Long-term immunotherapy with low-dose interleukin-2 and interferon-alpha in the treatment of patients with advanced renal cell carcinoma.

BACKGROUND: The objective of this study was to evaluate response, toxicity, and immunologic effects of an original immunotherapy schedule based on repeated cycles of low doses of recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFNalpha) in patients with metastatic renal cell carcinoma (mRCC). METHODS: Fifty patients who underwent nephrectomy received therapeutic cycles consisting of subcutaneous rIL-2 for 5 days per week and intramuscular rIFNalpha twice weekly for 4 consecutive weeks. The cycle was regularly repeated indefinitely at 4-month intervals in all patients, irrespective of their response. rIL-2 (1 x 10(6) IU/m(2)) was administered every 12 hours on Days 1 and 2 and once per day on Days 3-5 of each week; rIFNalpha (1.8 x 10(6) IU/m(2)) was given on Days 3 and 5. Toxicity was graded according to the World Health Organization (WHO) criteria. Forty percent of the patients had only one metastatic disease site at the time of treatment. The Kaplan-Meier method was used to estimate survival, and an analysis of variance was used to evaluate the effects on leukocytes and lymphocyte subsets over time. RESULTS: A total of 241 cycles were administered. One patient achieved a complete response, and five patients achieved a partial response. Five patients had stable disease, and 30 patients had progressive disease. Nine patients were not evaluable for response. The overall response rate was 12% (95% confidence interval, 3-21%) on the basis of an intent-to-treat analysis. The 36-month survival probability for all 50 patients was 47%. Treatment-related toxicity was limited to WHO Grades 1 and 2. Both lymphocyte and eosinophil levels significantly increased after all cycles (by 42% and 353%, respectively). The treatment also induced significant increases in the CD25 positive (24%), CD56 positive (28%), and CD3 negative/CD56 positive (54%) lymphocyte subsets. CONCLUSIONS: Long-term, repeated treatment with low doses of rIL-2 and rIFNalpha is feasible in patients with mRCC. The schedule induces clinical response rates and survival probabilities are similar to those obtained using higher doses.     

The clinical effects of prolonged treatment of patients with advanced cancer with low-dose subcutaneous interleukin-2 [corrected

Thirty-five patients with advanced malignant disease have been treated as outpatients with increasing doses (0.1-100 mcg) of interleukin 2 (IL2) by once daily self-administered subcutaneous (s.c.) injection, 5 days weekly for 8 weeks followed by a 4 week observation period. Systemic side effects were not experienced by patients at the 3 lower doses. Three patients required dose reduction from 100 mcg daily because of intolerance (fever, rash, lethargy, nausea and vomiting) and one patient was discontinued because of dyspnoea. We observed immunological effects at the 100 mcg dose (but not at the lower doses). These consisted of (a) a modest sustained lymphocytosis, (b) eosinophilia in six (out of nine) patients and (c) a significant rise in IL2-stimulated peripheral blood lymphocyte activated killer (LAK) cell activity in six (out of nine) patients to a mean of 2.0 times pretreatment levels (P less than 0.01). Two (out of nine) patients with renal cell carcinoma treated with 100 mcg daily had partial responses of duration 4 and 9 months respectively and a further three had disease stabilisation for at least 3 months. Low dose long-term s.c. IL2 is clinically and immunologically active, and in comparison to other IL2 regimens it has minor toxicity and is easy to administer. These characteristics make low dose s.c. IL2 suitable for study in the adjuvant setting.     

Long-term maintenance therapy in interferon-alpha2a/interleukin-2-pretreated advanced renal-cell carcinoma patients

PURPOSE: In this paper, we report on the long-term therapeutic efficacy of maintenance treatment in 12 advanced renal carcinoma patients. PATIENTS AND METHODS: Following prior systemic treatment with 8-week cycles of subcutaneous interferon- alpha2a (s.c. IFN-alpha2a) and subcutaneous interleukin-2 (s.c. IL-2)-based immunotherapy (5-day standard Atzpodien regimen), patients received prolonged maintenance treatment consisting of intermittent s.c. IFN-alpha2a and s.c. IL-2, combined with long-term daily peroral 13-cis-retinoic acid (p.o. 13cRA). RESULTS: Patients received a mean of 10 months (range, 0-27 months) of maintenance treatment. Median progression-free survival was calculated at 6 months (range, 0-61 months), and median overall suvival was 22 months (range, 2-65 months) from the start of maintenance therapy. Of 12 patients, 5 were still alive (> or = 60 months) and 2 patients remained progression-free (61 months) at last follow-up. Maintenance treatment was well or moderately tolerated. CONCLUSIONS: Maintenance treatment with s.c. IL-2/s.c. INF-alpha2a/p.o. 13-cRA may support long-term efficacy of prior s.c. IL-2/s.c. INF-alpha2a-based therapy in advanced renal carcinoma patients.     

Hormonal changes during a prolonged tamoxifen treatment in patients with advanced breast cancer

The effect of tamoxifen (TAM) on the serum levels of sexual hormones and on the sex hormone-binding globulin (SHBG) was investigated in 30 postmenopausal patients with advanced breast cancer. To study the 'prolactin reserve capacity' of the pituitary gland, thyrotrophin-releasing hormone (TRH) and sulpiride-induced prolactin release were measured prior to TAM treatment, then in the 2nd and 8th week of the therapy. The TRH (400 micrograms i.v.)-induced prolactin secretion was significantly suppressed by TAM after an 8-week treatment, but only in responding cases. Maximal prolactin stimulation occurred at the 15th min after TRH injection, being equal to 5,600 +/- 800 mlU/l in cancer patients, and decreasing to 2,400 +/- 150 mlU/l after 8 weeks. TAM did not suppress the sulpiride-inducable prolactin release either in responders or in nonresponders.     

Angiogenic and immune parameters during recombinant interferon-alpha2b adjuvant treatment in patients with melanoma.

As an adjuvant therapy for patients with high risk of recurrent melanoma, high-dose interferon (IFN)-alpha2b therapy has been shown to have some efficacy. We examined 22 patients with resected melanoma who were treated with repeated injections of recombinant IFN-alpha2b during the treatment. Both angiogenic and immune parameters were measured. White blood cells (WBCs) and lymphocyte numbers, lymphocyte subpopulations, serum concentrations of IFN-alpha and anti-IFN-alpha antibodies, and the serum vascular endothelial growth factor (VEGF), interleukin (IL)-8, and basis fibroblast growth factor (bFGF) concentrations were determined over time in resected, recurrence-free patients with American Joint Committee on Cancer (AJCC) stage III melanoma with one or less (LN+ < or = 1, n = 7) or more than one (LN+ > 1, n = 8) lymph nodes involved, and AJCC stage IV resected disease (n = 7). Follow-up and recurrence-free intervals were longer in stage III (LN+ < or = 1) patients compared with stage IV patients (P < 0.05). The number of WBCs and lymphocytes decreased during the treatment for all patient groups (P < 0.001). In addition, percentages of CD8 and CD20 were higher in stage IV patients than in stage III (LN+ > 1) and stage III (LN+ < or = 1) patients at the beginning of therapy (P < 0.05). A significant increase in the percentage of CD20+ cells, mostly B lymphocytes, was observed in the stage III (LN+ > 1) and stage III (LN+ < or = 1) patients over time but not in stage IV patients (P < 0.001). Low IL-8 and bFGF concentrations at the beginning of therapy were associated with significantly longer recurrence-free survival (P < 0.05). These results warrant a larger trial to determine if the differences observed in patients before treatment can provide prognostic markers in patients receiving IFN-alpha2b therapy.     

Phase I study of interleukin-2 and interferon alfa-2a as outpatient therapy for patients with advanced malignancy

Twenty-six patients were treated in this phase I study with the combination of interleukin-2 (IL2) administered as a continuous infusion and interferon alfa-2a (IFN alpha-2a) administered intramuscularly to patients in an outpatient setting. The maximum-tolerated dose of both agents given as outpatient therapy was 2 x 10(6) U/m2 days 1 to 5 of IL2 and 9 x 10(6) U/m2 days 1, 3, and 5 of IFN alpha-2a for 4 consecutive weeks. A 2- to 4-week rest period was permitted after each 4 weeks of treatment. Fatigue was the treatment-limiting toxicity, and serious clinical or laboratory abnormalities occurred infrequently during this study. Patients with colon cancer metastatic to the liver tolerated treatment worse than patients with other tumors. Twelve of the 15 patients with renal cell cancer were assessable for response determinations. Of these 12 patients, three exhibited complete tumor regression, three have had partial objective regression, and three patients experienced stabilization of rapidly progressive disease. This therapy appears to be well tolerated in an outpatient treatment setting and shows significant activity against advanced renal cell cancer.     

舒尼替尼单用与白细胞介素-2联合干扰素-α方案治疗晚期肾癌的疗效及预后比较

目的探讨舒尼替尼单用与白细胞介素-2联合干扰素-α方案治疗晚期肾癌患者临床疗效及预后的差异。方法选取2012年12月至2016年12月间陕西省西安市第九医院收治的90例晚期肾癌患者进行回顾性分析,根据治疗方案不同分组,采用舒尼替尼治疗的41例患者纳入观察组,采用白细胞介素-2+干扰素-α治疗的49例患者纳入对照组。两个疗程后,评估两组患者的近期疗效及用药安全性,治疗后随访2年,记录两组患者的生存情况。结果观察组患者的治疗有效率和疾病控制率分别为46. 3%和95. 1%,均高于对照组患者的22. 5%和79. 6%,差异均有统计学意义(均P <0. 05)。治疗前,两组患者外周血癌胚抗原(CEA)、骨桥蛋白(OPN)、铁蛋白(FERR)和β2-微球蛋白(β2-MG)比较,差异无统计学意义(P> 0. 05);治疗后,两组患者外周血中上述指标水平均低于治疗前,且观察组患者上述指标水平下降更为显著,差异均有统计学意义(均P <0. 05)。两组患者的药物不良反应发生率比较,差异无统计学意义(P> 0. 05)。观察组患者的无进展生存时间和总生存时间均长于对照组,1年生存率大于对照组,差异均有统计学意义(均P <0. 05)。两组患者的2年生存率比较,差异无统计学意义(P> 0. 05)。结论舒尼替尼单用与白细胞介素-2联合干扰素-α方案均是治疗晚期肾癌的有效方案,其中舒尼替尼在提升近期疗效和延长生存时间方面更具优势。     

Sequential interferon-alpha2b, interleukin-2 and fotemustine for patients with metastatic melanoma

The aim of this study was the evaluation of both the antitumour activity and toxicity of an immunochemotherapeutic regimen consisting of interferon-alpha2b and interleukin-2 in combination with fotemustine for patients with metastatic melanoma. To improve the penetration of fotemustine into the brain, it was given immediately after immunotherapy, when the blood-brain barrier is still disturbed. Of the 19 patients treated, three complete remissions (CRs) and one partial remission (PR) were induced, giving an objective response rate of 21% (95% confidence interval 6-46%). The durations of the CRs were 9, 19 and 44 months; the PR lasted for 59+ months. The overall survival times for the patients with CR were 21, 25 and 70+ months, and 59+ months for the PR. For nine patients (47%, 95% confidence interval 24-71%) disease was stabilized for a median period of 8 months (range 2-18 months), resulting in a median survival of 18 months (range 10-41+ months). No haematological toxicity of World Health Organization grade 3 or more was observed and in general toxicity was low. In summary, this immunochemotherapy regimen led to long-term survival in occasional patients, and about half of the patients achieved stable disease, with prolonged treatment- and progression-free survival compared with nonresponding patients. The occurrence of brain metastases, however, was not prevented, and in fact was the site of recurrence in those patients achieving a CR. Due to its low toxicity, this protocol can be applied at a community hospital level.     

Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer

We performed an escalating dose study of the combined administration of interleukin-2 (IL-2) and alpha-interferon (alpha-IFN) in 94 patients with metastatic cancer. Patients received alpha-IFN at a dose of 3 x 10(6) U/m2 in conjunction with IL-2 at doses of either 1 x 10(6) U/m2 (six patients), 3 x 10(6) U/m2 (32 patients), or 4.5 x 10(6) U/m2 (26 patients). Thirty patients received alpha-IFN at 6 x 10(6) U/m2 plus IL-2 at 4.5 x 10(6) U/m2. Patients each received cytokine as an intravenous bolus infusion every 8 hours for up to 5 consecutive days and after a 10-day rest received a second cycle of combination cytokines. Of the 91 patients evaluable for response, seven patients had a complete regression of cancer, and 18 had a partial regression. At the four increasing dose levels used in patients with renal cell cancer (35 patients) or melanoma (39 patients), objective responses were seen in 17% (of six patients), 24% (of 25 patients), 38% (of 16 patients), and 41% (of 27 patients), respectively. Of the 25 total responding patients, 16 are still responding 5 to 14 months after treatment. The toxicities associated with the combined administration of IL-2 and alpha-IFN were similar to those expected from each agent alone. There was one treatment-related death in the 94 patients treated in this study. Thus, using increasing doses of the combination of IL-2 and alpha-IFN, it appears that response rates may be related to the doses of the cytokines used, and that at the highest doses of these combination cytokines, response rates may be higher than those for either cytokine alone. A prospective randomized trial comparing the cytokine combinations with each cytokine administered alone is necessary as is the extension of this combination cytokine treatment to patients with other types of solid cancer.     

Colonic ischemia complicating immunotherapy with interleukin-2 and interferon-alpha

Colonic ischemia (CI) is a rare complication of high-dose interleukin-2 (IL-2) immunotherapy. This complication occurred in three of 141 patients (2.1%) with metastatic cancer treated with high-dose IL-2 therapy; CI only developed in patients receiving interferon-alpha (IFN) with IL-2 (three of 21, 14%) compared with none of 120 in those patients receiving IL-2 alone (P equals 0.0009). Severe diarrhea (greater than or equal to 7 bowel movements/day) also was significantly more common in patients receiving IFN with IL-2 (six of 21, 29%) than in those receiving IL-2 alone (three of 120, 2.5%, P equals 0.001) and preceded the clinical diagnosis of CI in all three patients. Three of nine patients with severe diarrhea had CI. Hematochezia occurred in four patients, all of whom received IFN with IL-2; three had CI, and the other patient had nonspecific colitis. Differences in vasopressor use did not explain the increased risk of CI in patients receiving IFN; those receiving IFN with IL-2 required phenylephrine less often than patients receiving IL-2 alone (P equals 0.01). The administration of lymphokine-activated killer (LAK) cells had no significant effect on the incidence of CI, severe diarrhea, peritonitis, or vasopressor use; two of three patients with CI, however, had their ischemic episode within 24 hours after the last of three LAK cell infusions. In conclusion, CI is an unusual complication of high-dose IL-2 and IFN immunotherapy. In patients receiving such combination therapy, severe diarrhea is a risk factor for the subsequent occurrence of CI.     

Autoimmune phenomena in patients with malignant carcinoid tumors during interferon-alpha treatment

Several previous reports suggest an association between treatment of patients with interferon-alpha (IFN-alpha) and development of autoantibodies and autoimmune disease. We here summarize the experience from a group of 135 patients with midgut carcinoid tumors treated with natural leukocyte IFN-alpha or recombinant IFN-alpha (rIFN-alpha). An unusual high incidence of antimicrosomal antibodies (MsAb) or anti-thyroglobulin antibodies (TgAb) and thyroid disease manifested as hyperthyroidism, hypothyroidism or a biphasic Hashimoto-like disease was seen, with female predominance. The incidence of antinuclear antibodies (ANA) was also increased, but equally in both sexes. Antibodies to parietal cells were found in 5 cases and 4 patients with pernicious anemia were detected. Two patients developed vasculitis of leukocytoclastic type and one a syndrome resembling systemic lupus erythematosus. Some patients treated with rIFN-alpha develop anti-IFN antibodies. Such antibodies may also be autoantibodies reacting with autologous IFN-alpha. They can neutralize the biologic activity of administrated IFN preparation and cause therapeutic failure. The implications of the various autoimmune manifestations during IFN-alpha treatment are discussed.     

Infusional interleukin-2 and 5-fluorouracil with subcutaneous interferon-alpha for the treatment of patients with advanced renal cell carcinoma: a southwest oncology group Phase II study

BACKGROUND: A Phase II trial was conducted to determine the response rate of patients with advanced renal cell carcinoma to a three-drug combination of 5-fluorouracil (5-FU), interleukin-2 (IL-2), and interferon-alpha-2b (IFN-alpha). METHODS: A 2-stage accrual plan was used that was designed to determine whether response to this regimen was consistent with a true response rate of >/= 30%. The regimen was comprised of 5 treatment days weekly for 4 weeks every 6 weeks. Each weekly treatment was comprised of 5-FU, 1750 mg/m(2), continuous intravenous (i.v.) infusion over 24 hours followed by IL-2, 6 MIU/m(2)/day, continuous i.v. infusion for 4 days. IFN-alpha, 6 MU/m(2), was given subcutaneously on Days 1, 2, and 5. RESULTS: Thirty-eight patients were entered on study, 3 of whom were ineligible. Among the 35 eligible patients there were 3 confirmed partial responses (PR) and 1 complete response (CR), for an overall response rate of 11% (95% confidence interval, 3-27%). One patient considered as having a PR had minimal evidence of residual disease and was free from disease progression at > 2.5 years of follow-up, as was the patient with CR. Three additional patients not qualified as having a PR were showing signs of response at the time they were removed from protocol, and another patient who was removed from protocol early for management of an infection subsequently responded to the same regimen off protocol. Thirteen patients were considered nonassessable (NASS) for response, many of whom had multiple poor risk features and were unable to complete 1 cycle of treatment. CONCLUSIONS: This multicenter study failed to confirm an advantageous overall response rate for this three-drug regimen. However, there were two durable responses and indications of responsiveness not scored as PRs among patients with more favorable risk factor patterns, and many poor risk NASS patients. For these reasons, the response rate reported in the current study may be a conservative reflection of the effectiveness of this regimen.     

Daily subcutaneous ultra-low-dose interleukin 2 with daily low-dose interferon-alpha in patients with advanced renal cell carcinoma.

A limited institution Phase II pilot study was performed using a very low-dose combination of daily s.c. interleukin (IL)-2 with IFN-alpha-2b in patients with advanced renal cancer in an attempt to duplicate or increase the response documented with higher dose schedules without the attendant toxicity profile. We selected a dose of IL-2 with documented immunological activity and combined it with clinically active low-dose IFN. Between August 1994 and September 1996, 19 patients with metastatic renal cell carcinoma, who had been judged incapable of tolerating high-dose i.v. IL-2, were treated with IL-2 (1 million units/m2/day) and IFN (1 million units/day), administered s.c. daily. All treatments were administered on an outpatient basis. Virtually all patients had bulky tumor burden with multiple sites of involvement, including five patients with bone metastases. No major objective responses were observed; however, one patient experienced a minor response lasting 13 months, with an associated improvement in performance status. Median survival was 6 months, and 1-year survival was 16%. Toxicity was generally mild and consisted almost entirely of constitutional symptoms. No serious grade 3 or 4 toxicity was observed, although two patients withdrew from treatment due to treatment-related fatigue. On therapy, mild eosinophilia but no lymphocytosis was noted; in fact, peripheral lymphocyte counts decreased, only to rebound after treatment was discontinued. No toxic deaths occurred. Despite the reasonable tolerability of this daily low-dose s.c. regimen, we conclude that this regimen is an ineffective treatment in metastatic renal cell carcinoma patients who are incapable of tolerating high-dose i.v. IL-2.     

Linomide and interleukin-2 in patients with advanced renal cell carcinoma

Quinoline-3-carboxamide (Linomide) is a novel, synthetic immunomodulator acting via immunologic and non-immunologic mechanisms. It has shown efficacy against various malignancies, experimental autoimmune encephalomyelitis, and septic shock in animal models and has been investigated for clinical use in minimal residual myeloid leukemia with promising results. Interleukin-2 has shown considerable efficacy in palliative anti-tumor-treatment of advanced renal cell cancer, revealing remission rates of up to 40% in combination therapy regimens. Linomide is reported to exhibit synergistic effects with interleukin-2. Here we report on a clinical phase I/II study examining tolerance and efficacy of a combination therapy schedule of SQ interleukin-2 and PO Linomide in advanced renal cell cancer. Seventeen patients received 10 IU/m2 interleukin-2 per week for 8 weeks, resting interleukin-2 for another 8 weeks. In week 5 they started 5 mg Linomide daily, continued with 10 mg from week 7 to 16. No objective remissions were observed. Among 15 patients evaluable for response, 10 (66.7%) were progredient during the study. Three patients died during the observation period, including two not evaluable for response. Median survival was 4.0 months, median progression-free survival 2.5 months with a Kaplan-Meier estimate of 3.63 months. Fever, reduced general condition, nausea/vomiting, dyspnea, anorexia, chills and hypotension were the most common side effects, reaching WHO grade 3 in 6 and grade 4 in 2 cases. In summary, Linomide in combination with interleukin-2 provides no advantages in efficacy or toxicity over other therapy regimens employing interleukin-2.     

Subcutaneous administration of interleukin-2 and interferon-alpha 2b in advanced renal cell carcinoma: long-term results

Clinical data have supported the combination of subcutaneous r-interleukin-2 (rIL-2) and r-interferon-alpha (rIFN-alpha) as a promising combination for advanced renal cell carcinoma (RCC), with a reduced toxicity. We evaluated the activity and safety of this outpatient immunotherapy and report on the clinical results and the long-term survival analysis. Objective responses was observed in 9 of 50 (18%) patients, 6 of whom (12%) achieved a complete response. Overall median survival is 12 months, six patients were surviving at a median follow-up of 24 months, and three (6%) are still progression-free.     

Phase I trial of high-dose bolus interleukin-2 and interferon alfa-2a in patients with metastatic malignancy.

PURPOSE: Based on preclinical evidence that the antitumor effects of the combination of interleukin-2 (IL-2) and interferon alfa (IFN alpha) are greater than those of either cytokine alone, we have performed a phase I trial of recombinant IL-2 (rIL-2) and recombinant human IFN alpha 2a (rHuIFN alpha 2a) in patients with refractory malignancies. This study was an extension of an earlier trial that identified reversible myelosuppression as the dose-limiting toxicity of this combination. The present trial used modified definitions of unacceptable toxicity to allow exploration of higher doses of rIL-2. PATIENTS AND METHODS: Both rHuIFN alpha 2a 10.0 x 10(6) U/m2 intramuscularly (IM) and rIL-2 were administered three times weekly for 4 consecutive weeks. IL-2 was given by intravenous (IV) bolus injection at doses that were escalated in successive cohorts of four to six patients, provided that toxicity at the preceding dose level was acceptable. Unacceptable toxicity was defined as an elevation of the serum creatinine level to greater than 5 mg/dL, an elevation of the serum bilirubin level to greater than 5 mg/dL, dyspnea at rest, hypotension refractory to pressors, altered mental status, or other toxicities of grade 3 to 4, using the National Cancer Institute (NCI) Common Toxicity Criteria. The doses of rIL-2 administered were 4.0 x 10(6), 6.0 x 10(6), 8.0 x 10(6), 10.0 x 10(6), 12.0 x 10(6), 14.0 x 10(6), 18.0 x 10(6), 22.0 x 10(6), and 26.0 x 10(6) BRMP (Hoffman-LaRoche) U/m2. At a dose of rIL-2 10.0 x 10(6) BRMP U/m2, patients were also treated with doses of rHuIFN alpha 2a of 1.0 x 10(6) and 0.1 x 10(6) U/m2. RESULTS: A total of 57 patients were treated. Intolerable side effects (hypotension, pulmonary, and CNS toxicity) were produced by rIL-2 26.0 x 10(6) BRMP U/m2 and rHuIFN alpha 2a 10.0 x 10(6) U/m2. Two of 21 patients with renal cell carcinoma showed objective responses, and five of 17 patients with malignant melanoma responded. Two of these responses in melanoma were complete and continue to be longlasting. CONCLUSIONS: When given with rHuIFN alpha 2a 10.0 x 10(6) U/m2 as described above, the maximum-tolerated dose of rIL-2 is 22.0 x 10(6) BRMP U/m2. This dose of rIL-2 is equivalent to 50 to 60 MIU/m2, depending on the conversion factor used. Based on this experience and other trials, we favor phase II trials in renal cell carcinoma using an alternative dose schedule of this cytokine combination, in which rIL-2 is administered by continuous infusion. We suggest that phase II trials of this combination in patients with melanoma use an rIL-2 dose of 8.0 x 10(6) BRMP U/m2 by IV bolus injection three times weekly in combination with rHuIFN alpha 2a 10.0 x 10(6) U/m2 IM three times weekly.     

Treatment of metastatic renal cell cancer patients with recombinant subcutaneous human interleukin-2 and interferon-alpha

We treated 17 patients who had progressive metastatic renal carcinoma with a combination of subcutaneous recombinant human interleukin-2 (administered every 12 hours, at 9.0 million IU/m2 on days one and two, followed by 1.8 million IU/m2, five days per week, over six consecutive weeks) and interferon-alpha 2b (given at 5 million U/m2 three times weekly, for six consecutive weeks). Treatment courses were repeated in patients presenting with stable or regressive disease after the six weeks of combination therapy (11 of 14 evaluable). Two and three of 14 evaluable patients achieved complete and partial remissions, respectively. Toxicity of this regimen was moderate, with local inflammation of the injection sites, grade I-II (WHO) fevers, chills, malaise, nausea/vomiting, and anorexia in more than two-thirds of the patients treated.     

Urinary excretion of polyamines by patients with advanced malignancy.

Levels of putrescrine, spermidine, and spermine in urine were determined by means of a sensitive ion-exchange chromatographic method in patients with advanced solid tumor malignancies, in patients with diseases other than cancer, and in normal control subjects. Elevation above 2 SDS of the normal mean were found in varying number of patients in each tumor category. For those malignancies studied that involved more than 20 patients, the greatest incidences of increased excretion were 66% for spermine in patients with colon carcinoma and 50% for putrescine and spermidine in patients with bronchogenic carcinoma. The highest levels and greatest frequency of elevated polyamine levels were found in patients with Burkitt's lymphoma, and changes in clinical tumor status associated with treatment appeared to correlate well with polyamine levels in this disease. Abnormal amounts of polyamines were also excreted by some patients with diseases other than cancer, indicating that increased polyamine excretion is not restricted or specific to the neoplastic state. It was also found that the levels of polyamines were apparently not affected by the intake of meat or the diet eaten, and remained in a rather narrow excretion range for any one individual at different time intervals. This study was carried out as part of a program to determine and evaluate biologic materials present in body fluids that may be used to follow and evaluate response or progression of neoplastic disease in patients during treatment regimens. The results suggest that abnormal urinary polyamine levels may be characteristic of neoplastic growth for some patients with malignant disease. Further studies are necessary to determine if these compounds may be helpful in assessing disease status for patients with such solid tumor malignancies as colon and bronchogenic carcinoma although their potential as useful "biologic markers" appears less promising than originally anticipated.     

Phase II trial of 5-fluorouracil and leucovorin in combination with interferon-alpha and interleukin-2 for advanced renal cell cancer

Recent clinical trials have demonstrated activity of chemoimmunotherapy with interleukin-2 (IL-2), interferon-[alpha], and 5-fluorouracil (5-FU) in advanced renal cell cancer. A phase II study was performed to evaluate the affect of adding the potentiating agent leucovorin to this combination regimen. Treatment courses consisted of IL-2 5 MIU/m2 subcutaneously days 1, 3, and 5 of weeks 1 to 4, interferon-[alpha] 3 MIU/m2 subcutaneously on days 1, 3, and 5 of weeks 1 to 4, and leucovorin 50 mg/m2 IV followed by 5-FU 450 mg/m2 IV infusion weekly weeks 1 to 4. Patients were given no treatment on weeks 5 and 6 of the 6-week treatment cycle. Of the 20 patients enrolled in the study, 16 were evaluable for toxicity and 15 were evaluable for tumor response. The most severe toxicities included three reports of grade IV diarrhea; overall, nine incidents of grade III or IV toxicity were reported. No objective antitumor responses were observed, and the median time to progression was 2.8 months. We conclude that this combination chemoimmunotherapy regimen has substantial toxicity but no significant antitumor activity in patients with advanced stage renal cell carcinoma.