MTHFR-1298 A>C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin.

Adjuvant treatment based on fluoropyrimidines (FL) improves the prognosis of stage II/III colorectal cancer (CRC). Validated predictive/prognostic biomarkers would spare therapy-related morbidity in patients with a good prognosis. We compared the impact of a set of 22 FL-related polymorphisms with the prognosis of two cohorts of CRC patients treated with adjuvant FL with or without OXA, including a total of 262 cases. 5,10-Methylentetrahydrofolate reductase (MTHFR) MTHFR-1298 A>C (rs1801131) polymorphism had a concordant effect: MTHFR-rs1801131-1298CC genotype carriers had a worse disease free survival (DFS) in both the cohorts. In the pooled population MTHFR-rs1801131-1298CC carriers had also a worse overall survival. We computed a clinical score related to DFS including MTHFR-rs1801131, tumor stage, sex and tumor location, where rs1801131 is the most detrimental factor (hazard ratio=5.3, 95% confidence interval=2.2-12.9; P-value=0.0006). MTHFR-rs1801131 is a prognostic factor that could be used as an additional criteria for the choice of the proper adjuvant regimen in stage II/III colorectal cancer patients.

A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen.

The discovery of pharmacogenomic markers in colorectal cancer (CRC) could be setting-specific. FOLFOX4 is employed in the adjuvant and metastatic setting in CRC. This prospective study is aimed to validate in the adjuvant setting the pharmacogenomic markers of toxicity reported in the metastatic setting (that is, GSTP1-rs947894, and -rs1138272; GSTM1-null genotype; AGXT-rs4426527, -rs34116584 and del-74 bp), and to discover additional markers. CRC patients (n=144) treated with adjuvant FOLFOX4 were genotyped for 57 polymorphisms in 29 genes. Grade ≥ 2 neurotoxicity was associated (false discovery rate-adjusted q-value <0.1) with single-nucleotide polymorphisms in ABCC1 (rs2074087: odds ratio=0.43(0.22-0.86)), and ABCC2 (rs3740066: 2.99(1.16-7.70); rs1885301: 3.06(1.35-6.92); rs4148396: 4.69(1.60-13.74); rs717620: 14.39(1.63-127.02)). hMSH6-rs3136228 was associated with grade 3-4 neutropenia (3.23(1.38-7.57), q-value=0.0937). XRCC3-rs1799794 was associated with grade 3-4 non-hematological toxicity (8.90(2.48-31.97), q-value=0.0150). The markers previously identified in metastatic CRC were not validated. We have identified new markers of toxicity in genes of transport and DNA repair. If validated in other studies, they could help to identify patients at risk of toxicity.

Vinorelbine is an effective and safe drug for AIDS-related Kaposi's sarcoma: results of a phase II study.

PURPOSE: To assess the safety and efficacy of vinorelbine in patients with AIDS-related Kaposi's sarcoma (KS). PATIENTS AND METHODS: From December 1994 to May 1997, within the Italian Cooperative Group on AIDS and Tumors, we enrolled 36 patients with AIDS-related KS who experienced disease progression after one or more regimens of systemic chemotherapy. Patients were treated with vinorelbine 30 mg/m(2) every 2 weeks by intravenous bolus. RESULTS: Of 35 assessable patients, three (9%) had a clinical complete response and 12 (34%) had a partial remission, for an overall objective response rate of 43% (95% confidence interval, 26% to 61%). For the 15 patients with objective responses, the median duration of response from the beginning of therapy until the development of progression was 176 days, whereas the median progression-free survival and the median survival durations for 35 assessable patients were 151 days and 216 days, respectively. Vinorelbine also induced responses in patients who had become resistant to regimens that included other vinca alkaloids. Overall, vinorelbine was well tolerated. Toxicity, including neurologic toxicity, was mild and reversible. Neutropenia was the most frequent dose-limiting toxicity. CONCLUSION: Vinorelbine is safe and effective in the treatment of patients with advanced KS who have been previously treated with one or more chemotherapy regimens.

Interactions of antineoplastic chemotherapy with zidovudine pharmacokinetics in patients with HIV-related neoplasms.

To evaluate the perturbations in zidovudine (ZDV) pharmacokinetics as a consequence of antineoplastic chemotherapeutic treatments, we performed a prospective crossover study in 13 HIV-infected patients with cancer. The subjects received 2-day regimens of ZDV (250 mg x 2/day). On the first day ZDV was administered alone, whereas on the second day it was combined with antitumor chemotherapies specific for the histological type (ZDV + chemotherapy). Blood sample and urine collections were performed over a 12-hour period following oral administration of the antiretroviral agent. ZDV was measured with high-performance liquid chromatography. Pharmacokinetic parameters of ZDV were calculated by a noncompartmental model. The mean ZDV area under curve (AUC) was not significantly different in the patients treated with ZDV alone and ZDV + chemotherapy. Comparison of plasma elimination half-life (t((1/2))), apparent systemic clearance (CL/F), and apparent volume of distribution (Vd/F) of ZDV did not show any significant difference before and after chemotherapy. Conversely, some significant differences were observed for both mean peak concentration (C(max)) of ZDV and the corresponding time (T(max)). There was a 57% reduction in C(max) (p<0.05) and a 66% increase in T(max) (p<0.05) after chemotherapy compared with treatment with ZDV alone. No differences were observed in the urinary excretion of ZDV and ZDV glucuronide and urinary metabolic ratio, as a consequence of antineoplastic treatment. In conclusion, this study demonstrates that some minor perturbations in ZDV pharmacokinetics (i.e. C(max) and T(max)) derived from antineoplastic chemotherapy. Based on the observation that antineoplastic chemotherapy had no significant effect on plasma ZDV concentration expressed as AUC, the observed pharmacokinetic interaction would not warrant by itself a change in the ZDV dosage during chemotherapy.

A risk and benefit assessment of treatment for AIDS-related Kaposi's sarcoma.

Kaposi's sarcoma is the most common malignancy observed in patients with HIV-1 infection, and causes considerable morbidity and, when the lungs are involved, mortality. Therapy should be based on an evaluation of prognostic factors, in particular the extent and rate of tumour growth, patient symptoms, immune system condition and concurrent complications of AIDS. Nevertheless, considering the palliative role of Kaposi's sarcoma therapy, the potential benefits of therapy must be weighed against the high risk of adverse effects. Therefore, quality of life assessment is an integral component of therapeutic decisions. Localised Kaposi's sarcoma cutaneous tumours have been successfully treated with surgical excision, laser therapy, liquid nitrogen cryotherapy and radiotherapy. In patients with moderately extensive cutaneous or mucosal disease and CD4+ cell counts of > or =200/ml, immunotherapy and antiretroviral drugs are indicated. Preliminary results indicate that antiretroviral therapy might be effective and well tolerated in the treatment of less advanced Kaposi's sarcoma. In patients with aggressive and extensive mucocutaneous disease or with visceral manifestations of Kaposi's sarcoma, systemic cytotoxic therapy is indicated. However, the optimal treatment has yet to be found. The combination of doxorubicin, bleomycin and vincristine (ABV) has produced high overall response rates and is indicated as first-line treatment for patients with life-threatening or visceral disease. In patients who are leucopenic and require chemotherapy, single or dual agents associated with lower myelotoxicity [i.e. bleomycin, vincristine/vinblastine or a combination of bleomycin and vincristine/vinblastine (BV)] are most widely used. Other effective cytotoxic regimens are liposomal anthracyclines, paclitaxel and vinorelbine. To date, 3 randomised trials have compared these drugs to ABV and BV. In a large phase III study, the efficacy of liposomal daunorubicin was comparable with that of ABV. In 2 phase III studies, liposomal doxorubicin was compared with ABV and BV regimens and was found to be significantly more effective in producing objective responses. Therefore, liposomal doxorubicin, although more myelosuppressive than the BV regimen, is now considered by many physicians as the first-line therapy in patients with advanced stage Kaposi's sarcoma. Paclitaxel and vinorelbine have potential in Kaposi's sarcoma, but additional studies are needed to evaluate different schedules and to compare their activity with that of the reference regimens. Institution or continuation of both effective antiretroviral therapy and prophylaxis of opportunistic infections should be recommended to all patients receiving systemic cytotoxic therapies. However, attention must be paid to the cross-toxicity and possible pharmacokinetic interactions between antiretrovirals and antineoplastics.

Hodgkin's disease in 35 patients with HIV infection: an experience with epirubicin, bleomycin, vinblastine and prednisone chemotherapy in combination with antiretroviral therapy and primary use of G-CSF.

BACKGROUND: The optimal therapeutic approach for patients with Hodgkin's disease and human immunodeficiency virus infection (HD-HIV) is unknown. In an attempt to improve the results previously obtained with EBV (epirubicin, bleomycin and vinblastine) without G-CSF (Cancer 1994; 73: 437-44), in January 1993 we started a trial using chemotherapy (CT) consisting of EBV plus prednisone (EBVP), concomitant antiretroviral therapy (zidovudine, AZT or dideoxinosyne, DDI), and G-CSF. PATIENTS AND METHODS: Up to August, 1997, 35 (30 M/5 F) consecutive previously untreated patients (median age 34, range 21-53 years) with HD-HIV were enrolled in the European Intergroup Study HD-HIV. Their median performance status was 1 (range 1-3). At diagnosis of HD, 26% of the patients had AIDS, 90% had B symptoms at HD presentation and 83% had advanced-stage HD. Patients received E 70 mg/m2 i.v. on day 1, B 10 mg/m2 i.v. on day 1, V 6 mg/m2 i.v. on day 1 and P 40 mg/m2 p.o. from day 1 to day 5 (EBVP). Courses were repeated every 21 days for six cycles. AZT (250 mg x 2/day), or DDI (200 or 300 mg x 2/day) if AZT had been previously used, were given orally from the beginning of CT. G-CSF was given at the dose of 5 mcg/kg/day s.c. from day 6 to day 20 in all cycles. RESULTS: An overall response rate of 91% was observed. There were 74% complete responses (CR) and 17% partial responses (PR). Toxicity was moderate, with grade 3-4 leukopenia and thrombocytopenia in 10 (32%) and three (10%) patients, respectively. The median number of administered cycles was 6 (range 3-6). Twenty-three of 35 patients received AZT and nine patients received DDI. Three (8%) patients had opportunistic infections (OI) during or immediately after CT. The median CD4+ cell count was 219/mm3 (6-812) at HD diagnosis and 220/mm3 (2-619) after the end of combined therapy, and these numbers remained unchanged. Ten of 26 (38%) patients who achieved CR relapsed. Twenty-three patients died of HD progression alone or in association with OI, being the cause of death in 48% and 9% of patients respectively. The median survival was 16 months, with a survival rate of 32% and a disease-free survival of 53% at 36 months. CONCLUSIONS: The combined antineoplastic and antiretroviral treatment is feasible, but HD in HIV setting is associated with a more adverse prognosis than in the general population. Although the CR rate obtained was satisfactory, the relapse rate was high. Furthermore, comparison of the results of our two consecutive prospective studies demonstrated no overall improvement in the current trial with respect to the CR rate and survival.

Treatment of non-Hodgkin's lymphoma in the elderly: an update.

Recent studies specifically directed toward assessing the outcome of older patients with non-Hodgkin's lymphoma (NHL) indicate that age per se is an important and independent prognostic factor for response and survival. We report a review of the clinical trials of the literature and the Aviano Group experience in the treatment of NHL in the elderly. Prospective studies have addressed therapeutic approaches in these patients. Direct comparison of trial results is difficult since different age limits were set for the inclusion of patients under study. These studies suggest that older patients with aggressive NHL should be treated with curative intent.

CHOP is the standard regimen in patients > or = 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group.

PURPOSE: We report the results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC) Lymphoma Group, which compared a chemotherapy regimen specifically devised for elderly patients, ie, etoposide, mitoxantrone, and prednimustine (VMP), versus the standard regimen of cyclophosphamide, doxorobucin, vincristine, and prednisone (CHOP) in patients older than 70 years of age with intermediate- and high-grade non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients older than 70 years of age with stage II, III, or IV intermediate- and high-grade NHL, with an Eastern Cooperative Oncology Group (ECOG) performance status less than 4 and acceptable cardiac, renal, and liver function were randomized to receive six courses of VMP or six courses of CHOP. Between February 1989 and June 1994, 130 patients aged 70 to 93 years (median, 75) were enrolled and 120 were assessable for response, 60 patients in each arm. RESULTS: Overall objective response rates were 50% and 77% in VMP- and CHOP-treated patients, respectively (P = .01), while complete response (CR) rates were borderline significant (27% v 45%; P = .06). At 2 years, the progression-free survival (PFS) rate was 25% with VMP versus 55% with CHOP (P = .002) and the overall survival (OS) rate was 30% with VMP versus 65% with CHOP (P = .004). Statistically significant more alopecia and neurologic and gastrointestinal toxicities were reported with CHOP. CONCLUSION: CHOP is the standard regimen for patients > or = 70 years of age with stage II to IV intermediate- and high-grade NHL.

Malignant tumors and AIDS.

One in six patients with acquired immunodeficiency syndrome (AIDS) both in the USA and Europe develop malignancies, in particular Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL). After an initial rapid increase, the proportion of AIDS patients with KS steadily declined in the USA and in Europe, while the proportion of AIDS-NHL has been stable during the last decade in the USA and Europe. Human immunodeficiency virus (HIV) infected patients are living longer due to advances in antiretroviral therapy and treatment of prophylaxis against opportunistic infections, yet because of their immunodeficiency they are at high risk for cancers, especially NHL. The natural history of cancers in patients with HIV infection differs from that of the general population. Unusual aspects of tumor localization, growth behavior and therapeutical response distinguish tumors in patients with HIV infection from those without. The pathologic and virological aspects of HIV-related tumors are peculiar and a pathological classification of HIV-associated systemic lymphomas based on the morphological features of the two main types, ie, blastic and anaplastic cell lymphomas, has been formulated. The treatment of HIV-related neoplasms is controversial as it is not clear whether conventional therapy, particularly chemotherapy, is able to modify the natural history of these malignancies in the HIV setting. Moreover the treatment of HIV-related tumors presents several problems due to the aggressive behaviors of tumors and because of immunosuppressive chemotherapy employed in patients with immunodeficiency. This paper reviews the most relevant data on the epidemiology, pathology and treatment of malignant tumors in patients with HIV infection.

Treatment of lymphoma in the elderly: an update.

Recent studies specifically directed toward assessing the outcome of older patients with non-Hodgkin's lymphoma (NHL) indicate that age per se is an important and independent prognostic factor for response and survival. Prospective studies have addressed therapeutic approaches in these patients. Direct comparison of trial results is difficult since different age limits were set for the inclusion of patients in study. These studies suggest that older patients with aggressive NHL should be treated with curative intent. We report on selected prospective clinical trials of the literature and the Aviano Group experience in the treatment of NHL in the elderly. In particular we refer our data of a randomized study (CHOP vs VMP), conducted within the EORTC Lymphoma Group, and the results obtained with chemotherapy and granulocyte colony-stimulating factor.