradoxical patterns will permit their effective use in monitoring the disease course and perhaps in the early prediction of the therapeutic response.

Clinical trials have been initiated with Apo2L/TRAIL (Genentech) and agonistic mAbs to TRAIL receptors, -R1 and -R2 (Human Genome Sciences). The apoptosis-inducing ability of these mAbs and different TRAIL preparations, in the presence or absence of histone deacetylase inhibitors (HDACi), varied markedly against primary chronic lymphocytic leukaemia (CLL) cells and various tumor cell lines, demonstrating an unanticipated preferential apoptotic signaling via either TRAIL-R1 or -R2. Contrary to literature reports that TRAIL-induced apoptosis occurs primarily via signaling through TRAIL-R2, CLL cells, in the presence of HDACi, undergo predominantly TRAIL-R1-mediated apoptosis. Consequently, Apo2L/TRAIL, which signals primarily through TRAIL-R2, is virtually devoid of activity against CLL cells. To maximize therapeutic benefit, it is essential to ascertain whether a primary tumor signals via TRAIL-R1/-R2, prior to initiating therapy. Thus combination of an agonistic TRAIL-R1 Ab and an HDACi, such as the anticonvulsant sodium valproate, could be of value in treating CLL.

An increased incidence of malignancies has occurred in recipients of organ transplantation who are immunosuppressed. Although testicular cancers have been uncommon, seminomas are extremely rare. Two patients with long-standing diabetes mellitus and renal transplants developed clinical stage I seminoma of the testis. These patients posed a therapeutic problem with respect to the use of radiation therapy. In one, none was given because of a combination of kidney rejection and antibiotic-induced renal damage. The second patient received radiation therapy with shielding of the transplanted kidney. The surgical distortion of lymph node architecture increases the problems in the use of radiation therapy. Individual factors need to be considered in the use of postorchiectomy radiation therapy for seminoma in transplant patients.

Fifteen patients with biopsy-proven mediastinal germ cell tumors treated with platinum-based chemotherapy were reviewed. They had a period of 4 to 6 weeks between the onset of symptoms and diagnosis. Four patients had sarcomatous elements in their tumor in association with common germ cell histologies. The sarcomatous components consisted of one angiosarcoma, one rhabdomyosarcoma, and two cases with mixed angiosarcoma and rhabdomyosarcoma. All patients with sarcomatous elements died; the median survival for these patients was 9 months. In contrast, six (54%) of the patients who did not have sarcomatous elements in their tumor are long-term disease-free survivors 5 to 8 years after diagnosis. The occurrence of sarcomatous elements in a mediastinal germ cell tumor is a poor prognostic sign, and therapy should be oriented to include drugs and regimens that may be effective against sarcoma.

This is the authors final draft version. Pls note the published version can be accessed through http://www.nature.com/leu/journal/v21/n12/abs/2404836a.html

Adjuvant therapy in the treatment of breast cancer commonly refers to therapies that supplement primary treatment, traditionally mastectomy and, more recently, breast-conserving surgery. The present paper examines the evolution of systemic therapies and radiotherapy in their role as adjuvants to mastectomy, and offers a brief description of current treatment regimens for early and locally advanced disease.

Familial high-tone hearing loss in males is a recessive trait often unrecognized. Cisplatin chemotherapy may be associated with hearing loss. A review was made of audiograms in 85 patients with testicular carcinoma prior to cisplatin chemotherapy to determine the extent of preexisting familial hearing loss. Clinical histories defined patients exposed to high noise levels and other common causes of hearing loss. Audiometric findings were classified according to normal hearing or mild, moderate, and severe hearing impairment. Pretreatment audiograms were normal in 51 patients and abnormal in 19 patients with histories of high-level noise exposure, and in 15 patients with high-frequency hearing loss there was no history of noise exposure, ear infection, or other potential causes of hearing loss. These last 15 patients were judged to have recessive familial hearing loss. Awareness of familial hearing loss is important in male patients in whom cisplatin chemotherapy is planned. Pretreatment hearing assessment, including audiograms, is recommended for such male patients.

PURPOSE The Truquant BR radioimmunoassay (RIA) (Biomira Diagnostics Inc, Rexdale, Canada) uses the monoclonal antibody B27.29 to quantitate the MUC-1 gene product (CA 27.29 antigen) in serum. We evaluated CA 27.29 antigen in a controlled, prospective clinical trial for its ability to predict relapse in stage II and stage III breast cancer patients. PATIENTS AND METHODS Over a 2-year period, 166 patients who had completed therapy for stage II (80.1%) or III (19.9%) breast cancer and were clinically free of disease were serially tested for CA 27.29 antigen levels. The study was double-masked and cancer recurrence was documented based on clinical findings. Patients with two consecutive CA 27.29 antigen test results above the upper limit of normal were considered positive. RESULTS The Truquant BR RIA had a sensitivity of 57.7%, specificity of 97.9%, positive predictive value of 83.3%, and negative predictive value of 92.6%. The recurrence rate was 15.7%. A Cox regression analysis showed that the only variable to correlate with recurrent disease was the CA 27.29 antigen test result. Patients with a positive test result had increased odds of having a recurrence (odds ratio, 6.8; P < .00001). The test was effective in predicting recurrence in patients with both distant and locoregional disease. In a subgroup of patients with bone pain, CA 27.29 antigen level was found to identify reliably patients who would subsequently develop recurrent disease. CONCLUSION These data demonstrate that the Truquant BR RIA can be used as an aid to predict recurrent breast cancer in patients with stage II and III disease.

Systemic treatments with hormones and/or chemotherapy attained outstanding success in producing objective regressions of local and distant metastases of breast cancer. With these demonstrations, similar therapies were employed in the adjuvant setting for stage II patients resulting in improved disease-free and overall survival (1,2). For locally advanced disease, systemic treatments caused substantial shrinkage of unresectable primary tumors (3,4). Because of the poor prognosis of stage III breast cancer, a positive approach to its management has been neglected or at least variable. This has been associated, in part, with the changing of staging systems of breast cancer. Further confusion occurred with clinical trials that incorporated stages IIB and III breast cancer. For clarification in this report, reference will be made to stage IIIB breast cancer (5,6). Stage IIIB breast cancer consists of tumors of any size with direct extension to the chest wall or skin (T4) with axillary node involvement (N1 and ...

Background : Nonseminomatous germ cell tumors (NSGCT) (testicular carcinoma) are a curable disease. Stages I and II are nearly 100% curable. Stage III has had remarkable progress in attaining complete regression, but a substantial number fail to be cured. Using platinum-based regimens such as vinblastine, bleomycin, and cisplatin (VBP), or using etoposide instead of vinblastine (BEP), or without bleomycin (EP), four courses of chemotherapy have become a national standard. Based on our prior experience with mithramycin (plicamycin), which used six courses, six courses of VBP chemotherapy were utilized as our treatment goal. This report challenges the concept that standard therapy for stage III testicular carcinoma is four courses. Method : From 1976 to 1990, 74 patients with advanced NSGCT were treated with standard doses of platinum-based chemotherapies. Five or more courses were delivered to 41 patients and fewer than five courses to 33 patients. The intent of therapy was to attain as close to six courses as possible. Because of physician preference, patient adherence, or toxicity, some patients did not reach that goal. Results : Of 33 patients receiving less than five courses, there were 28 (85%) complete responders, and 26 (78.8%) are alive. Of 41 patients receiving five or more courses, 38 (92.7%) had complete responses, and 34 (83%) are alive. One person in each group is living with nonresectable teratoma present. In the group receiving 5+ courses, two died from causes unrelated to testis cancer and had no testis cancer present. As a result of the initial treatment, there was no evidence of cancer in 24 (72.8%) in the group receiving less than five courses and 35 (85.4%) had no cancer after five or more courses. In considering only patients with advanced level of stage III disease in contrast to minimal or moderate stage III disease, there were fewer complete regressions with less than five courses (64.3%) than with five or more courses (88.0%). Conclusions : For minimal stage III disease, four courses of chemotherapy may be adequate. For advanced stage III disease, more chemotherapy provides fewer treatment failures. Once a complete response is achieved without restriction to an arbitrary number of courses, two additional courses may constitute a more curative regimen.

The follicular non-Hodgkin's lymphomas (NHL) have been among those tumors demonstrated to show frequent responses to alpha interferon in phase I and II clinical trials. In addition, there are data suggesting that alpha interferon demonstrates synergistic antitumor activity with alkylating agents in animal models for a number of tumors. Based on these data, Cancer and Leukemia Group B (CALGB) undertook a phase II pilot study of the combination of interferon rlFNα2b (2 × 106 IU/m2 s.c. tiw) and cyclophosphamide (100 mg/m2 per day orally) with the ultimate purpose of examining this combination as long-term therapy of follicular lymphoma in comparison to oral cyclophosphamide alone. One hundred five advanced stage III or IV eligible patients with pathologically diagnosed International Working Formulation B or C histology were entered on CALGB 8553 to determine toxicity and response rates to the combination. Both previously chemotherapy-treated patients (32) and patients without prior chemotherapy (73) were entered on study. For patients without prior chemotherapy the overall response rate to the combination regimen was 86% with 58% of chemotherapy-treated patients achieving complete response. Chemotherapy-treated patients had a total response rate of 62% with only 25% complete responders. Complete responses in patients without prior chemotherapy were positively correlated with absence of B symptoms, and good performance status and negatively correlated with the histological subtype of follicular mixed small-cleaved and large cell histology (IWF C); only performance status was significantly correlated with response in patients who had previously had chemotherapy. Survival at 5 years is estimated to be 63% for those without chemotherapy and 39% for those previously treated with chemotherapy patients. The maximum toxicities experienced during therapy with the combination regimen of cyclophosphamide and interferon alpha were primarily related to myelosuppression. Sixty-seven percent of patients without prior chemotherapy and 65% of patients receiving prior chemotherapy experienced severe leukopenia while severe thrombocytopenia and anemia occurred in 6-31% of these patients. Non-myelosuppressive toxicities were less frequently seen. These response rates are similar to those achieved in a previous CALGB trial with oral cyclophosphamide as a single agent, although severe myelotoxicity was increased to approximately 60% of patients from less than 10% with the single-agent therapy. The combination of alpha interferon and cyclophosphamide administered in this fashion is safe when peripheral counts are carefully monitored. Randomized studies of this regimen in comparison to oral cyclophosphamide are currently in progress. © 1994 Wiley-Liss, Inc.

Objective The major purpose of this study was to document the modes of presentation, diagnostic methods, clinical management, and outcome of gastric cancer as reported by tumor registries of US hospitals and cancer programs approved by the American College of Surgeons. Summary background data Gastric cancer continues to diminish in the US, but the stage of disease and survival outcome after surgical resection is unchanged despite increased availability and sophistication of diagnostic techniques. This is in contrast to the marked improvement in survival outcome in Japanese and other Eastern series over the last decades. Possible reasons for the improved Japanese results have been earlier detection secondary to active diagnostic surveillance of the population and widespread adoption of aggressive surgical resection emphasizing wide-field node (R2) dissection. Although selected US centers using the Japanese approach report better survival data, the approach has not been widely adapted by US treatment centers. Methods Tumor registries at American College of Surgeons (ACS) approved hospitals were mailed a study protocol in 1987. They were instructed to review 25 consecutive patients with gastric cancer treated in 1982 (long-term study) and 25 patients treated in 1987 (short-term study). A detailed protocol included significant history, diagnostic results, staging, pathology findings, and treatment results. The data forms on 18,365 patients were returned and analyzed (11,264 patients in the long-term study and 7101 patients in the short-term study). Results Of 18,365 patients, 63% were males. The median ages were 68.4 years in males and 71.9 years in females. There was a history of gastric ulcer in 25.5% of the patients. Lesion location was upper third in 31%, middle third in 14%, distal third in 26%, and entire stomach in 10% of patients (and the site was unknown in 19%). Gastric resection was performed for 80% of upper third cancers and 85% of distal third cancers; 50% of patients with total gastric involvement had gastric resection. The extent of gastric resection varied according to location. For lower third lesions, subtotal gastrectomy was done in 55% of the cases, extended resection in 21%, and total gastrectomy in 6%. For proximal lesions, 29% had subtotal, 4.6% had total, and 41% had extended gastrectomies (including esophagus), and 13.6% had dissection of celiac nodes. The operative mortality rate was 7.2%. Staging (American Joint Committee on Cancer [AJCC]) was as follows: I, 17%; II, 17%; III, 36%; and IV, 31%. The overall survival rate reflecting deaths from all causes was 14% among 10,891 patients diagnosed in 1982, and it was 19% in patients having resection. The disease specific survival rate was 26%. The survival rate after resection was 19% and 21% for lower and mid third cancers, 10% for upper third cancers, and 4% if the entire stomach was involved. The stage-related survival rates were 50% (stage I), 29% (stage II), 13% (stage III), and 3% (stage IV). Among patients with pathologically clear margins, the survival rate was 35% versus 13% in those with microscopically involved margins, and it was 3% in those with grossly involved margins. Conclusion This report of gastric cancer treatment by American College of Surgeons approved institutions in the US provides an overview of the disease as commonly treated throughout the US. Although the results are less favorable than those reported by centers with large institutional experiences with this disease and are inferior to those of the Japanese and other Eastern centers, they suggest potential for increasing survival by upstaging through earlier diagnosis and using resectional techniques demonstrated to more adequately control local regional disease.

The TNM system for classification of tumors has become the principal method for determining prognosis for cancer patients and providing a reliable means for reporting results of treatments. Progress in the treatment of stomach cancer required the development and unification of the TNM system for tumor classification. Although a system had already been developed more than 40 years ago, attempts were made to unify and improve the various later emerging ones through a series of international meetings. Through this process of evolution, a unified international system for classification of stomach cancer was developed. It is to be expected that small variations in the classification system may occur that will result from additional data and improvements in technology in the future.

The charts of eleven patients with abdominal germ cell tumors were reviewed; one had a seminoma. They all had normal testes by physical examination. Therapy consisted of cisplatin-based chemotherapy and, in some cases, surgical debulking. A complete clinical response occurred in seven patients (63%). Two patients relapsed after achieving pathology complete responses and died of progressive disease despite second-line chemotherapy. All patients that failed to achieve a complete clinical response died of progressive disease. Five patients (45%) are long-term disease-free survivors, having no recurrence 4-10 years from the time of the diagnosis (median 6 years). The outcome for this group of patients did not differ significantly from that for patients with mediastinal germ cell tumors in this institution. They do not fare as well as patients with testicular cancer.

OBJECTIVE: To assess nationally the use of questionable cancertherapies. DESIGN: Survey of cancer patients or their families regardinguse of questionable methods of cancer treatment; sample survey ofphysicians' perception of use. PARTICIPANTS: 36,000 households; 5,047individuals; 91 physicians. RESULTS: The prevalence of use of questionablecancer methods was nine percent overall. An increase in use was directlyproportional to increased income and education. Prolonged illness andcertain types of cancer were more commonly associated with use. Harmfulside effects of questionable cancer treatments were regarded as modest (sixpercent). There was a wide range in cost. Third-party reimbursement wasreported by 25 percent of patients. Important discrepancies were foundbetween patients' and physicians' perceptions of questionable therapies. CONCLUSIONS: While some questionable therapies are harmless or inexpensive, others have toxic effects and may be costly, and none have scientificallyproven efficacy. Although the percentage of usage reported is relativelylow, overall large numbers of patients are involved, especially in certaingroups. The physician plays a key role in encouraging or preventing the useof questionable methods, and substantial improvements in public andprofessional education are needed.

In 1965 we reported mithramycin (plicamycin) to produce objective regression in 7 of 12 patients with advanced testicular carcinoma. Between 1963 and 1975 mithramycin was administered to 62 patients with advanced testicular carcinoma as the initial chemotherapy and to 30 patients who failed to respond to prior chemotherapies. There were 13 complete regressions (23%) in 56 patients who as initial chemotherapy received more than one course of mithramycin. The median follow-up is 23 years with 10 patients still alive. A partial regression occurred in 11 (18%), all of whom are dead. Of 30 patients receiving mithramycin after prior chemotherapies, none had a complete regression, 5 had a partial regression, and all are dead. Of 13 patients undergoing complete regression, 85% never had a recurrence of testicular carcinoma. The median follow-up of 23 years implies that these patients are cured.

Between 1970 and 1980, 82 patients with pathologic stage II nonseminomatous germ cell testicular carcinoma were treated at the University of Minnesota. Of the 30 patients treated with a retroperitoneal lymph node dissection, 22 (77%) relapsed. Of the 18 patients treated with retroperitoneal lymph node dissection and adjuvant radiotherapy, 12 (63%) relapsed. Sixteen patients received adjuvant chemotherapy before 1976, and 14 (87.5%) relapsed. After 1976, 18 patients received adjuvant chemotherapy (11 with cisplatin) and 2 (11%) have relapsed. No patient treated with cisplatin-based adjuvant chemotherapy has relapsed. The toxicity has been modest. Cisplatin-based chemotherapy is an effective and a safe adjuvant therapy for stage II nonseminomatous germ cell testicular carcinoma.

Reversal of myelofibrosis and splenomegaly is described in a 41 year old woman with metastatic breast cancer. After intensive chemotherapy and hormonal therapy, the tumor regressed, the splenomegaly receded, the hemogram showed no abnormalities, and the dense collagen and reticulin fibers in the marrow disappeared. The severe thrombocytopenia and leukoerythroblastosis noted before therapy were not obstacles to clinical management. In our report we document that myelofibrosis associated with breast cancer is not an ominous sign. Patients may benefit from an intensive, but well titrated, therapeutic program.

The factors important in predicting survival in the non-Hodgkin's malignant lymphomas have not previously been clearly identified. This study evaluates the prognostic usefulness, in predicting survival, of a modified Rappaport pathologic classification, the Ann Arbor clinical staging classification, initial bone marrow involvement, symptoms, extranodal involvement, age, and sex in 128 consecutive adult patients with malignant lymphoma. Conventional life table analysis indicates that symptoms, pathology, and clinical stage are the most important factors in predicting survival. However, multiple regression analysis identifies pathology, symptoms, and bone marrow involvement as the three most important variables. Clinical stage when considered with other risk factors (in the multiple regression analysis) adds little prognostic information. Age, sex, and extranodal involvement do not significantly influence survival in either analysis. Pathology, symptoms, and bone marrow involvement appear most important in designing adequate clinical treatment trials in patients with non-Hodgkin's lymphoma.

(First of Two Parts) THIS review is warranted by the recent progress in understanding and treating testicular cancer. For example, it has been established that nearly all these cancers originate in...

Estrogen receptor contents (ER), determined by a sucrose gradient method in 250 primary or metastatic breast cancers, were analyzed with respect to the influence of the patient's menopausal status, chemotherapy, and tissue sampling. The incidence of the presence of estrogen receptors (ER+) increased in the order of para-, pre- and postmenopausal status of the patient, suggesting that a tumor occurring at the paramenopausal phase tends to be a hormone-independent type. Chemotherapy did not alter the incidence of ER(+), nor the quantity of ER in metastatic lesions. Multiple biopsies done simultaneously or sequentially in the same patient are consistent in their qualities and quantities of ER, provided histological confirmation and examination of the amount of cellularity are included in the process of interpretation.

We studied the return of ejaculation in 31 patients who had undergone retroperitoneal lymphadenectomy for stage I or II nonseminomatous germ cell testicular cancer. Ejaculation returned spontaneously in 13 patients and was restored by sympathomimetic drugs in 5 of 8 patients treated. Both patients known to have tried to father a child succeeded. We also studied the effects of chemotherapy (vinblastine and bleomycin with or without cisplatin) in 34 patients, 24 of whom also had undergone retroperitoneal lymphadenectomy. Although chemotherapy profoundly depressed spermatogenesis during treatment 75 per cent of the patients tested 18 months or more after completion of treatment had some return of function, as evidenced by normal follicle-stimulating hormone levels and/or the presence of live sperm in the ejaculate. We concluded that it is possible to perform a therapeutically sound retroperitoneal lymphadenectomy for low stage nonseminomatous testicular cancer that permits return of ejaculation in many patients and that spermatogenesis recovers in a significant number of patients treated for this cancer with modern chemotherapy. Thus, traditional beliefs that operative and drug treatment of nonseminomatous testicular cancer invariably causes infertility must be revised.

Particles with the density and enzymatic activity characteristic of known oncornavirus have been previously described in bone marrow cells from patients with leukemia in relapse and in remission. We have confirmed these findings and studied two patients in whom preleukemia was among the diagnostic considerations. Following cultivation of bone marrow from these patients for 1 week in conditioned media with dexamethasone, a high-speed pellet of the supernatant fluid and disrupted cells was prepared and analyzed on a sucrose gradient for enzymatic activity characteristic of RNA-directed DNA polymerase (reverse transcriptase). Peaks of endogenous DNA polymerase activity showing ribonuclease sensitivity and/or stimulation with the synthetic template poly(rC)-(dG)12-18 were demonstrated in both patients at densities of 1.15 to 1.19 and 1.21 to 1.24 g/ml. Subsequently, diagnosis 2 and 4 months after initial evaluation revealed acute myelogenous leukemia and malignant histiocytosis, respectively. Prior studies have suggested a possible etiological significance of such particles in human leukemia. The demonstration of similar particles preceding clinically overt disease in these patients supports this hypothesis and offers the possibility of early diagnosis and treatment.

Twelve male patients with mediastinal nonseminomatous germ cell tumors were treated with chemotherapy (with or without operation and radiation therapy) between 1963 and 1980. Eight patients, treated with only chemotherapy and radiotherapy, died with a median survival from diagnosis of 6 months (range, 3 to 12 months). The 4 survivors remain alive at 12, 15, 34, and 56 months from diagnosis; all are without evidence of disease. All surviving patients were treated with surgical resection of disease either before or after chemotherapy. A major problem in the management of mediastinal nonseminomatous germ cell tumors is the persistence of local disease, which may be overcome by vigorous cytoreductive intervention. Multicenter collaboration will be required to define the optimal combined-modality approach.

Between 1950 and 1981, 31 patients with mesothelioma were treated at the University of Minnesota. An average of 0.2 to 0.6 patients were seen per year between 1950 and 1970, and since 1970 there has been an average of 1.4 to 2.4 patients per year. Twenty-seven of the 28 patients with malignant mesothelioma are known or presumed dead. Mesotheliomas occurred in all areas of Minnesota, and 28.6% of the patients had a definite history of asbestos exposure. This was also a probable cause of the disease in an additional 25% of patients. The clinical findings and course of the disease were similar to other series. The median survival of all patients was eight months. Doxorubicin-treated patients survived a median of 16 months (range, 2-36 months). Malignant mesothelioma is being increasingly recognized in Minnesota and has a grim prognosis in spite of doxorubicin therapy.

The relative efficacy of hormonal, chemical, or combined therapy was investigated in a prostate cancer animal model. 96 Copenhagen-Fischer hybrid rats were implanted with equal-sized fragments of the Dunning H strain transplantable prostatic adenocarcinoma. These animals were randomly assigned to 1 of 6 treatment groups: (1) control, (2) testosterone, (3) testosterone followed by cyclophosphamide, (4) cyclophosphamide, (5) orchiectomy or (6) orchiectomy followed by cyclophosphamide. Animals in the control group had the shortest survival, fastest tumor growth rate, and largest tumor size. Testosterone, when compared to the control group, did not accelerate tumor growth. Cyclophosphamide alone, orchiectomy alone, cyclophosphamide plus orchiectomy, and testosterone plus cyclophosphamide were each equally effective in decreasing tumor growth rate. Tumor size in the testosterone plus cyclophosphamide-treated animals was equivalent to that in orchiectomized animals. The survival of all groups treated with cyclophosphamide was reduced because of toxicity. Testosterone administered prior to cyclophosphamide eliminated and shortened survival from cyclophosphamide. The best overall results were obtained by orchiectomy alone, orchiectomy plus cyclophosphamide, and testosterone plus cyclophosphamide. Although chemotherapy alone was effective in shrinking tumor size, it was highly toxic.

The epipodophyllotoxin derivative VP 16--213 (NSC 141540) was studied by the Cancer and Leukemia Group B in a broad phase II trial at three dose levels: 60 mg/m2, 90 mg/m2, and 135 mg/m2 I.V. twice weekly. No correlation between dose of VP 16--213 and response frequency in a particular disease category could be demonstrated. Of the 382 patients, 8% obtained a complete (CR) or partial remission (PR), 8% showed improvement, and 14% had stable disease. By tumor type the best responses were obtained in lymphomas (8/31 CR + PR), uterus (2/9), prostate (1/5), rhabdomyosarcoma (2/6), neuroblastoma (2/4), colon/rectum (5/81), other gastrointestinal (4/32). In lung tumors, 4/80 patients obtained CR or PR. VP 16--213 has definite antineoplastic activity but the response frequency with the twice weekly schedule may be lower than that reported with other schedules.

Thirty-eight patients with advanced Hodgkin's disease were treated with a combination of cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP). Complete remissions were obtained in 74% of patients. Response rates were similar for previously untreated and previously extensively irradiated patients. Fifty-six percent of patients older than 50 and 50% of patients with bone marrow involvement responded. All patients with mixed cellularity Hodgkin's disease responded compared with 74% of patients with nodular sclerosis. At the present time the median duration of complete remission is 27+ months. However, of the responders, 75% (21 of 28) remain in continous complete remission for 14+ to 49+ months. Only five patients have relapsed but two have died from apparent sepsis without evidence of recurrent disease. The complete remission rate for CVPP is comparable of that for MOPP, CVPP is an easily administered, well-tolerated alternative to MOPP chemotherapy for patients with advanced Hodgkin's disease.

The world's population is aging. Older age is associated with an increase in the incidence of cancer, especially cancer of the breast, lung, prostate, and colon. The management of older patients with cancer is biased by the simple fact of their chronologic age. Underscreening, understaging, less aggressive therapy, lack of participation in clinical trials, or no treatment at all reflect this bias. Although an age-related reduction in the physiologic function of many organs occurs with age, these are not contraindications to treatment with surgery, radiation therapy, or chemotherapy. Chronologic age alone should not be used as a guide for cancer management. Rather, physiologic function or existence of comorbid conditions should be major factors in determining treatment. As a result of the impending need for improved cancer management in older persons, a new subspecialty is evolving: geriatric oncology. This field stresses an important interaction between geriatricians and oncologists, development of research directed at the problems of cancer in older persons, and education at all levels with respect to cancer prevention, cancer detection, and cancer therapy. Physicians and oncologists need to be prepared for the projected increase of cancer in older persons.

Surgical removal of bulky metastases of non-seminomatous germ-cell testicular cancer has been advocated as an adjuvant to chemotherapy in patients whose disease probably is too extensive to be cured by chemotherapy or surgery alone. However, in 8 of our patients, cytoreductive surgery was followed by a sudden and dramatic exacerbation of the disease. In some cases, a marked rise in the serum levels of alpha-fetoprotein and human chorionic gonadotropin was the only evidence. The cause and prevalence of such exacerbations are unknown. Cytoreductive surgery in patients with advanced testicular tumor is accepted treatment and should be advocated, but it appears that in some cases such surgery may adversely alter the course of the malignancy. This must be considered in planning treatment for patients with advanced disease.

The influence of local tumor spread (T-classification) and of tumor size on the occurrence of metastases was studied in 241 patients with testicular germ-cell neoplasms. All patients underwent thorough clinical or pathologic staging, or both, and were treated at the University of Minnesota Hospitals. Spread of tumor through the tunica vaginalis (T2) was associated with abdominal lymph node or distant metastases in eight of nine patients. Local tumor extension to the spermatic cord (T4a) was associated with metastatic spread in 29 of 31 men. Tumor size did not appear to correlate with metastatic rate. These findings are an important aid in designing adjuvant therapy trials and in establishing a "no treatment" approach after orchiectomy.

Thirty men with metastatic germ cell cancer were treated with cisplatin (20 mg/m2 administered intravenously, days 1-5), vinblastine, and bleomycin at 3- to 4-week intervals for four to six courses. There was a sequential fall in serum magnesium (P less than 0.001) with each course of therapy: 26 of the 30 patients (87%) became hypomagnesemic, and the median magnesium nadir was 1.1 meq/l. No acute clinical effects of the hypomagnesemia were observed. The mean creatinine clearance declined from 115 ml/minute before therapy to 65 ml/minute, and the mean serum creatinine rose from 0.9 mg/dl to 1.6 mg/dl after six courses of therapy. With a minimum follow-up of 36 months, 13 of the patients (43%) have clinical evidence of Raynaud's phenomenon. Severity of prior hypomagnesemia predicted an increased risk of Raynaud's phenomenon. Renal dysfunction, hypomagnesemia, and Raynaud's phenomenon are common chronic toxicities of vinblastine, bleomycin, and cisplatin therapy.

The activity of m-AMSA was evaluated IN 39 patients with advanced malignant melanoma. Seventy-nine percent of the patients had some prior chemotherapy. The others had some combination of surgery, radiotherapy, and immunotherapy prior to this study. Patients were treated every 3 weeks starting with 60 or 120 mg/m2 of m-AMSA depending on the extent of prior treatment. Doses were escalated if nadir WBC counts were greater than 2500/microliter. Leukopenia was the dose-limiting toxicity with 7.5% of patients having nadir WBC counts less than 1000/microliter. Of the 39 patients evaluable for response, all had progressive disease. In this study, m-AMSA in myelosuppressive doses was not active in malignant melanoma.