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Biomedical subjects

C R Franks

Publications and source records attributed to C R Franks.

At least 19 recordsLinked to original sources
PubMed1995

A phase III study of recombinant interleukin-2, 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in patients with unresectable or metastatic colorectal carcinoma.

135 patients with locally advanced or metastatic colorectal cancer were entered into a phase III trial evaluating the efficacy of chemoimmunotherapy [recombinant interleukin 2 (rIL2)/5-fluorouracil (5-FU) and leucovorin (LV)] versus chemotherapy alone (5-FU/LV). A cycle of chemoimmunotherapy comprised a constant intravenous infusion of rIL2 at a dose of 18 x 10(6) U/m2/24 h for 120 h, followed by three bolus injections of 5-FU (600 mg/m2) and LV (25 mg/m2) at weekly intervals. Patients receiving chemotherapy alone received 5-FU/LV at the same dose at weekly intervals for 6 weeks followed by a rest period of 2 weeks, constituting one cycle of therapy. A maximum of 6 months therapy was given in both arms of the study. The response rates (complete and partial responses) were 17% in patients receiving rIL2/5-FU/LV versus 16% in those in the 5-FU/LV arm of the study. Median survival and progression-free survival were comparable for the two groups of patients, although there was a trend for a prolongation of survival in patients receiving chemoimmunotherapy compared with chemotherapy alone, beyond 12 months. Retrospective subgroup analyses revealed a significantly increased survival in poor prognosis patients (ECOG 1) treated with rIL2/5-FU/LV when compared to those receiving chemotherapy alone. Therefore, further studies evaluating the dose and duration of chemoimmunotherapy in patients with metastatic colorectal cancer seem warranted.

Adult↗
PubMed1994

Persistent augmentation of natural-killer- and T-cell-mediated cytotoxicity in peripheral blood mononuclear cells pulsed in vitro with high-dose recombinant interleukin-2 prior to culturing with a low maintenance dose.

The toxicity of high-dose recombinant interleukin-2 (rIL-2) treatment limits its use in tumour therapies. This paper describes in vitro studies of whether a single, peak rIL-2 dose, followed by low maintenance doses, could enhance the cytotoxic potential of peripheral blood mononuclear cells (PBMC) without inducing a significant sustained release of secondary cytokines, known to contribute to undesirable side-effects of therapy. Pre-pulsing of PBMC with high-dose rIL-2 (16,000 IU/ml for 30 min), followed by low-dose (5 IU/ml) maintenance culturing, was found to induce persistent augmentation of cytotoxic activity towards natural-killer(NK)-sensitive and -insensitive tumour targets, as well as increased T-cell-mediated target cell killing. Under these conditions the level of killing was as high as that achieved by higher maintenance doses (20-100 IU/ml). Although not reflected by overexpression of cell surface markers, enhanced activation of cytotoxic capacities by high-dose pre-pulsing remained clearly apparent for at least 12 days of culture. Increased secondary cytokine production (tumour necrosis factor, interleukin-6 and interferon gamma) was only evident during the first 24-72 h after pulsing, and not at later stages of culturing at the low maintenance dose of 5 IU rIL-2/ml. These results may warrant a human phase-1 B study to investigate the in vivo effect of high-dose prepulsing, followed by low-dose maintenance.

Animals↗
PubMed1994

The development of anti-interleukin-2 (IL-2) antibodies in cancer patients treated with recombinant IL-2.

Serum samples from 217 cancer patients participating in phase I/II clinical trials were analysed for the development of anti-interleukin-2 (IL-2) antibodies. Patients received recombinant human IL-2 (rIL-2) by continuous intravenous infusion (c.i.v.; n = 86) or by subcutaneous (s.c.) injections (n = 131). Both patient groups developed anti-rIL-2 antibodies as detected by ELISA with similar frequencies and titres: 52% (median titre, 23) and 47% (median titre, 24), respectively. Using an IL-2-dependent T-cell proliferation assay, sera from 5 c.i.v.-treated patients (6%) and 13 s.c.-treated patients (10%) exhibited neutralising activity. Immunoabsorption studies with rIL-2-coated beads, demonstrated that in 8 of 15 patients with neutralising sera, the neutralising activity was correlated with specific anti-rIL-2 immunoglobulin. All 8 patients had received at least two cycles of rIL-2 by s.c. injections. Specific IL-2 neutralising activity affected both recombinant and natural IL-2 in all 8 patients. Development of anti-rIL-2 antibodies, irrespective of whether these exhibited neutralising activity or not, did not affect the frequency or duration of clinical responses.

Antibodies, Neoplasm↗
PubMed1994

The treatment of metastatic renal cell carcinoma by continuous intravenous infusion of recombinant interleukin-2.

Between March 1989 and June 1990, 133 patients were treated with interleukin 2 (rIL-2) for metastatic renal cell carcinoma (RCC) in a multicentre open non-randomised study. The results show an objective response rate of 14% (95% confidence interval 8-21) with 4 patients achieving a complete remission. This is in keeping with the data from previous studies using rIL-2 by continuous infusion. It is of interest that 87% of objective responses occurred in hospitals that entered 5 or more patients.

Adult↗
PubMed1993

Interleukin 2 therapy: current role in surgical oncological practice.

The use of recombinant interleukin 2 (rIL-2) in clinical practice has opened up new and beneficial avenues in the treatment of certain malignant diseases. Although rIL-2 can stimulate a range of host antitumour defence mechanisms, only 30-40 per cent of patients who are treated will respond to such therapy as assessed by a reduction in tumour volume. The effect of rIL-2-based treatment schedules on delaying progression of disease and on overall survival in comparison with standard current treatments and chemotherapeutic regimens is not clear. Randomized clinical trials are required to evaluate precisely the role of rIL-2 in various therapeutic combinations and to ascertain the optimum therapeutic regimens for individual tumour types. Studies currently under way should provide more insight into the possible beneficial effects of immunotherapy with rIL-2. More basic research is required to ascertain how rIL-2 may produce its antitumour effects and why the therapeutic results obtained in humans have been so selective and less beneficial than those in experimental animals.

Cytokines↗
PubMed1993

A phase-III study of recombinant interleukin 2 and 5-fluorouracil chemotherapy in patients with metastatic colorectal cancer.

Sixteen patients with metastatic colorectal cancer have been treated with a regimen involving an 120 h continuous infusion of rIL-2, 18 x 10(6) iu m-2 day followed by three injections of 5FU 600 mg m-2 at weekly intervals. Entry criteria included no previous chemotherapy, ambulatory performance status, and a measurable lesion. In most cases side effects were easily manageable and only one patient required transfer to an intensive care unit with the capillary leak syndrome. In three patients persistent hypotension was found to be unrelated to treatment with rIL-2, being caused respectively by a line infection, pulmonary embolus, and bowel perforation. This last proved a fatal complication. Five patients (33%; [95% confidence limits, 11.8%-61.6%]) achieved a partial response, and two non-responders later achieved a partial response when treated with weekly 5FU. This regimen is currently being evaluated in a phase-III randomised controlled trial.

Abdominal Neoplasms↗
PubMed1993

The impact of interleukin-2 on survival in renal cancer: a multivariate analysis.

The purpose of this analysis was to compare the survival of patients with advanced renal carcinoma treated with intravenous recombinant interleukin-2 to the survival of matched patients taken from the large and well characterised database of the Eastern Cooperative Oncology Group (ECOG). Recombinant interleukin-2 (rIL-2) given by continuous intravenous infusion was used to treat 387 patients with advanced adenocarcinoma of the kidney in five multi-centre studies and 327 of these patients fulfilled the study eligibility criteria and were evaluable for response, toxicity and survival. The survival of patients treated with rIL-2 was compared in a multi-variate survival analysis taking account of all identified prognostic factors to 390 control patients receiving chemotherapy derived from the database. Thirteen patients treated with rIL-2 achieved a complete remission of their disease and 32 a partial remission giving an overall response rate of 14%. Remissions were durable with a median duration of 357 days for partial remissions and a median duration in excess of 926 days for complete remissions. Most patients experienced fever or mild to moderate hypotension and other toxicities are described. However, only 11 patients required admission to intensive care and in only five cases was this judged to be due to treatment toxicity. There were three deaths judged to be probably due to treatment toxicity. rIL-2 treatment was associated with significantly prolonged survival compared to the ECOG control patients. Patients with good prognostic features appeared to have a greater survival benefit from rIL-2 than those with poor prognostic features. This analysis provides the first evidence that rIL-2 prolongs survival in patients with advanced renal cancer but cannot provide proof which should be sought in randomised prospective trials drawing on the hypotheses generated herein.

Adult↗
PubMed1993

Subcutaneous recombinant interleukin-2 and alpha-interferon in patients with advanced renal cell carcinoma: results of a multicenter Phase II Study.

A phase II multiinstitutional clinical trial was conducted to evaluate the safety and efficacy of the subcutaneous outpatient administration of recombinant human interleukin-2 and alpha-interferon in patients with progressive metastatic renal cell carcinoma. One hundred and forty-five patients were entered on this study between October 1989 and May 1991. Among 134 patients evaluable for treatment response, there were six complete (4.5%) and twenty partial (14.9%) responders, with an overall response rate of 19.4% (95% confidence interval, 13-26%). The median duration of complete remissions was 228 (range 51(+)-520+) days; the median duration of partial tumor regressions was calculated at 226 (range 112-473+) days. The overall median survival from start of therapy was 14.2 (range 1-23+) months. Fever, chills and general fatigue occurred in the majority of patients treated and were measured at grade II, III and IV in up to 55%, 24% and 3% of all evaluable patients, respectively. Three patients each developed grade III hypotension, dyspnea and diarrhea; two patients each had grade III and grade IV elevations of alkaline phosphatase; two and one patients respectively, exhibited grade III anemia and grade IV thrombocytopenia; two patients experienced severe cutaneous toxicity. The majority of patients received treatment in the outpatient setting. In summary, the outpatient use of subcutaneous interleukin-2 and alpha-interferon was effective in patients with advanced metastatic renal cell carcinoma; it was associated with less toxicity and thus, could improve the therapeutic index of interleukin-2 based biologic therapy when compared against high dose intravenous therapy.

Adult↗
PubMed1993

Lithium clearance measurements during recombinant interleukin 2 treatment: tubular dysfunction in man.

Renal tubular function was evaluated in nine patients undergoing recombinant interleukin 2 (rIL2) treatment for metastatic colorectal carcinoma. A lithium clearance technique was used and the activities of the lysosomal enzyme N N-acetyl-beta-D-glucosaminidase were also measured in the patients' urine, before treatment, during treatment, and then 2 days and 23 days after rIL2 therapy had finished. Significant reductions in clearances of creatinine, sodium, and lithium were observed. The fractional excretions of sodium and lithium were also reduced. Twenty-three days following cessation of rIL2 treatment, there was still a significant reduction in creatinine clearance compared with pretreatment values (p < .01). The clearances of sodium and lithium were also reduced compared with pretreatment values although this did not achieve significance. The fractional reabsorption of sodium and water by the proximal nephron increased during rIL2 treatment, from 0.707 +/- 0.030 (pretreatment) to 0.793 +/- 0.043. This increased reabsorption of sodium and water persisted, rising to 0.849 +/- 0.029, 2 days following cessation of treatment (p < .001, means +/- SEM). Twenty-three days later this had returned toward the pretreatment value, being 0.781 +/- 0.036. The fractional reabsorption of sodium by the distal nephron was also significantly elevated, both during and 2 days after completing rIL2 treatment. Twenty-three days after cessation of rIL2, this value had returned to the pretreatment value. However, in contrast, the fractional reabsorption of water by the distal nephron demonstrated no change during rIL2 treatment, but 2 days posttreatment was significantly reduced and remained low for a further 3 weeks.

Acetylglucosaminidase↗
PubMed1992

Recombinant interleukin-2 treatment in patients with metastatic colorectal cancer: effect on natural cytotoxicity.

Natural cytotoxicity (natural killer, NK, and lymphokine-activated killer, LAK, activity) was documented in 12 patients with metastatic colorectal cancer, both before and after a 5-day course of continuous therapy with intravenous recombinant interleukin-2 (rIL-2). Treatment induced a substantial increase in circulating CD56+ lymphocytes (pretreatment: 12.1 +/- 6.9%, mean +/- SD; posttreatment: 39.2 +/- 6.9%. Maximal NK cell activity was induced by treatment with rIL-2 but only suboptimal augmentation of LAK cell cytotoxicity was obtained. This study indicates that although continuous infusion of rIL-2 does have a significant effect on natural cytotoxicity, this is suboptimal and further studies are necessary to define the most efficacious immunity-enhancing regimens of therapy, thereby hopefully improving clinical outcome of rIL-2 treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Chemo-immunotherapy in patients with metastatic melanoma using sequential treatment with dacarbazine and recombinant human interleukin-2: evaluation of hematologic and immunologic parameters and correlation with clinical response.

We have treated 18 patients with metastatic malignant melanoma (MM) with high-dose IL-2 administered by continuous iv infusion in combination with dacarbazine (DTIC), and correlated the clinical response with various hematologic and immunologic parameters. Two regimens differing in the sequence of treatment were employed, and 1-6 treatment cycles were given, depending on patient response. Two patients had a complete response (CR, 46+m, 14m), two patients a partial response (PR, 16m,6m), one a minimal response and four had a stable disease lasting 2-7 months, thus the response rate (CR+PR) was 22%. None of the following parameters, tested prior to initiation of the therapy and 1-2 days after termination of each course of IL-2, correlated with the clinical response: WBC counts (total and differential), levels of blood CD4 and CD8 T cells, NK cells, monocytes and B cells, production of IL-1 and IL-1 inhibitor by monocytes, responsiveness to 3 mitogens, NK/LAK cell activity, and serum levels of IL-1 alpha, IL-2, soluble IL-2 receptor, and TNF alpha. The only prognostic parameter was the greater increase in the level of IL-2 receptor (Tac)-bearing lymphocytes in the responding patients after 1-3 cycles of IL-2. The data suggests that non-specific immune parameters have no prognostic value for patients undergoing IL-2-based immunotherapy.

Adolescent↗
PubMed1992

Continuous infusion of recombinant interleukin-2 with or without autologous lymphokine activated killer cells for the treatment of advanced renal cell carcinoma.

Data have been analysed for 327 patients with advanced renal cell carcinoma receiving a continuous infusion of recombinant interleukin 2 (rIL-2) alone (225 patients) or rIL-2 plus lymphokine activated killer (LAK) cells (102) on a normal oncology ward. Eligibility criteria were uniform across protocols, all patients having advanced progressive disease, but with an ambulatory performance status. The baseline characteristics of patients receiving rIL-2 alone did not differ significantly from those receiving LAK, with the exception that the LAK treated patients had a better performance status. Despite similar treatment intensity, toxicity was more severe in the patients receiving LAK. The addition of LAK did not lead to higher response rates or to prolonged response duration, progression-free survival or survival. This review confirms the activity of rIL-2 for the treatment of advanced renal cell carcinoma and demonstrates that the addition of LAK cells does not lead to increased efficacy.

Adult↗
PubMed1992

A phase II study of sequential recombinant interleukin-2 followed by dacarbazine in metastatic melanoma.

16 patients with disseminated malignant melanoma (1 with primary ocular melanoma) entered a multicentre phase II study of recombinant interleukin-2, (rIL-2) given by continuous intravenous infusion on days 1-5 at 18 x 10(6) IU/m2 per day, followed by dacarbazine 850 mg/m2 on day 8. After a 2 week rest, a second course was given. In the absence of disease progression, monthly maintenance cycles were given for up to four cycles. 16 patients received one cycle, 14 received two and 6 patients three or more. All 16 patients are evaluable for toxicity and 15 for response. 2 patients responded (13%). 1 patient with lung and pleural metastases achieved partial remission after two cycles and went off treatment after six cycles. 3 months later a complete response was noted lasting 396+ days. A second patient with lung metastases had a partial response lasting 153 days. 3 patients (20%) had stable disease. Mean rebound lymphocytosis (24-48 h after the end of rIL-2 therapy), cell count 4.9 x 10(9)/l (2.6-8.8 x 10(9)/l) was within the expected limits. Other toxicity was as expected. Thus sequential treatment with rIL-2 and dacarbazine is feasible but synergy did not occur.

Adult↗
PubMed1992

Intravenous interleukin-2 in patients over 65 with metastatic renal carcinoma.

The present study was designed in order to evaluate the response rate and the toxicity of continuous infusion of Interleukin 2 (IL2) in patients over 65 with metastatic renal cell carcinoma. Twenty-five patients, median age 69 (range 65-77), without any prior systemic anticancer therapy received a continuous infusion of IL2 at a dose of 18 x 10(6) iu m-2 d-1 for 2 periods of 5 days separated by a 6 day break. Toxicity was not different compared with younger patients (e.g. fever, hypotension, rise in creatinine level), except for cardiac toxicity which was of great concern. Despite normal cardiac tests prior to inclusion into the study, abnormalities of the cardiac rhythm ranging from tachycardia to ventricular extrasystoles occurred in 44% of the patients and IL2 cardiac toxicity was responsible for one toxic death. Three objective responses, i.e. one partial and two complete persistent responses, were seen in 22 evaluable patients. Thus, if age does not seem to modify the potential for response to IL2 therapy, cardiac toxicity appears as a limiting factor for intravenous schedules of IL2.

Aged↗
PubMed1992

Interleukin 2 therapy in cancer: identification of responders.

C-reactive protein (CRP) levels in serum were measured in fifteen patients with metastatic colorectal carcinoma, prior to and during treatment with a continuous intravenous infusion of rIL.2. Patients were subsequently classified as responders or non-responders to this therapy. Baseline serum CRP levels, prior to treatment, were significantly lower in the responders (range < 2-8 mg l-1) when compared with the non-responders (range 7.5-116 mg l-1), P = 0.004. Furthermore, the responding patients demonstrated significantly and grossly elevated CRP stimulation indices (SI) compared with non-responders at different time intervals during the rIL2 infusion. At the cessation of rIL2 therapy, the CRP stimulation index was 31.3 +/- 9.3 in the responders, and only 1.6 +/- 0.3 in the non-responders (means +/- s.e.m, P = 0.014). These findings suggest that it is possible to predict those cancer patients who are most likely to respond to and benefit from rIL2 therapy, either prior to the commencement of or during the first course of rIL2.

Adult↗
PubMed1992

Prognostic factors for survival in patients with advanced renal cell carcinoma treated with recombinant interleukin-2.

A database of 327 patients with advanced Renal Cell Carcinoma (RCC) has been analyzed in order to identify potential baseline prognostic factors predicting for survival, following recombinant Interleukin-2 treatment (rIL-2). All patients received a continuous infusion (CIV). Eligibility criteria were uniform across studies, and included patients with an ambulatory performance status (PS), measurable disease, no CNS metastases, and no major organ compromise. Multivariate analyses identified baseline PS (ECOG 0 vs. 1), time from diagnosis to treatment (DTI greater than 24 months vs. less than or equal to 24 months), and the number of metastatic sites (1 vs. greater than or equal to 2, where lung, bone and other sites are considered as separate sites) as important predictors for survival. Patients can be classified into 4 subgroups, which are a function of the number of risk factors present. Median survival for each subgroup is 28, 17, 10 and 5 months, respectively. The model was validated in an independent cohort of 125 patients with RCC treated with subcutaneous (s/c) rIL-2, and predicted for survival accurately. By determining in which risk group category patients may fall, treating physicians may be better equipped to decide on patient management. The model may also be of value in order to stratify patients in randomized clinical trials.

Aged↗
PubMed1992

Phase I trial of recombinant interleukin-2 followed by recombinant tumor necrosis factor in patients with metastatic cancer.

In this Phase I trial, the feasibility of sequential administration of continuous intravenous recombinant interleukin-2 (rIL-2) at 18 x 10(6) IU/m2/day for 6 days, followed by three daily bolus intravenous recombinant tumor necrosis factor (rTNF) infusions at doses escalating between 10 and 120 micrograms/m2/day, was investigated in 31 patients with metastatic malignancies. Prophylactic use of indomethacin prior to and during rTNF administration was found to significantly reduce toxicity. However, despite prophylactic indomethacin, a maximum tolerated dose of rTNF of 120 micrograms/m2 was reached. The limiting toxicity was hypotension. Predictable flu-like toxicities (i.e., fever/chills, hypotension, gastrointestinal toxicity, edema, malaise) were seen in most patients. These started during the rIL-2 infusion and continued during rTNF administration, particularly in the absence of indomethacin. Hematological, renal, and hepatic toxicities were not dose limiting. These toxicities were all reversible after treatment interruption. Pulmonary toxicity [i.e., anaphylactic-like reactions, bronchospasms, and adult respiratory distress syndrome (ARDS)] was seen in several patients immediately after rTNF infusions, irrespective of the rTNF dose or treatment cycle, and mainly in patients with extensive pulmonary metastases. The combined effect of treatment-related ARDS, lung metastases, and a Guillain-Barré syndrome led to the death of one patient. Two partial responses were seen in this study (i.e., breast and renal cancer). Based on these results, a Phase II trial of rIL-2 followed by rTNF has been initiated in metastatic breast cancer patients.

Adolescent↗