Phase II study of subcutaneously administered interleukin-2 in combination with medroxyprogesterone acetate and antioxidant agents as maintenance treatment in advanced cancer responders to previous chemotherapy.

An open, non-randomized phase II study was carried out including patients with advanced solid tumors who achieved an objective response or disease stabilization as a result of previous chemotherapy, to receive a maintenance treatment with recombinant interleukin-2 (rIL-2) plus medroxyprogesterone acetate (MPA) plus antioxidant agents alpha-lipoic acid (ALA) and N-acetyl cysteine (NAC). The first study endpoints were to define clinical outcome and toxicity as well as the evaluation of quality of life. As secondary endpoints we measured the changes of lymphocyte absolute count, the serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin after treatment. rIL-2 was administered at a dose of 1.8 MIU subcutaneously 3 times/week on alternate days for the first two weeks of every month and MPA was given orally at a dose of 500 mg/day at alternate days without interruption. ALA 300 mg/day orally and NAC 1800 mg/day orally were also administered continuously. Twenty-eight patients were enrolled in the study. The median duration of maintenance treatment was 10 months (6-30+). The response to maintenance treatment at September 15, 2001 was: CR 11 patients (39.3%); SD 2 patients (7.1%); PD 15 patients (53.6%). The median duration of response was 11 months (6-34+). The median follow-up duration was 11 months (6-34+). The median OS was not reached. The median PFS was 21.5 months (1-40+). The 1-year survival rate was 72.2%. At September 15, 2001, 16 patients were still surviving. No grade 3/4 toxicity and one grade 2 skin toxicity were observed. We found a significant increase of the absolute lymphocyte count and serum levels of IL-2 and a significant decrease of TNF alpha after treatment. The evaluation of patient subgroups showed the following: the patients alive at the end of study had a significant increase of lymphocyte count, IL-2 and leptin, and a significant decrease of IL-1 beta, IL-6 and TNF alpha, whereas the patients who had died had only a significant increase of lymphocyte count and IL-2. Among the patients alive, those in objective clinical response (CR + PR) + those in SD had a significant increase of lymphocyte count, IL-2 and leptin and a significant decrease of IL-1 beta, IL-6 and TNFalpha, whereas those with PD had no significant changes in any of the above values. We conclude that the combination of s.c. rIL-2 with oral MPA and anti-oxidant agents ALA and NAC in an intermittent schedule, repeated for a long-term period, is feasible, has a very low toxicity and results in the improvement of biological markers which are predictive for patient outcome.

Six-week induction chemotherapy followed by concomitant chemoradiation therapy in stage IV head and neck cancer: a phase II study with organ-sparing purposes.

The purpose of the study was to assess response rate, clinical outcome, organ/function preservation and toxicity in head and neck cancer patients treated with induction chemotherapy followed by concomitant chemoradiotherapy and, when necessary, limited surgery. The study was a phase II non-randomized trial. Induction chemotherapy consisted of 6 weekly doses of carboplatin at AUC of 2 and docetaxel 30 mg/m(2) (1 h) followed by 5 cycles of docetaxel 25 mg/m(2)/day 1, 5-FU 600 mg/m(2) c.i. days 1-5, hydroxyurea 500 mg orally every 12 h for 11 and concomitant twice daily radiation therapy at 150 cGy/fraction given every other week per 5 cycles (TFHX), for a total radiation dose of 75 Gy. 13 cis-retinoic acid was administered for chemoprevention and systematic prophylaxis of mucositis with systemic amifostine and local GM-CSF was administered to all patients during TFHX. Conservative surgical resection was reserved to patients with no optimal response (PR > or =70%), whereas radical surgery was performed as salvage treatment. Thirteen patients (mean age 54.9 years, range 44-62; 12/13 site oropharynx, all stage IV) were enrolled: 31% of patients had ECOG performance status (PS) 0 and 69% had PS 1. Response to induction chemotherapy was analyzed in 12 patients: 2/12 (16.7%) achieved a partial response (PR) for an overall response (ORR) of 16.7%, 10/12 (83.3%) achieved stable disease (SD). TFHX was administered to 7 patients: 2 patients (28.6%) had complete remission (CR), 1 patient (14.3%) had PR for an ORR of 42.9%, 3 patients (42.8%) had SD and 1 patient (14.3%) had PD. At the completion of TFHX, 1 patient underwent local therapy. The toxicity was mild and consisted in: grade 3/4 neutropenia (7.7%), anemia (23.1%), diarrhea (15.4%), mucositis (7.7%), neurotoxicity (7.7%) during induction chemotherapy. During TFHX only 42.8% of grade 3/4 mucositis was observed. All patients spared organ/function. In conclusion, this regimen has been found feasible for its acceptable toxicity, particularly mucositis. However, the overall response rate and the data on survival were not satisfactory.

Quantitative evaluation of oxidative stress, chronic inflammatory indices and leptin in cancer patients: correlation with stage and performance status.

In advanced cancer patients, the oxidative stress could take place either at the onset of disease or as a function of disease progression. To test this hypothesis, the following parameters were investigated: the erythrocyte activity of the enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), the serum activity of glutathione reductase (GR) and the serum total antioxidant status (TAS). The total antioxidant capacity of plasma LMWA was evaluated by the cyclic voltammetry methodology. We further determined the serum levels of proinflammatory cytokines (IL-6 and TNFalpha), IL-2, leptin and C-reactive protein (CRP). All of these parameters have been correlated with the most important clinical indices of patients such as Stage of disease, ECOG PS and clinical response. Eighty-two advanced stage cancer patients and 36 healthy individuals used as controls were included in the study. Our findings show that SOD activity was significantly higher in cancer patients than in controls and GPx activity was significantly lower in cancer patients than in controls. Serum values of IL-6, TNFalpha and CRP were significantly higher in patients than in controls. Serum leptin values of cancer patients were significantly lower than controls. SOD activity increased significantly from Stage II/ECOG 0-1 to Stage IV/ECOG 0-1, whereas it decreased significantly in Stage IV/ECOG 3. GPx activity decreased significantly in Stage IV/ECOG 2-3. An inverse correlation between ECOG PS and serum leptin levels was found. Serum levels of IL-2 decreased from Stage II/ECOG 0-1 to Stage IV/ECOG 2-3. A direct correlation between Stage/ECOG PS and serum levels of both IL-6 and CRP was observed. Cisplatin administration induced a significant increase of GPx after 24 hr. In conclusion, this is the first study that shows that several "biological" parameters of cancer patients such as antioxidant enzyme activity, cytokines, leptin and CRP strictly correlate with the most important clinical parameters of disease such as Stage and ECOG PS.