Since rising serum lactate dehydrogenase (LDH) heralds progression in patients with lymphoma or myeloma we investigated the significance of its elevations during chemotherapy supported by granulocyte (G-) or Granulocyte-Macrophage (GM-) colony stimulating factors (CSF). To exclude effects of resistant disease we analyzed 52 courses of therapy in 36 responding patients. During hematologic recovery LDH increased above normal in 53% and 85% of patients with leukocyte counts of 10,000/mUL and 15,000/kmUL, respectively. After CSF discontinuation LDH fell to or towards normal during 20 courses with adequate follow-up. Therefore rising serum LDH in patients with lymphoma or myeloma may be caused the CSF administration during chemotherapy and not by progressive disease. Proper identification of this effect can prevent unnecessary tests or treatment delays. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Forty-eight adult patients with recurrent or refractory intermediate grade or immunoblastic lymphoma received high-dose carmustine (BCNU), etoposide, Ara C and cyclophosphamide (BEAC), followed by autologous bone marrow transplantation (BMT). Median follow-up is 906 days (range 613-2067 days). The complete remission rate was 42% and 22% had a partial response. Actuarial failure-free survival is 30% ± 6.6%. Twenty one patients relapsed or progressed. Only one relapse occurred > 1 year after autologous BMT. Adverse prognostic factors for failure-free survival include high LDH at the time of autologous BMT, chemotherapy-refractory disease and multiple prior relapses. Patients with chemotherapy responsive first salvage (those achieving first CR only with salvage chemotherapy and those with first relapse, responding to salvage chemotherapy) had a failure-free survival of 52% ± 10% vs 12% ± 6% for those with more advanced disease. Of 13 patients who had no adverse factors, only two relapsed. Treatment-related mortality occurred in 23%, including infection (n = 4), cardiac toxicity (n = 4), pulmonary toxicity (n = 2) and hemorrhage (n = 1). Pulmonary toxicity was more common among patients who had received prior radiation-therapy to the chest. BEAC chemotherapy with autologous BMT is an effective but relatively toxic regimen for patients with relapsed or refractory lymphomas. The combination of chemotherapy-responsive disease after failure of one chemotherapy regimen and normal LDH identifies patients with a favorable prognosis. Alternative cytotoxic regimens require evaluation, with the goal of reducing treatment related mortality. More effective cytoreductive therapy is required for patient with poor prognostic features.

Background: Few effective treatments are available for patients with Waldenstrom's macroglobulinemia that is resistant to standard therapies. We assessed the activity of 2-chlorodeoxyadenosine (2CdA) in patients with resistant macroglobulinemia in order to identify those most likely to benefit. Patients and methods: 2-chlorodeoxyadenosine was given to 46 consecutive patients with Waldenstrom's macroglobulinemia resistant to a combination of an alkylating agent and a glucocorticoid. Two courses were administered to outpatients at a dose of 0.1 mg/kg body weight per day for a 7-day continuous infusion using a portable pump through a central venous catheter. Responding patients were followed without further therapy. Results: Twenty of 46 patients responded to 2CdA therapy (43%; 95 CI; 29 to 60%) with a significantly higher frequency of benefit among patients with disease relapsing off therapy (78%) or with primary resistant disease within the first year (57%) than in those with later phases of disease (22%). The median survival after treatment was 28 months and the median progression-free survival of responding patients was 12 months. The longest survival was measured in patients with primary refractory disease (projected median 36 months) and the shortest in those with disease in refractory relapse (median 13 months). Conclusion: 2-Chlorodeoxyadenosine is active against macroglobulinemic lymphoma resistant to standard regimens and most effective in patients with disease relapsing off treatment or during the first year of primary refractory disease. Little benefit was observed among patients with later phases of resistant disease who should receive alternative treatments. © 1995 Kluwer Academic Publishers.

Primary lymphoma of the prostate was diagnosed in 3 patients corresponding to 0.1 percent of those with previously untreated lymphoma and 0.09 percent of those with previously untreated prostatic malignancy presenting to our cancer between January 1, 1980 and December 31, 1993. All 3 patients had prostatism at presentation that caused renal failure in 2. After treatment with doxorubicin-based combination chemotherapy appropriate for the stage and the specific histological subtype, all 3 patients achieved a complete remission and remained free of disease after a minimum followup of 3 years. Our results suggest that primary prostatic lymphoma is not necessarily associated with a poor outcome. Review of the literature suggests that the poor prognosis reported for prostatic lymphoma might be explained by treatment that was acceptable at the time but would be considered suboptimal by current criteria. We recommend through staging in all patients with prostatic lymphoma and treatment with a doxorubicin-based regimen according to disease stage and histological classification. © 1995 American Urological Association, Inc.

Manifestations of macroglobulinemic lymphoma include lymphadenopathy, splenomegaly and bone marrow involvement. Renal presentations are unusual and complications of renal function are even less frequent. A review of all patients diagnosed with Waldenström macroglobulinemia at our institution from January 1987 to December 1993, revealed 4 cases (6% with renal presentations. We describe these cases with their associated clinical and radiologic features. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

The clinical spectrum of MM is variable. Infiltration of bone and bone marrow by malignant plasma cells results in severe osteopenia, lytic lesions, pathological fractures and anaemia. Occasionally, significant numbers of plasma cells circulate in the bloodstream. Hypercalcaemia and Bence Jones proteinuria are the main reasons for renal impairment, but amyloidosis and monoclonal immunoglobulin deposition should also be considered. Neurological impairment is most often due to spinal cord pressure by an extradural plasma cell tumour. In some patients, symptoms and signs of peripheral neuropathy may be present. Amyloidosis complicates the course of a minority of patients with MM and further impairs the performance of affected patients. Circulating monoclonal protein may increase serum viscosity, impair the function of platelets and coagulation factors, and behave as a cryoglobulin. The levels of uninvolved immunoglobulins are usually decreased, rendering patients susceptible to various bacterial infections. One or more of these complications provides a clue for the diagnosis, forms the basis for defining prognosis and must be managed expeditiously and concurrently, with the institution of specific treatment for the myeloma. © 1995 Baillière Tindall. All rights reserved.

Few effective treatments are available for patients with multiple myeloma that is resistant to vincristine-doxorubicin by continuous infusion with high dose dexamethasone (V AD). In order to modulate p-glycoprotein, the multidrug resistance gene product, we administered a VAD-cyclosporine combination to patients with confirmed resistance to VAD. Twenty-five patients with multiple myeloma resistant to VAD received cyclosporine 4 mg/kg infused over 2 hours followed by a continuous infusion of 10 mg/kg/24 hrs for a total of 108 hours. VAD was given concurrently as a continuous infusion of vincristine 0.3 mg and doxorubicin 9 mg/m2 daily for 4 days with oral dexamethasone 20 mg/m2/day for 4 days beginning on days 1,9 and 17. Clinical response and toxicity were correlated with MDR expression in plasma cells and the effects of cyclosporine on liver function. Six of 25 patients responded (24%; 958 CI 9-45% with a median remission time of 7 months. Clinical response did not correlate with either the measured or the calculated MDR expression in plasma cells. Responses occurred more frequently in patients who developed high cyclosprine blood levels and paralytic ileus. The occasional benefit from VAD-cyclosporine for resistant multiple myeloma appeared to be due to a higher bioeffective dose of VAD rather than successful modulation of MDR. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Myeloablative therapy supported by autologous bone marrow or blood stem cell transplantation was assessed in 41 patients who had multiple myeloma resistant to vincristine‐doxorubicin by continuous infusion with high‐dose dexamethasone (VAD) or other high‐dose dexamethasone regimens. In patients who had high or intermediate tumor mass, the myeloma cell mass was reduced by more than 75% in 56% of patients and the survival time quadrupled in comparison with that of a matched control group. Later treatment resulted in a lower response rate and shorter remission. Current myeloablative regimens supported by autologous stem cells provided a useful treatment for patients who had advanced primary resistant multiple myeloma. Such treatment should be given early in the disease course to provide the best chance for remission, collecting blood stem cells with facility, and preventing complications that would increase the risk of the procedure. Copyright © 1995 AlphaMed Press

High-dose thioTEPA is used frequently in myeloablative regimens for marrow transplantation, but the need for dose adjustments in obese patients has not been explored. We determined the pharmacokinetics of thioTEPA and its metabolite TEPA during first-dose infusion of thioTEPA 150-250 mg/m2 given daily for 3 days in combination with busulfan and cyclophosphamide, and evaluated the results for correlations with toxicity and dosing strategies. The study included 15 adults undergoing marrow transplantation for hematologic malignancies. Plasma samples were obtained at various times over a 24-h period, and concentrations of thio TEPA and TEPA were measured by gas chromatography. At 22-24 h after initiation of a 4-h infusion, the mean ±SE plasma concentration of thioTEPA was 124±63 ng/ml, while that of TEPA was 235±69 ng/ml. For CFU-GM and BFU-E growth in vitro, the IC50s of thioTEPA were 83 ng/ml and 16 ng/ml, respectively, and the IC50s of TEPA were 141 ng/ml and 47 ng/ml, respectively. Using a twocompartment model, the mean thioTEPA Vc was 47.4±4.7 l/m2, t1/2α 19±5 min, t1/2β 3.7±0.5 h, and plasma clearance 302±21 ml/min per m2. The mean AUCs were 6.9-16.2 mg h/l for thioTEPA and 8.9-21.2 mg h/l for TEPA, while the mean peak concentrations were 0.95-2.08 μg/ml for thioTEPA and 0.88-1.90 μg/ml for TEPA. There was a significant association of grades 2-4 maximum regimen-related toxicity (RRT) with TEPA peak >1.75 μg/ml and with combined thioTEPA and TEPA AUC >30 mgh/l (5/6 vs 0/9, P=0.01 for both comparisons), suggesting that drug exposure was an important determinant of toxicity and, potentially, efficacy. ThioTEPA Vc correlated best with adjusted body weight (r=0.74, P=0.0015). In an evaluation of 74 adults receiving thioTEPA 750 mg/m2 in combination with busulfan and cyclophosphamide, the maximum RRT for patients at ideal weight was significantly greater than that for obese patients dosed on ideal weight (mean RRT grade 1.7 vs 1.0, P=0.004) but did not differ from the maximum RRT for obese adults dosed on actual or adjusted weights. We recommend that for obese patients thioTEPA be dosed on adjusted body weight. Measurements at time-points after 24 h are needed to determine when thioTEPA and TEPA concentrations are below myelosuppressive levels and safe for marrow infusion. © 1995 Springer-Verlag.

Objective To assess whether it is worthwhile to screen asymptomatic men for prostate Cancer using serum prostate specific antigen (PSA) and to determine how many patients could be cured of prostatic carcinoma if detected by screening. Patients and methods Between June 1992 and January 1994 the serum PSA level of 1400 asymptomatic men over 50‐years‐old was assessed. Those men with PSA levels < 4 ng/mL were not evaluated further. Those men with PSA levels of 4–10 ng/mL underwent digital rectal examination (DRE) and transrectal ultrasonog‐raphy (TRUS) and biopsies were taken when there were significant findings on DRE and/or TRUS. If the PSA levels were > 10 ng/mL patients were submitted for DRE and TRUS and. even if both examinations were negative, random biopsies were taken. Where Cancer was detected the tumour was staged and if it was a clinically confined tumour a radical retropubic prostatectomy was performed. The pathological and clinical stages of the disease were then compared. Results The majority of patients (95%) had PSA levels of < 4 ng/mL. Forty‐nine men had PSA levels of 4–10 ng/mL and of these 28 were biopsied, which detected 12 (24.5%) carcinomas. There were 20 men with PSA levels > 10 ng/mL and among them 11 (55%) were found to have carcinomas. Combining these figures, among the 1400 men there were 69 cases with PSA levels >4 ng/mL and, using DRE and TRUS, 23 patients (33%) were diagnosed as having prostatic adenocarcinomas. Among these, one had metastatic disease, three had lymph node micrometast‐ases during surgical exploration and 19 underwent radical prostatectomies. The pathological and clinical stages agreed in only eight patients. Conclusion Only eight patients can be considered as cured because of the screening protocol and even this result is overoptimistic, as the future biological behaviour of these tumours is unknown. Therefore we cannot recommend screening for prostatic carcinoma among asymptomatic men in Greece. Copyright © 1995, Wiley Blackwell. All rights reserved

Purpose: To assess the prognostic significance of magnetic resonance (MR) imaging in patients with newly diagnosed asymptomatic multiple myeloma. Patients and Methods: Thirty-eight consecutive patients with asymptomatic myeloma of low tumor mass and negative skeletal surveys underwent MR imaging of the thoracic and lumbosacral spine. The presence and patterns of marrow involvement were correlated with standard laboratory parameters and time to disease progression. Results: Nineteen patients (50%) had evidence of marrow involvement at spinal MR imaging. MR patterns of marrow involvement were classified as diffuse (five patients), variegated (nine), and focal (five). Patients with abnormal MR imaging studies required therapy after a median of 16 months, versus 43 months for those with normal MR studies (P < .01). Conclusion: Abnormal marrow patterns were present in half of patients with asymptomatic myeloma. An abnormal MR study of the spine identified asymptomatic patients who were likely to require treatment earlier than those with a normal MR study. A normal MR pattern provided additional justification to defer institution of chemotherapy. However, MR imaging remains an investigational tool to stage patients with multiple myeloma until more data are accumulated.

In this Phase I clinical trial, six multiple myeloma patients who had not responded to conventional therapy and were scheduled for bone marrow transplantation received a bone-seeking radiopharmaceutical for bone marrow ablation. The pharmacokinetics, dosimetry, and toxicity of this radiopharmaceutical were studied. Methods: Patients received from 519 mCi to 2.1 Ci (19.2 GBq to 77.7 GBq) of holmium-166 (166Ho) complexed with a bone-seeking agent, DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetramethylene-phosphonic acid). The reproducibility of pharmacokinetics from multiple injections of 166Ho-DOTMP administered to these myeloma patients was demonstrated from blood (r2 = 0.926) and whole-body retention (r2 = 0.983), which allowed therapeutic parameters to be determined from a diagnostic study. Results: Over 50% of the 166Ho-DOTMP injected dose was excreted within 2-3 hr postinjection, increasing to 75%-85% over a 24-hr period. Rapid blood clearance minimized radiation dose to nontarget tissue: less than 10% of the injected activity was retained in the blood pool at 1 hr postinjection, and less than 2% remained after 5 hr. The total radiation absorbed dose delivered to the bone marrow for the six patients ranged from 7.9 Gy to 41.4 Gy. Conclusion: All patients demonstrated severe bone marrow toxicity with a white blood cell (WBC) count < 1,000 cells/μl, two patients exhibited marrow ablation (WBC count < 100 cells/μl), and no other toxicity ≥grade 2 was observed in any of the patients.

Purpose: To determine the significance of the International Prognostic Index (IPI) score in adults with testicular lymphoma treated with doxorubicin-based regimens. Patients and Methods: Untreated adults with testicular lymphoma who presented between 1969 and 1993 were studied. Those with Ann Arbor stages III and IV were included if they had a testicular mass at presentation. Results: We identified 22 patients, 21 with intermediate-grade and one with high-grade lymphoma. All 10 patients with an IPI score ≤ 1 had Ann Arbor stage I disease, whereas the 12 with an IPI score more than 1 had Ann Arbor stage II to IV disease. Complete remission (CR) was achieved in 73% of patients. At 153 months, 22% of all complete responders and 40% and 0% of those with IPI scores ≤ 1 and more than 1, respectively, remained in CR (P = .01). With a median follow-up time of 113 months for survivors, the failure-free survival (FFS) rate at 153 months was 16% for all patients or 32% and 0% for those with IPI scores ≤ 1 and more than 1, respectively (P = .02). The CNS or contralateral testis were involved in all patients who failed to respond to primary therapy and in 50% of those who relapsed from CR. Conclusion: The prognosis of patients with testicular lymphoma appears poor despite doxorubicin-based chemotherapy. On the basis of failures in the CNS and contralateral testis, we recommend prophylactic intrathecal chemotherapy and scrotal radiotherapy for all patients. Those with an IPI score ≤ 1 can be treated with conventional doxorubicin-based regimens, but those with an IPI score more than 1 should be considered for investigational systemic therapy. © 1995 by American Society of Clinical Oncology.

After a sequence of standard and intensive therapies, approximately 70% of patients with multiple myeloma achieve a remission of good quality and of many months duration. Yet the disease remains incurable because the high residual burden of approximately 1010 tumor cells cannot be eradicated. Initial disease control, followed by long unmaintained or maintained remissions and by repeated recontrol of relapsing disease, provides the best chance for a long survival time of good quality. Since melphalan-prednisone became available, many other chemotherapy programs have been studied. For selected groups of patients, the most useful regimens are VAD, high-dose dexamethasone, high-dose alkylating agent therapy, and myeloablative therapy plus autologous cell transplantation. Other programs, such as treatments using combinations of alkylating agents in standard doses or interferon alfa, remain unproven despite prolonged study. Until the mortality rate associated with allogeneic bone marrow transplantation can be reduced substantially, the role of intensive treatment supported by this procedure will be limited. Current testing of agents such as paclitaxel, new agents that suppress MDR, topoisomerase I inhibitors, and myeloablative bone-seeking isotopes may lead to future improvements.