Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA).

BACKGROUND: The purpose of the protocol was to reduce the treatment burden in clinical stage I (CSI) seminoma by offering risk-adapted treatment. The protocol aimed to prospectively validate the proposed risk factors for relapse, stromal invasion of the rete testis and tumor diameter >4 cm, and to evaluate the efficacy of one course of adjuvant carboplatin. PATIENTS AND METHODS: From 2007 to 2010, 897 patients were included in a prospective, population-based, risk-adapted treatment protocol implementing one course of adjuvant carboplatin AUC7 (n = 469) or surveillance (n = 422). In addition, results from 221 patients receiving carboplatin between 2004 and 2007 are reported. RESULTS: At a median follow-up of 5.6 years, 69 relapses have occurred. Stromal invasion of the rete testis [hazard ratio (HR) 1.9, P = 0.011] and tumor diameter >4 cm (HR 2.7, P < 0.001) were identified as risk factors predicting relapse. In patients without risk factors, the relapse rate (RR) was 4.0% for patients managed by surveillance and 2.2% in patients receiving adjuvant carboplatin. In patients with one or two risk factors, the RR was 15.5% in patients managed by surveillance and 9.3% in patients receiving adjuvant carboplatin. We found no increased RR in patients receiving carboplatin <7 × AUC compared with that in patients receiving ≥7 × AUC. CONCLUSION: Stromal invasion in the rete testis and tumor diameter >4 cm are risk factors for relapse in CSI seminoma. Patients without risk factors have a low RR and adjuvant therapy is not justified in these patients. The efficacy of adjuvant carboplatin is relatively low and there is need to explore more effective adjuvant treatment options in patients with high-risk seminoma. The data do not support the concept of a steep dose response for adjuvant carboplatin.

One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group.

BACKGROUND: SWENOTECA has since 1998 offered patients with clinical stage I (CS I) nonseminoma, adjuvant chemotherapy with one course of bleomycin, etoposide and cisplatin (BEP). The aim has been to reduce the risk of relapse, sparing patients the need of toxic salvage treatment. Initial results on 312 patients treated with one course of adjuvant BEP, with a median follow-up of 4.5 years, have been previously published. We now report mature and expanded results. PATIENTS AND METHODS: In a prospective, binational, population-based risk-adapted treatment protocol, 517 Norwegian and Swedish patients with CS I nonseminoma received one course of adjuvant BEP. Patients with lymphovascular invasion (LVI) in the primary testicular tumor were recommended one course of adjuvant BEP. Patients without LVI could choose between surveillance and one course of adjuvant BEP. Data for patients receiving one course of BEP are presented in this study. RESULTS: At a median follow-up of 7.9 years, 12 relapses have occurred, all with IGCCC good prognosis. The latest relapse occurred 3.3 years after adjuvant treatment. The relapse rate at 5 years was 3.2% for patients with LVI and 1.6% for patients without LVI. Five-year cause-specific survival was 100%. CONCLUSIONS: The updated and expanded results confirm a low relapse rate following one course of adjuvant BEP in CS I nonseminoma. One course of adjuvant BEP should be considered a standard treatment in CS I nonseminoma with LVI. For patients with CS I nonseminoma without LVI, one course of adjuvant BEP is also a treatment option.

Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer.

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377-1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478-496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497-513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group.

BACKGROUND: To describe incidence, risk factors, and influence of treatment on occurrence of central nervous system (CNS) relapse or progression in younger patients with aggressive B-cell lymphoma. PATIENTS AND METHODS: We analyzed 2210 patients with aggressive B-cell lymphoma treated on various studies for CNS relapse/progression. Treatment consisted of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) ± etoposide. Six hundred and twenty patients also received rituximab. CNS prophylaxis was intrathecal methotrexate on High-CHOEP and MegaCHOEP phase III studies if upper neck, head, bone marrow, or testes were involved. RESULTS: Fifty-six of 2196 patients (2.6%) developed CNS disease. It occurred early (median 7.0 months), median survival was 5.0 months. Patients with age-adjusted International Prognostic Index (aaIPI) 0 or 1 treated with rituximab showed a low risk for CNS disease (2-year rates: 0% or 0.5%), and rituximab decreased the risk (relative risk 0.3, 95% confidence interval 0.1-0.9, P = 0.029). Patients with aaIPI 2 or 3 showed a moderate risk (4.2%-9.7%) and no significant reduction of CNS disease with rituximab. CNS prophylaxis was of no significant benefit. CONCLUSIONS: In younger patients with aaIPI 0 or 1, CNS relapse/progression is very rare; in patients with aaIPI 2 or 3, the risk is higher (up to 10%) and requires new diagnostic strategies and treatment.

Feelings of loss and uneasiness or shame after removal of a testicle by orchidectomy: a population-based long-term follow-up of testicular cancer survivors.

Few data illustrate the man's reaction to orchidectomy. We investigated long-lasting feelings of loss and uneasiness or shame about the body after removal of a testicle by orchidectomy. We identified 1173 eligible men diagnosed with non-seminomatous testicular cancer treated according to the national cancer-care programmes Swedish-Norwegian Testicular Cancer Group I-IV between 1981 and 2004. We asked the survivors about feelings of loss and uneasiness or shame after having had a testicle removed by orchidectomy. We obtained information from 960 (82%) testicular cancer survivors. We found that 32% of these men miss or previously missed their removed testicle(s) and that 26% have or previously had feelings of uneasiness or shame about their body because of the removed testicle(s). Men who had never been offered a prosthesis reported feelings of loss [relative risk (RR): 2.0; 95% confidence interval (CI): 1.3-3.0] and uneasiness or shame (RR: 2.0; 95% CI: 1.3-3.2) to a higher extent than those who had been offered, but rejected a prosthesis. An orchidectomy may result in long-lasting feelings of loss and uneasiness or shame in some men; offering a testicular prosthesis may hinder this experience.

High risk of azoospermia in men treated for childhood cancer.

Childhood cancer survivors (CCS) have an increased risk of impaired spermatogenesis, but data regarding the disease- and treatment-related risk factors of azoospermia are scarce. Such information is crucial both for counselling CCS and for selecting patients for testicular tissue cryopreservation. The proportion of azoospermic men in CCS was 18% [95% confidence interval (CI): 12-26], specifically for leukaemias (19%; 95% CI: 5.5-42), Hodgkin's disease (53%; 95% CI: 29-76), non-Hodgkin's lymphoma (11%; 95% CI: 0.28-48) and testicular cancer (11%; 95% CI: 0.28-48). In CCS treated with high doses of alkylating agents, the proportion of azoospermic men was 80% (95% CI: 28-99) and if radiotherapy was used additionally, the proportion was 64% (95% CI: 35-87). In CCS with subnormal Inhibin B levels, the proportion of azoospermic men was 66% (95% CI: 47-81) and for those with elevated follicle-stimulating hormone (FSH) levels, the proportion was 50% (95% CI: 35-67). Among CCS with subnormal testicular volume (≤ 24 mL), azoospermia was found in 61% (95% CI: 39-80) of the cases. Most childhood cancer diagnoses are associated with an increased risk of azoospermia, especially in CCS receiving testicular irradiation, high doses of alkylating drugs and other types of cytotoxic treatment, if combined with irradiation. Inhibin B, FSH and testicular volume can be used as predictors for the risk of azoospermia.

Long-term follow-up after risk-adapted treatment in clinical stage 1 (CS1) nonseminomatous germ-cell testicular cancer (NSGCT) implementing adjuvant CVB chemotherapy. A SWENOTECA study.

BACKGROUND: To offer minimized risk-adapted adjuvant treatment on a community and nationwide basis for patients with clinical stage 1 (CS1) nonseminomatous germ-cell testicular cancer (NSGCT). The aim was to reduce the risk of relapse and thereby reducing the need of later salvage chemotherapy while maintaining a high cure rate. PATIENTS AND METHODS: From July 1995 to January 1998, a total of 232 Swedish and Norwegian patients were treated for CS1 NSGCT. All were eligible for inclusion into one of two community-based multicenter Swedish and Norwegian Testicular Cancer Project (SWENOTECA) III studies. One study was a prospective randomized study for patients without vascular invasion in the testicular tumor (VASC-), evaluating the effect of one adjuvant course of cisplatin, vinblastine and bleomycin (CVB) compared with surveillance. The second study was a prospective study evaluating the effect of two adjuvant courses of CVB for VASC+ patients. RESULTS: Due to slow accrual and emerging data on toxicity of CVB, the studies were prematurely closed for inclusion in 1998. Of the 232 CS1 patients treated during the study period, only 97 were included in the studies. As all remaining patients were managed according to the SWENOTECA III protocol, although not randomized, the data were pooled. At a median follow-up of 10.1 years, there have been 24 relapses. While one course of CVB to VASC- patients had limited effect on the relapse rate, two courses of adjuvant CVB reduced the relapse rate among VASC+ patients by >90%. Toxicity was high in patients administered adjuvant CVB as 24% of patients experienced grade 3 or 4 obstipation/ileus and 23% grade 3 or 4 infection. CONCLUSIONS: There was no statistical difference in relapse rate between one course of adjuvant CVB and surveillance for VASC- NSGCT patients. Two courses of adjuvant CVB for VASC+ NSGCT patients reduced the relapse rate with >90% in comparison to the surveillance group. Toxicity was unacceptably high for all patients receiving CVB. Adjuvant CVB chemotherapy has no place in the treatment of CS1 NSGCT.

Sperm DNA integrity in cancer patients: the effect of disease and treatment.

As oncological treatment might impair the patients' fertility, male cancer patients are offered to cryopreserve semen prior to treatment. Impaired sperm DNA quality is associated with reduced fertility, and in case of assisted reproduction, sperm DNA integrity may have an impact on choice of method. Therefore, we have assessed sperm DNA integrity in cancer patients, comparing pre- and post-treatment quality. Sperm DNA integrity was investigated in cryopreserved semen from 121 cancer patients, the predominating diagnoses were germ cell cancer (GCC) and Hodgkin's lymphoma (HL). Post-treatment samples, with a median follow-up of 3 years, were analysed for 58 of the men, allowing a pre- and post-treatment analysis on an individual basis. Sperm DNA integrity was assessed using the Sperm Chromatin Structure Assay and expressed here as the DNA Fragmentation Index (DFI%). One hundred and thirty-seven fertile men served as controls. Before treatment, GCC (n = 84) and HL (n = 18) patients had higher DFI% than controls (n = 143) with a mean difference of 7.7 (95% CI 3.2-8.8) and 7.0 (95% CI 2-12), respectively. The same trend was observed for other cancer diagnoses, but without reaching statistical significance (mean difference 3.6, 95% CI -1.2 to 8.4). No increase was seen in DFI% comparing pre- and post-treatment semen, regardless of treatment modality. A moderate elevation of DFI% was observed in cryopreserved semen from cancer patients. Oncological treatment, generally, did not induce any increase in DFI. These findings should be considered when discussing the utilization of pre-treatment cryopreserved semen vs. post-treatment fresh sperm in cancer patients undergoing assisted reproduction.

Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: a multicenter experience.

Between 1981 and 1986, 200 consecutive patients with metastatic nonseminomatous testicular cancer were entered into the Swedish Norwegian Testicular Cancer (SWENOTECA) project from 14 hospitals. The treatment plan was four chemotherapy cycles (cisplatin, vinblastine, and bleomycin) followed by surgical resection of residual tumor masses. After a median observation time of 75 months, the overall 5-year survival rate was 82%. In a univariate analysis, the following parameters influenced the prognosis significantly: the extent of the disease (Medical Research Council [MRC] grouping); the prechemotherapy levels of serum alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH); the patients' age; the presence of extrapulmonary hematogeneous metastases; and/or particularly large lymph node metastases. Patients fared better when more than 3 weeks elapsed between orchiectomy and start of chemotherapy as compared with those who were treated within this interval. The place of treatment (a large oncology unit v smaller units) also represented a significant prognostic factor for patients with large-volume (LV) and very-large-volume (VLV) disease combined. Multivariate analysis (Cox regression proportional hazards model) performed in all 193 assessable patients showed the following adverse prognostic factors: high-volume metastatic burden, age older than 35 years, prechemotherapy AFP greater than 500 micrograms/L and/or HCG greater than 1,000 U/L, and an interval between orchiectomy and start of chemotherapy of less than 3 weeks. The place of treatment also significantly influenced the final outcome. If patients with LV and VLV disease were combined, the presence of two of the following risk factors represented an additional prognostic factor: AFP greater than 1,000 micrograms/L, HCG greater than 10,000 U/L, liver metastases, brain metastases, bone metastases, retroperitoneal tumor greater than or equal to 10 cm, and mediastinal tumor greater than or equal to 5 cm.

Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. Swedish-Norwegian Testicular Cancer Group.

Between 1981 and 1986, 279 consecutive patients with clinical stage I (CS1) nonseminomatous germ cell tumors (NSGCT) of the testis underwent pathological staging (PS) with retroperitoneal lymphadenectomy (RPLND). Patients with retroperitoneal metastases (PS2) received adjuvant chemotherapy. The median follow-up time after RPLND was 50 months (range, 30 to 90). Clinical and histopathologic features were registered prospectively and analyzed for association with risk of having PS2, relapse despite pathological stage 1 (PS1) or the combined risk of either event, metastatic disease (MET). Seventy-five (26.9%) of the patients had PS2 disease, and 30 (14.7%) of the 204 PS1 patients relapsed, indicating that at least 105 (37.6%) of this CS1 population had subclinical MET at the time of orchiectomy. Four (1.4%) of the 279 CS1 patients died of testicular cancer. Multivariate analyses showed several variables to be significantly associated with outcome for the CS1 patients; vascular invasion in primary tumor and normal preorchiectomy serum alpha-fetoprotein (Pre-AFP) level indicated PS2 disease. If Pre-AFP was excluded from the model, the absence of teratoma or yolk sac elements in the primary tumor became significant predictors of PS2. Vascular invasion, absence of teratoma, and a short interval between orchiectomy and RPLND indicated increased risk of relapse in PS1 patients. Vascular invasion, normal Pre-AFP, absence of teratoma elements, and a short orchiectomy to RPLND interval were predictive of MET. Our results indicate that prognostic factors useful for stratification of CS1 patients with NSGCT to different treatment options may be established.

Radioimmunotherapy using 131I-labeled anti-CD22 monoclonal antibody (LL2) in patients with previously treated B-cell lymphomas.

Experience in using rapidly internalizing antibodies, such as the anti-CD22 antibody, for radioimmunotherapy of B-cell lymphomas is still limited. The present study was conducted to assess the efficacy and toxicity of a 131I-labeled anti-CD22 monoclonal antibody (mAb), LL2, in patients with B-cell lymphomas failing first- or second-line chemotherapy. Eligible patients were required to have measurable disease, less than 25% B cells in unseparated bone marrow, and an uptake of 99mTc-labeled LL2Fab' in at least one lymphoma lesion on immunoscintigram. Eight of nine patients examined with immunoscintigraphy were unequivocally found to have an uptake, and therapy with 131I-labeled anti-CD22 [1330 MBq/m2 (36 mCi/m2)] preceded by 20 mg of naked anti-CD22 mAb was administered. Three patients achieved partial remission (duration, 12, 3, and 2 months), and one patient with progressive lymphoma showed stable disease for 17 months. Four patients exhibited progressive disease. The toxicity was hematological. Patients with subnormal counts of neutrophils or platelets before therapy seemed to be more at risk for hematological side effects. Radioimmunotherapy in patients with B-cell lymphomas using 131I-labeled mouse anti-CD22 can induce objective remission in patients with aggressive as well as indolent lymphomas who have failed prior chemotherapy.

Effects of cisplatin and amphotericin B on DNA adduct formation and toxicity in malignant glioma and normal tissues in rat.

In an attempt to modify the cytotoxicity of cisplatin, amphotericin B (AmB) was given as pretreatment to BDIX rats with intracerebral BT4C glioma implants. Ten animals given AmB 5 mg/kg i.p. followed by cisplatin 5 mg/kg i.p. displayed massive haematuria within 24 h after treatment and died a few days later. The antitumoral effect could not, therefore, be evaluated. Histopathological examination of the kidneys showed extensive tubular necrosis. No signs of apoptotic cell death were found using in situ end labelling with biotin-labelled nucleotides or with DNA integrity analysis in agarose gel electrophoresis. An immunohistochemical method for analysis of cisplatin-DNA adducts was used to elucidate the distribution of cisplatin in brain tumour, normal brain and kidney. Addition of AmB to cisplatin caused increased adduct formation in kidneys, particularly in tubular cells. It seems plausible that the nephrotoxicity, at least in part, was mediated by increased levels of cisplatin-DNA adducts. Pretreatment with AmB did not have any obvious effect on the formation of adducts in the cerebral cortex. The adduct levels in the tumours from animals pretreated with AmB were not significantly increased compared with those treated with cisplatin only. Thus, addition of AmB to cisplatin caused excessive nephrotoxicity suggesting a decrease in the therapeutic ratio of cisplatin.

Risk-adapted treatment of clinical stage 1 non-seminoma testis cancer.

250 patients with clinical stage 1 non-seminomatous germ cell tumours of the testis (NSGCT 1) were included into a prospective multicentre protocol during 1990-1994 and treated according to three risk strata: patients without tumour cell invasion of vascular structures in the testis (VASC-) and elevated serum AFP levels (AFP+) at orchiectomy were considered low risk (LR) and only observed closely. VASC- and AFP- or VASC+ and AFP+ patients were presumed intermediate risk (IR) and pathologically staged (PS) by retroperitoneal lymph node dissection (RPLND). VASC+ and AFP-patients were regarded as high risk (HR) and received adjuvant chemotherapy (PEB x 3). At a median observation time of 40 (7-68) months, all patients were alive and without evidence of active germ cell cancer. The actuarial relapse rate in the 106 LR patients was 22%, and 70% (14/20) had elevated serum tumour markers at relapse. One of 32 (3%) HR patients relapsed with a resectable retroperitoneal mature teratoma despite adjuvant chemotherapy. Only 14% of the 99 IR patients who underwent RPLND had PS2 disease, and the actuarial relapse rate in 85 PS1 patients was 18%. This multicentre study demonstrated that excellent therapeutic outcome is possible when 18 comparatively small urological and oncological centres follow a strict and formal cancer care programme. The useful prognostic effect of VASC was once again verified. Pathological staging by RPLND in NSGCT1 is, in our opinion, not necessary, with presumed low-risk patients offered surveillance and high-risk patients offered adjuvant chemotherapy.

Prednimustine v cyclophosphamide-vincristine-prednisolone in the treatment of non-Hodgkin's lymphoma with favorable histopathology: results of a national cancer care program in Sweden.

In a nationwide multicenter study, single-agent treatment with prednimustine (PM) was compared with combination chemotherapy with CVP (cyclophosphamide, vincristine, and prednisolone) in patients with stage III-IV non-Hodgkin's lymphoma (NHL) with favorable histology (Rappaport groups nodular lymphocytic poorly differentiated, nodular mixed, and diffuse lymphocytic poorly and well-differentiated). From January 1979 to May 1982, 217 evaluable patients were randomized, and at present analysis, the median follow-up time is 42 months. Overall response rate in the PM group was 63% (complete, 40%; partial, 23%) compared with 66% in the CVP group (complete, 32%; partial, 34%). There was no significant difference in relapse-free survival (RFS) or survival between the two groups, median RFS being 30 months and median survival being 42 months, respectively. Reclassification of the lymphomas according to the Kiel system (possible in 80%) revealed high-grade malignant NHL in 22 patients (12 in PM group, 10 in CVP group). Within this small group, there was a marked difference in survival in favor of CVP-treated patients. However, treatment with PM was less toxic and better tolerated than the CVP regimen. It was concluded that for patients with low-grade malignant NHL treatment with PM is equally effective and less toxic than the CVP regimen.

Prognostic implications of BCL6 rearrangement in uniformly treated patients with diffuse large B-cell lymphoma--a Nordic Lymphoma Group study.

The purpose of this study was to investigate the prognostic implications of BCL6 rearrangement in a uniformly treated population of patients with diffuse large B-cell lymphoma (DLBCL) and to characterise the relationship between BCL6 rearrangement and prognostic factors. A total of 269 patients with DLBCL entered a randomised trial comparing the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) to the MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) regimen. In 44 cases, frozen tissue was available for assessment of BCL6 status by Southern blot analysis. BCL6 was rearranged in six of 43 evaluable cases (14%), and was associated with elevated lactate dehydrogenase (LDH), and a higher patient age. No association between BCL6 status and expression of BCL2, Ki-67 or TP53 was found. Patients presenting with BCL6 rearrangement displayed a weak trend towards better overall and failure-free survival (67 and 67% at 5 years), compared to patients with germline BCL6 (63 and 52%), but the difference was not statistically significant. In accordance with previously published series, the presence of BCL6 rearrangement does not define a prognostically distinct subgroup of DLBCL. Assessment of BCL6 status may, however, be of clinical interest when related to other prognostic variables.

Cisplatin pharmacokinetics and pharmacodynamics in patients with squamous-cell carcinoma of the head/neck or esophagus.

The pharmacokinetics of total platinum (Pt) in plasma and cisplatin (CDDP)-DNA adducts in different cell types were described in ten patients with squamous-cell carcinoma of the head/neck or esophagus after their first cycle of chemotherapy containing a CDDP dose of 100 mg/m2. Nephrotoxicity was studied in terms of urinary excretion of marker proteins (protein HC, IgG, and albumin). Pharmacodynamic relationships between pharmacokinetic parameters and toxicity were investigated. A population-based model with limited sampling was found feasible for producing pharmacokinetic information, in accordance with literature data. The kinetics of two normal cell types with different turnover (lymphocytes and buccal cells) appeared to have different kinetic profiles of CDDP-DNA adducts. Analysis of urinary excretion of marker proteins (protein HC, albumin, and IgG) showed that the nephrotoxicity was displayed first as tubular damage and later as impaired glomerular barrier function. There were indications that tubular nephrotoxicity may be predicted by pharmacokinetic parameters of plasma Pt. We found older patients to have a lower Pt clearance and more extensive early tubular damage. There was no correlation between CDDP-DNA adducts in normal cells and nephrotoxicity. Larger studies are warranted to define the pharmacokinetic window of CDDP. Limited sampling for analysis of CDDP pharmacokinetics may then be a possible avenue for individualizing the dose and, thus, improving the clinical use of the drug.

Pharmacokinetics and tissue distribution of cisplatin in nude mice: platinum levels and cisplatin-DNA adducts.

The pharmacokinetics of platinum (Pt) and cisplatin (CDDP)-DNA adducts were studied in nude mice after single-dose CDDP treatments. Whole blood, serum, kidney, lever, testis, brain, and tumor were collected at different intervals after injection of CDP at different dose levels. Pt was measured with flameless atomic absorption spectrometry (FAAS) or adsorptive voltammetry (AdV) and CDDP-DNA adducts with quantitative immunohistochemistry. The drug was immediately absorbed into the blood circulation (peak serum Pt levels were reached within 5 min) after i.p. CDDP administration, and distribution into most tissues also occurred rapidly (tissue Pt levels peaked at 15 min). With a sampling period of 7 days there was a biphasic elimination of Pt from blood, serum, and tissues. In the brain the pharmacokinetics differed with a gradual accumulation of Pt occurring during the 1st week. Formation of CDDP-DNA adducts in tissues was a slower process, with maximal levels being achieved at between 30 min and 4 h after drug administration, followed by a steady state lasting for at least 24 h. Each tissue type had its specific immunohistochemical staining pattern of adducts. With escalating CDDP doses there was a linear, or almost linear, increase in Pt concentrations and CDDP-DNA adduct levels in all sample types examined. These results suggest that a fair estimation of the amount of drug in tumor and normal tissues can be made from analysis of serum Pt at a fixed time point after a single dose of CDDP.

Cladribine for untreated or early low-grade non-Hodgkin's lymphoma.

PATIENTS AND METHODS: Forty-four patients, with low-grade non-Hodgkin's lymphoma (LG-NHL) were included in a phase II study between June 1993 and May 1995 and treated with cladribine (CdA) 0.12 mg/kg as a 2 h i.v. infusion daily x 5, repeated after 28 days for up to 6 courses. Thirty-four patients were previously untreated and 10 had progressive disease after initial response to limited chlorambucil treatment. Five patients had also received involved field radiotherapy. Eight patients had mantle cell lymphomas, 22 follicle centre lymphomas, 5 lymphoplasmacytoid lymphomas, 4 small cell lymphocytic lymphomas, 4 marginal zone B-cell lymphomas and I had unclassified low-grade NHL. The response rate was 64%, with 11 (25%) CR and 17 (39%) PR while 5 (11%) patients progressed during treatment. The response rate was similar in previously treated and untreated patients. The median number of CdA courses delivered was 3 (1-6) in non-responding patients and 6 (2-6) in responders. Median survival from inclusion was not reached with a median follow-up of 40 months. The median time to progression was 7 mo for all patients, 25+ mo for CR and 16 mo for PR patients. Toxicity was sometimes severe with 2 treatment related deaths, one infectious related and one due to a mucocutaneous syndrome and pulmonary microembolism. In addition, 5 grade 3 or 4 infectious episodes were seen. Seven patients experienced grade 3 or 4 thrombocytopenia and 20 had grade 3 or 4 neutropenia. We conclude that the majority of patients with low-grade non-Hodgkin's lymphoma respond to CdA but that the adverse effects may be severe.

Primary localized non-Hodgkin's lymphoma of the thyroid: a retrospective clinicopathological review.

Primary localized non-Hodgkin's lymphomas (NHL) of the thyroid are rare. The data presented are derived from 819 consecutive patients with NHL and six patients with anaplastic thyroid carcinomas of small cell type investigated and treated at our department between 1970 and 1981. The present analyses are based on the 19 patients, who were found to have localized primary thyroid lymphomas. Four of these patients were initially considered to have undifferentiated small cell carcinomas of the thyroid but revealed to be lymphomas at re-examination supplemented with immunohistopathologic staining. Prognosis has been evaluated with regard to initial stage, histopathology according to the Kiel classification and therapy. Median follow-up was 5 years. The crude survival was 77% 5 years after diagnosis. This was not significantly less (4.2%) than the overall-survival in an age- and sex-matched population, despite the majority of patients having tumours which were locally advanced, often with spread to regional lymph nodes, and in many cases a histology showing a high-grade malignancy according to Kiel classification. The excellent prognosis in the current study compared to other studies is probably mainly attributed to more extensive staging procedures. The biologic behaviour supports the hypothesis that these lymphomas represent lymphomas of mucosa associated lymphoid tissue (MALT). According to present results anaplastic thyroid carcinoma of small cell type must be extremely rare.

Reproducibility of tumor response evaluation in patients with high-grade malignant non-Hodgkin's lymphoma.

Estimation of complete response (CR) and partial response (PR) in patients with non-Hodgkin's lymphoma (NHL) is associated with a number of potential sources of error. The aim of this study was to define the reproducibility of response evaluation performed by an independent review committee (RC). In a phase III study of patients >60 yr with aggressive NHL, 60 patients who were already evaluated by the independent review committee (RC 1) for response were randomized to three groups and re-evaluated (RC 2). The assessment was classified into one of seven mutually exclusive categories, where the important borderlines with regard to one of the major end-points of the study, the CR rate, were between CR, "CR uncertain" (CR(U)), and PR. A discrepancy between RC 1 and 2 was found in 8/60 patients (13.3%), influencing the CR/CR(U) status in four of these patients. Two CR and two PR patients were reclassified as CR(U). Thus, CR/CR(U) was changed in 4/60 (6.7%). The reports of the local investigators were compared with that of RC 1 in 254 patients. The CR/CR(U) status was affected in 41 of these patients (16.1%). It is concluded that an independent RC is a major prerequisite for a uniform response evaluation in phase III clinical trials. However, the good RC reproducibility does not motivate a second assessment. Moreover, in the phase III setting end-points other than the CR rate, such as time to treatment failure, cause specific and overall survival are preferred.