Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.

BACKGROUND: There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up. PATIENTS AND METHODS: Six hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials. RESULTS: Elderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors. CONCLUSIONS: Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. TRIAL NUMBERS: ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).

Treatment of metastatic renal cell carcinoma with subcutaneous interleukin 2: evidence for non-renal clearance of cytokines.

The circulating cytokine concentrations following administration of subcutaneous recombinant interleukin 2 (IL-2) in combination with interferon alpha and 5-fluorouracil used to treat advanced renal cancer were studied. One patient was anephric and on dialysis, and seven had normal biochemical renal function, although five had undergone single nephrectomy. The pharmacokinetics of IL-2 and changes in IL-6 and tumour necrosis factor (TNF)-alpha were essentially similar in all patients including the anephric patient, irrespective of the periods of dialysis, although at some time points, IL-2 concentrations were slightly higher in the anephric patient than in the others. These results show that for subcutaneous administration of low-dose IL-2, renal clearance of IL-2 is not important. This contrasts with high-dose, intravenous IL-2 where blood concentrations are higher and renal clearance seems to occur, perhaps because of saturation of the non-renal mechanisms of clearance. The subcutaneous route is certainly preferred if IL-2 is used in anephric patients and in those with impaired renal function, and it may be generally preferred for most purposes.

A phase II study of interferon-alpha, interleukin-2 and 5-fluorouracil in advanced renal carcinoma: clinical data and laboratory evidence of protease activation.

OBJECTIVE: To confirm the activity and evaluate the toxicity of the combination of subcutaneous interferon-alpha (IFN-alpha) and interleukin-2 (IL-2) with intravenous 5-fluorouracil (5-FU) in patients with advanced and recurrent renal carcinoma and of performance status 0-2. Additionally, to examine protease, complement and neutrophil activation as potential mediators of IL-2 toxicity. PATIENTS AND METHODS: Fifty-five patients were treated in an 8-week cycle with IFN-alpha (6 MU/m2 on day 1 in weeks 1 and 4 and thrice weekly in weeks 2-3, and 9 MU/m2 thrice weekly in weeks 5-8) IL-2 (20 MU/m2 on days 3-5 in weeks 1 and 4 and 5 MU/m2 thrice weekly in weeks 2-3) and 5-FU (750 mg/m2 on day 1 of weeks 5-8). Patients responding to the first cycle were eligible to continue with further cycles. Toxicity and effects on quality of life were assessed using World Health Organization criteria and the Rotterdam Symptom Checklist and Hospital Anxiety and Depression Scale. Serum levels of C3a, prekallikrein and elastase-alpha 1 proteinase inhibitor (elastase-alpha 1-antitrypsin) were assayed in a subset of patients before, during and after the administration of high-dose IL-2 in week 1. RESULTS: There were partial remissions in nine patients, with responses in 24% (95% CI 10-38%) of evaluable patients and 16% of all patients. Amongst 25 evaluable patients who had undergone nephrectomy, the response rate was 32% (95% CI 14-50%), whereas there was only one response amongst 22 patients who had not undergone nephrectomy. The median survival for patients with stable disease or partial remission exceeded 22 months. Outcome and survival were related to performance status, number of sites of metastases and nephrectomy. This group of patients was of relatively poor performance status and 18 patients (36%) failed to complete one 8-week treatment cycle. Cardiovascular and renal toxicities were less than those seen with intravenous IL-2 schedules but 44% of patients experienced at least one grade III toxicity and only 14% reported less than two grade II toxicities. Plasma levels of elastase-alpha 1 proteinase inhibitor exceeded the normal range in three of seven patients tested before treatment and increased in all seven patients after treatment with IL-2. The same three patients had raised levels of C3a before treatment and in all patients examined, C3a increased after treatment with IL-2. In contrast, plasma prekallikrein concentrations were below normal before treatment and decreased further afterwards. CONCLUSIONS: This study confirms the activity of this regimen in patients of good performance status, with limited sites of disease and in those who are fit for nephrectomy, but also showed that treatment was associated with considerable toxicity. The administration of IL-2 is associated with protease activation which may be a suitable target for pharmacological intervention in attempts to ameliorate toxicity.

Double modulation of 5-fluorouracil with interferon alpha 2a and high-dose leucovorin: a phase I and II study.

Twenty-nine patients with adenocarcinomas of gastrointestinal or unknown primary, and three with advanced neuroendocrine tumours, were entered into a study of bolus plus infusional 5-fluorouracil (FUra) modulated with high-dose leucovorin (LV) and recombinant interferon alpha 2a (IFN-alpha). Successive cohorts of > or = 4 patients received IFN-alpha at 1.5, 3, 4.5, 6 and 9 MU on alternate days throughout the treatment period. The FUra/LV regimen consisted of: LV 200 mg m-2 i.v. infusion over 2 h, FUra 400 mg m-2 i.v. bolus then FUra 400 mg m-2 i.v. infusion over 22 h, all repeated on day 2, on a 14-day cycle. FUra was given at 75% dose for the first course, increasing (in the absence of WHO grade > or = 2 toxicity) to 87.5% for the second and 100% for subsequent courses up to a maximum of 12. The maximum tolerated dose (MTD) of IFN-alpha was 6 MU on alternate days, with 7/8 patients at 9 MU requiring dose reductions. At 6 MU IFN-alpha, the MTD of FUra was not exceeded at 100% (i.e. 400 mg m-2 bolus and infusion, days 1 and 2), and FUra-related toxicities (mucosal, haematological, dermatological) were extremely mild. Twenty-nine patients were assessable for tumour response, among whom WHO criteria partial responses were seen in 7/14 with colorectal, 1/4 with gastric, 0/1 with pancreatic, 1/3 with neuroendocrine and 3/6 with unknown primaries. Median response duration was 51 weeks. Minor responses and stable disease were seen in a further six patients. Median survival of patients with advanced adenocarcinomas was 9 months, with 33% surviving beyond 18 months. This schedule offers a safe way of co-administering FUra, LV and IFN-alpha. The addition of IFN-alpha, while causing significant independent toxicity, does not significantly increase the dose-limiting mucosal toxicities of FUra/LV. Further investigation is required to determine the contribution of IFN-alpha to the anti-tumour activity of the combination.

A less toxic regimen of 5-fluorouracil and high-dose folinic acid for advanced gastrointestinal adenocarcinomas.

The combination of high-dose folinic acid with 5-fluorouracil has shown improved response rates in several trials in advanced colorectal carcinoma. This however is at the expense of increased toxicity: regimens using weekly bolus injections produce diarrhoea in most patients and occasional toxic deaths from this, whilst those using daily injections for one week in four report both diarrhoea and severe oral mucositis. Both types of regimen have significant rates of myelosuppression. A recent report described a different schedule of 5-fluorouracil and folinic acid, which appeared better tolerated but equally active (De Gramont et al., 1988). Here we report results using the same programme, in 64 patients with advanced adenocarcinomas. (Forty three colorectal, ten gastric, six pancreatic and five of unknown primary.) Patients received 200 mg m-2 folinic acid by infusion over 2 h followed by an IV bolus of 5-fluorouracil 400 mg m-2 then an infusion of 5-fluorouracil 400 mg m-2 over 22 h. This was repeated over the next 24 h. The schedule was given every 2 weeks for a total of six to 12 courses depending upon the response. The overall response rate was 26% in 62 evaluable patients. No toxicity greater than WHO Grade II occurred. Diarrhoea and mucositis did occur in around 10% of treatments but were not troublesome. No febrile neutropenic episodes were seen. Despite previous reports which described only modest activity for this combination against stomach cancers, this regimen demonstrates low toxicity but retains good activity in the palliative treatment of both gastric and colonic adenocarcinomas.