Adipose tissue as target organ in the treatment of hormone-dependent breast cancer: new therapeutic perspectives.

Breast cancer is the female malignant neoplasia with the highest incidence in the industrialized world. Despite many undeniable therapeutic successes obtained, breast cancer still remains, however, a major health issue. In the last few years, thanks to aromatase inhibitors, the hormone therapy for oestrogen-dependent breast cancer has evolved in terms of efficacy and tolerability; at the same time, it has enabled us to better define the role of oestrogens in the etiopathogenesis of this tumour. Weight increase and obesity have been identified as the most important risk and prognostic factors for breast cancer in postmenopausal women. Several hypotheses have been proposed to explain the association of obesity with postmenopausal breast cancer. A more recent hypothesis suggests that adipocytes and their autocrine (paracrine and endocrine actions) are at the centre of such an etiopathogenetic mechanism. A better understanding of the main mechanisms that link together menopause, body-weight increase and hormone-dependent breast cancer is paramount to enable the identification of key molecules involved in the development of breast carcinoma and suggest new therapeutic options. The present review will discuss important findings on the therapeutic aspects of adipose tissue and adipokines as a target for treatment of hormone-dependent breast cancer.

Reactive oxygen species, antioxidant mechanisms and serum cytokine levels in cancer patients: impact of an antioxidant treatment.

OBJECTIVE: So far, it is not well established whether oxidative stress found in cancer patients results from an increased production of oxidants in the body or from a failure of physiological antioxidant systems. To further investigate this question we have assessed the blood levels of reactive oxygen species as a marker of free radicals producing oxidative stress and the most relevant of the physiological body enzymes counteracting reactive oxygen species, namely glutathione peroxidase and superoxide dismutase. Serum levels of proinflammatory cytokines and IL-2 were also investigated. All these parameters were studied in relation to the clinically most important index of disease progression, namely Performance Status (ECOG PS). We also tested the reducing ability of different antioxidant agents on reactive oxygen species levels by measuring the increase in glutathione peroxidase activity, and the reduction of serum levels of IL-6 and TNF. DESIGN, SETTING AND SUBJECTS: We carried out an open non randomized study on 28 advanced stage cancer patients (stage III, 10.7%, and stage IV, 89.3%) with tumours at different (8) sites: all were hospitalized in the Medical Oncology Dept, University of Cagliari Interventions. The patients were divided into 5 groups and a different antioxidant treatment was administered to each group. The selected antioxidants were: alpha lipoic acid 200 mg/day orally, N-acetylcysteine 1800 mg/day i.v. or carboxycysteine-lysine salt 2.7 g/day orally, amifostine 375 mg/day i.v., reduced glutathione 600 mg/day i.v., vitamin A 30000 IU/day orally plus vitamin E 70 mg/day orally plus Vitamin C 500 mg/day orally. The antioxidant treatment was administered for 10 consecutive days. RESULTS: Our results show that all but one of the antioxidants tested were effective in reducing reactive oxygen species levels and 2 of them (cysteine-containing compounds and amifostine) had the additional effect of increasing glutathione peroxidase activity. Comprehensively, the "antioxidant treatment" was found to have an effect both on reactive oxygen species levels and glutathione peroxidase activity. The antioxidant treatment also reduced serum levels of IL-6 and TNF. Patients in both ECOG PS 0-1 and ECOG PS 2-3 responded to antioxidant treatment.

[Lymphedema secondary to breast cancer treatment: possibility of diagnostic and therapeutic prevention]. / Linfedema secondario al trattamento del cancro mammario: possibilità di prevenzione diagnostica e terapeutica.

We performed a prospective randomized study upon 50 patients who had undergone a breast cancer treatment, considering particularly the possibility of appearance of arm secondary lymphedema. The patients were divided in two groups of 25 patients each. In the 1st group, we performed only a clinical follow-up, whilst in the 2nd one, we used also lymphoscintigraphy. The aim of the study was to compare the incidence of arm secondary lymphedema in the two groups, and relate the data with those of the international literature, in order to identify diagnostic procedures indicative of the risk of development of lymphedema and find proper therapeutic preventive measures. It is certainty complex to foresee the appearance of arm lymphedema due to breast cancer treatment. No specific preventive therapeutic methods based upon particular diagnostic investigations were ever reported. Patients had undergone surgery and radiation for breast cancer in the period between April 1992 and June 1994, and controlled at over 5 years after operation. Upper limb lymphoscintigraphy was performed only in one of the two groups of 25 patients, before operation and, furthermore, after 1-3-6 months and 1-3 years from the treatment. Patients who presented lymphoscintigraphic alterations (dermal back flow, diffused or delayed transit of the tracer, etc.), before edema appeared clinically, underwent physical and rehabilitative therapy (bandages, manual lymphatic drainage, mechanical lymph drainage, elastic garments, etc.) and microsurgery (lymphatic-venous anastomoses at the arm), performed early (stages Ib and II) in patients not responsive to physical therapy. In the first group followed only clinically, secondary arm lymphedema occurred in 9 cases (36%), and appeared after a period variable from 1 week to 2 years (3-6 months averagely). In the second group, lymphoscintigraphy, performed preoperatively, permitted to find lymphatic impairment (absence of deltoid way, reduced axillary lymph nodal tracer uptake, delayed transit of the tracer) at the upper limb in 4 patients (15%). After breast cancer surgery, lymphoscintigraphy pointed out alterations of lymphatic circulation in 5 patients (20%) after 1 month, in other 6 cases (56%) at 6 months, other 5 (76%) after 1 year and 3 (88%) at 3 and 5 years. Physical preventive therapy performed in patients with positive lymphoscintigraphy, even before the clinical appearance of edema, allowed to find a clinically evident lymphedema only in 2 cases (8%). The last two patients underwent early (at stage Ib and II) microsurgical operation of lymphatic-venous anastomoses, with complete regression of edema and improved lymphatic drainage of the arm controlled by lymphoscintigraphy (appearance of preferential lymphatic pathways, absence of dermal back flow). Secondary arm lymphedema due to breast cancer treatment appears in 20-25% of cases till 35% when surgery is associated with radiotherapy. Lymphoscintigraphy allows to pointout alterations of lymphatic drainage before the clinical appearance of edema. Preventive physical and rehabilitative measures allows to reduce the clinical appearance of lymphedema significantly. Microsurgical operation performed precociously, at the early stages of the disease, permits to obtain the complete regression of the pathology thanks to the repair of preferential lymphatic pathways before of fibrosclerotic tissural alterations occur, which cause progressive worsening of clinical conditions, together with recurrent attacks of acute lymphangitis.

Long-term results after lymphatic-venous anastomoses for the treatment of obstructive lymphedema.

Over the past 25 years, 665 patients with obstructive lymphedema have been treated with microsurgical lymphatic-venous anastomoses; of these, 446 patients were available for long-term follow-up study. Objective assessment was undertaken by water volumetry and lymphoscintigraphy. Lymphangioscintigraphy, lymphangiography (in patients with gravitational reflux pathology), and echo-Doppler were used preoperatively. Subjective improvement was noted in 578 patients (87%). Objectively, volume changes showed a significant improvement in 552 patients (83%), with an average reduction of 67% of the excess volume. Of those patients followed up, 379 patients (85%) have been able to discontinue the use of conservative measures, with an average follow-up of more than 7 years and average reduction in excess volume of 69%. There was a 87% reduction in the incidence of cellulitis after microsurgery. In those patients who improved, drainage resulted in increased softness of the limbs. Peripheral edema (hand and foot) diminished considerably in most patients. These long-term results indicate that lymphatic-venous anastomoses have a place in the treatment of obstructive lymphedema and should be the therapy of choice in patients who are not sufficiently responsive to nonsurgical treatment. Improved results can be expected with earlier operations because patients referred earlier usually have fewer lymphatic alterations.

The use of vein grafts in the treatment of peripheral lymphedemas: long-term results.

This study evaluates long-term results of the treatment of peripheral lymphedemas by the microsurgical reconstructive technique of interposed vein grafts. The technique consists of the use of autologous vein grafts to reconstruct lymphatic pathways where there is a block to the lymphatic circulation of the limb, whether of congenital or acquired etiology. The venous segment represents a sort of "bridge" between afferent and efferent lymphatic collectors (lymphatic-venous-lymphatic plasty [LVLA]). The results also proved to have positive long-term effects after microsurgical operation. Follow-up evaluation was performed clinically by water volumetry and instrumentally by lymphangioscintigraphy. With this LVLA technique, peripheral lymphedemas can be treated when derivative lymphovenous shunts cannot be used because of impaired venous circulation in the same lymphedematous limb. The new aspect of the study is that we report long-term clinical and instrumental results.

Serum values of proinflammatory cytokines are inversely correlated with serum leptin levels in patients with advanced stage cancer at different sites.

Leptin is a recently identified hormone produced by the adipocyte ob gene which acts as a negative feedback signal critical to the normal control of food intake and body weight. A number of proinflammatory cytokines, such as interleukin 6, tumor necrosis factor alpha, and interferon gamma, have been proposed as mediators of cancer cachexia; these data suggest that abnormalities in leptin production/release or in its feedback mechanism play a role in cancer patients. We therefore studied the relationship between serum leptin and serum cytokines interleukin 6 and tumor necrosis factor alpha levels in advanced-stage cancer patients. Twenty-nine advanced stage cancer patients (all but one stage IV) with tumors at various sites were included in the study. A direct correlation between body mass index and serum leptin levels was found both in cancer patients and in healthy individuals. The serum levels of interleukin 6 were significantly higher in cancer patients than in healthy individuals. In cancer patients an inverse correlation was found between serum levels of leptin and proinflammatory cytokines. There was an inverse correlation between the Eastern Cooperative Oncology Group performance status scale and serum levels of leptin. Regarding survival, patients with very high serum levels of proinflammatory cytokines and very low levels of leptin had very short survival. Although obtained in a cancer patient population not overtly cachectic, our results provide further evidence that a simple dysregulation of leptin production and/or release cannot be involved in cancer-associated pathophysiological changes leading to cachexia.

Managing cancer-related anorexia/cachexia.

Cancer-related anorexia/cachexia (CAC) is a complex phenomenon in which metabolic abnormalities, proinflammatory cytokines produced by the host immune system, circulating tumour-derived catabolic factors, decreased food intake, and probably additional unknown factors, all play different roles. This review examines the mechanisms of CAC and its management. All the potential modalities of intervention from nutritional to pharmacological approaches are included with a clear distinction between unproven, investigational and well established treatments. Among the latter, the progestogens are currently considered the most effective and safest drugs for the management of CAC. Agents currently under investigation for CAC include thalidomide, pentoxifylline and melatonin, which most probably act on cytokine release, and clenbuterol, which acts on muscle mass and to antagonise protein wasting. Our personal experience with the synthetic progestogens megestrol and medroxyprogesterone supports their use as first-line agents. In addition, our work on the potential role of antioxidant agents in counteracting the oxidative stress, which appears to be involved in CAC, shows them to be promising agents when used in combination chemotherapy regimens either alone or with other 'biologics'. There is an ongoing need for quality of life questionnaires which specifically address the most significant symptoms present in patients with CAC.

Immunotherapy (recombinant interleukin 2), hormone therapy (medroxyprogesterone acetate) and antioxidant agents as combined maintenance treatment of responders to previous chemotherapy.

An open, non-randomized phase II study was carried out including all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response or stable disease (SD) for more than three months, to receive 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 main study endpoints were clinical outcome and toxicity. The secondary endpoints were effects of treatment on cancer-related anorexia/cachexia syndrome (CACS) symptoms, on serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin as well as the evaluation of quality of life (QL). rIL-2 was administered at a dose of 1.8 MIU subcutaneously three times/week on alternate days for the first two weeks of every month and MPA was given orally at a dose of 500 mg once a day at alternate days without interruption. ALA 300 mg/day orally and NAC 1800 mg/day orally were also administered. The treatment was administered until progression of disease or appearance of toxicity. From July 1998 to May 2000, 16 patients were enrolled in the study (M/F ratio: 15/1; mean age: 62 years, range 45-71). The median duration of maintenance treatment was 10 months (range 5-22). The response to maintenance treatment at September 2000 was: CR (persistent throughout the treatment) 4 patients (25%); SD 1 patient (6.2%); PD 11 patients (68.8%). The median duration of response was 9.8 months (range: 5-22+). The median follow-up duration was 19 months (range: 8-102). The median OS was not reached. The median PFS was 14 months (range 1-29). The 1-year survival rate was 25%. At September 2000, 9 patients are still surviving. No grade 3/4 toxicity was observed. One Grade 2 skin toxicity was observed and Grade 1: 2 fever, 2 thrombocytopenia, 1 neutropenia and 1 skin were observed. The ECOG PS did worsen significantly, the body weight and BMI increased significantly after treatment, whereas the appetite did not change significantly. The QL evaluation showed a significant amelioration of cognitive functions and a borderline significant amelioration of emotional functions after treatment, whereas a borderline worsening of dyspnea was observed. The absolute lymphocyte count increased significantly after the maintenance treatment, as well as the serum IL-2, TNFalpha decreased at borderline statistical significance; the serum levels of leptin did not change significantly. The evaluation of patient subgroups showed that responders/survivors had a pattern superimposable to that of whole patient population, the patients who rapidly progressed and died exhibited no significant changes of these parameters during treatment. The results of the present study suggest that the host immune response, evaluated by several parameters, after IL-2 administration, (e.g. lymphocytosis), are worth further study as potential markers for the major end points of cancer treatment, i.e. OS and QL, in an adequate number of patients.

Restoration of functional defects in peripheral blood mononuclear cells isolated from cancer patients by thiol antioxidants alpha-lipoic acid and N-acetyl cysteine.

The ability of Alpha-Lipoic Acid (ALA) and N-Acetyl Cysteine (NAC), two active antioxidant agents, to correct in vitro the most significant functional defects of peripheral blood mononuclear cells (PBMC) isolated from advanced stage cancer patients was studied. The proliferative response of PBMC isolated from cancer patients to anti-CD3 monoclonal antibody (MAb) and the expression of CD25 (IL-2R) and CD95 (Fas) on unstimulated and anti-CD3 MAb-stimulated PBMC were studied, and the serum levels of proinflammatory cytokines IL-1, IL-6, TNFalpha as markers of pro-cachectic activity in cancer patients, and the serum levels of IL-2 and sIL-2R were assessed. Twenty patients (mean age 64.6 years) with cancer of lung, ovary, endometrium, and head and neck, all in advanced (III, IV) stage of disease, were studied. The serum levels of IL-1beta, IL-2, IL-6, TNFalpha, and sIL-2R were significantly higher in cancer patients than in normal subjects. The response of PBMC isolated from cancer patients to anti-CD3 MAb was significantly lower than that of controls. The addition of either ALA 0.001 mM or NAC 0.004 mM in the PBMC cultures stimulated with anti-CD3 MAb significantly increased the response of PBMC isolated from cancer patients and normal subjects. After 24 and 72 hr of culture with anti-CD3 MAb, the expression of CD25 and CD95 on PBMC isolated from cancer patients was significantly lower than that of PBMC isolated from normal subjects. The addition of either ALA or NAC into cultures of PBMC isolated from cancer patients significantly increased the percentage of cells expressing CD25 as well as those expressing CD95. The results of the present study show a favorable effect of antioxidant agents ALA and NAC on several important T-cell functions in vitro in advanced-stage cancer patients.

Phase II study of induction chemotherapy followed by concomitant chemoradiotherapy in advanced head and neck cancer: clinical outcome, toxicity and organ/function preservation.

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 design was a phase II non-randomized trial in hospitalized patients setting. The treatment plan consisted of 3 cycles of induction chemotherapy with cisplatin, fluorouracil (5-FU), leucovorin and interferon alpha2b (PFL-IFN) followed by 7 cycles of 5-FU, hydroxyurea and concomitant radiation for 5 days (FHX) for a total radiation dose of 70 Gy. Surgical resection was performed, when necessary, with the intent to spare organ/function. Seventeen patients were treated at one institution. Three patients had stage III and 14 patients stage IV disease. Twelve patients were analyzed for response to PFL-IFN: 2/12 (16.7%) patients achieved a CR and 10/12 (83.3%) achieved a PR for an ORR of 100%. FHX was administered on protocol to 10 patients: 4 patients (40%) had CR, 3 (30%) had PR >/=70% for an ORR of 70%, 1 patient (10%) had SD and 2 patients (20%) had PD. As for local therapy, of the 8 eligible patients who completed chemoradiotherapy, the 3 patients with CR were submitted to random biopsies, results of which were histologically negative, 3 patients with PR >/=70% underwent conservative organ-preserving surgery, and 1 patient with PR >70% refused surgery, whereas the patient with SD underwent salvage surgery, preserving voice. Thus, organ preservation was achieved in all 8 patients at the completion of all therapy: 4 patients had no surgical procedure and 4 patients only conservative surgery. Overall, after completion of all therapy, 5/8 (62.5%) patients were rendered disease-free. The median overall survival time was 23 months, the median duration of response was 6 months and the median time to progression was 9 months. Both induction chemotherapy and concomitant chemoradiotherapy resulted in significant toxicity, which consisted mainly of mucositis and thrombocytopenia. In conclusion, PFL-IFN was very active, producing high ORRs and, followed by FHX, resulted in high overall survival rates permitting an optimal organ preservation, at the cost of a severe toxicity.

Results of a dose-intense phase 1 study of a combination chemotherapy regimen with cisplatin and epidoxorubicin including medroxyprogesterone acetate and recombinant interleukin-2 in patients with inoperable primary lung cancer.

Based on the role of cytokines in the pathogenesis of cancer-related anorexia-cachexia and the ability of progestins, such as medroxyprogesterone acetate, to reduce cytokine production and relieve cancer-related anorexia-cachexia symptoms, the authors designed an open, dose-finding phase I study of a combined chemotherapy regimen (cisplatin [CDDP], epidoxorubicin [EPI]), including recombinant interleukin-2 (IL-2) and medroxyprogesterone acetate for patients with stage IIIB to IV inoperable primary lung cancer. The end points were clinical response and toxicity with definition of dose-limiting toxicity and maximal tolerable dose; relief of cancer-related anorexia-cachexia symptoms; the assessment of patient serum levels of IL-1beta, IL-6, tumor-necrosing factor-alpha (TNF-alpha), and soluble IL-2 receptor (sIL-2R). From March to October 1997, 16 patients (M:F ratio, 14:2; mean age, 60.5 years; age range, 41 to 74 years) were enrolled. All patients were evaluable for toxicity and 14 of them for response. The patients were assigned to increasing dose levels of drugs according to a dose-escalation schedule. The weekly schedule consisted of a combination of CDDP given intravenously on day 1, EPI given intravenously on day 1, 1 g/day medroxyprogesterone acetate given orally on days 1 to 7, and recombinant IL-2 1.8 MIU administered subcutaneously on days 2 to 7 plus 300 microg granulocyte-colony stimulating factor support given subcutaneously on days 2 to 5. Administration of medroxyprogesterone acetate began 1 week before the first cycle. Dose escalation of the drugs was as follows: 30 mg x m2 x week(-1) CDDP and 25 mg x m2 x week(-1) EPI (first level, two patients); 30 mg x m2 x week(-1) CDDP and 33 mg x m2 x week(-1) EPI (second level, 2 patients); 40 mg x m2 x week(-1) CDDP and 33 mg x m2 x week(-1) EPI (third level, 6 patients); and 40 mg x m2 x week(-1) CDDP and 40 mg x m2 x week(-1) EPI (fourth level, 6 patients). Six cycles were planned for each patient. The actual dose intensity delivered was more than 80% of the projected dose intensity of all drugs. After six cycles, clinical response (according to World Health Organization criteria), toxicity (according to World Health Organization criteria), Eastern Cooperative Oncology Group (ECOG) performance status, body weight, appetite, and serum levels of cytokines were evaluated. After six cycles, 9 of 14 patients (64.3%) had partial response, 3 of 14 (21.4%) had stable disease, and 2 of 14 (14.3%) had progressive disease, and the objective response rate was 64.3%. ECOG performance status and body weight did not change significantly after treatment, whereas appetite showed an increase that was of borderline statistical significance. Toxicity was acceptable and only hematologic. Dose-limiting toxicity was established at the fourth dose level; consequently, maximal tolerable dose was assessed at the third dose level. Before treatment, the serum levels of IL-1beta, IL-6, and TNF-alpha were significantly greater in the patients than in healthy persons. The comparison between pretreatment and posttreatment serum values of IL-1beta, IL-6, TNF-alpha, and sIL-2R did not reveal significant differences in the patients. Similar results were obtained when the patients were considered as responders (partial response) or non-responders (stable or progressive disease) to therapy. Only IL-6 serum levels were increased (p = 0.014) after treatment.

Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites.

Leptin is a recently identified hormone produced by the adipocyte ob gene which acts as a negative feedback signal critical to the normal control of food intake and body weight. A number of proinflammatory cytokines, such as interleukin (IL) 1alpha, IL-6, tumor necrosis factor (TNF) alpha and interferon (IFN) gamma, have been proposed as mediators of cancer cachexia. These data suggest that abnormalities in leptin production/release or in its feedback mechanism play a role in cancer patients. To elucidate this we studied the relationship between total serum leptin and serum cytokines IL-1alpha, IL-6, TNFalpha as well as the production of leptin and cytokines by peripheral blood mononuclear cells (PBMC) isolated from cancer patients. Sixteen advanced cancer patients (mainly stage IV) with tumors at different sites were included in the study. The serum levels of leptin in cancer patients were significantly lower than those of healthy individuals at all times (7 a.m., noon, 3 p.m.). No significant differences were found in circadian rhythm between patients and controls. Serum levels of IL-1alpha, IL-6, and TNFalpha were significantly higher in cancer patients than in healthy individuals. An inverse correlation between serum levels of leptin and IL-6 was found in cancer patients. The production in culture of leptin by unstimulated PBMCs and those stimulated by phytohemagglutinin M or by phorbol myristate acetate isolated from cancer patients was very low; no differences were observed in comparison with leptin production by PBMCs from healthy individuals.

Phase II study of induction chemotherapy followed by concomitant chemoradiotherapy in advanced head and neck cancer: clinical response and organ/function preservation.

We planned to conduct a trial of induction chemotherapy followed by concomitant chemoradiotherapy with the goal of organ-function preservation in advanced head and neck cancer patients with the response rate and local control of disease as primary endpoints and the assessment of toxicity as secondary endpoint. The overall treatment plan consisted of 3 cycles, each q. 28 days, of induction chemotherapy with cisplatin, 5-FU, leucovorin and interferon alpha2b (PFL-IFN), followed by response evaluation and local therapy with concomitant chemoradiotherapy with 5-FU, hydroxyurea and concomitant radiotherapy (FHX). The evaluation of clinical response was performed during the 2nd week after the 3rd cycle of induction chemotherapy and FHX was initiated 28 days after the 3rd cycle of induction chemotherapy. Hydroxyurea was administered orally at doses of 1 g every 12 h x 11, 5-FU was administered on days 1 through 5 at 800 mg/m2/d for 5 days. Daily fraction of radiotherapy were administered at 2.0 Gy on days 1 through 5. FHX cycles were repeated every 14 days until completion of radiotherapy. Total radiotherapy doses consisted of 70 Gy. Seventeen patients (mean age 56.53 years, range 40-73, male/female 15/2, site: oral cavity 6, 35.29%; oropharynx 3, 17.6%; hypopharynx 3, 17.65%; larynx 2, 11.76%; paranasal sinuses 2, 11.76%; salivary glands 1, 5.88%; ECOG PS 0/1: 10/7, stage: III/IV 3/14) were enrolled from January 1998 to August 1998. All 17 patients initiated induction chemotherapy on this protocol. Twelve patients were analyzed for response (5 patients were not evaluable): 2/12 (16.7%) patients achieved a CR and 10/12 (83.3%) achieved a PR for an ORR of 100%. Concomitant chemoradiotherapy was administered on protocol to 10 patients: 4 patients (40%) had CR, 3 patients (30%) had PR >/=70% for an ORR of 70%, 1 patient (10%) had SD and 2 patients (20%) had PD. As for local therapy, according to treatment plan, of the 8 eligible patients who completed chemoradiotherapy, the 4 patients with CR were submitted to random biopsies, which resulted histologically negative, the 3 patients with PR >/=70% underwent conservative organ-preserving surgery, the patient with SD underwent salvage surgery, preserving voice. Thus, organ-preservation was achieved in all 8 patients at the completion of all therapy: 4 patients had no surgical procedure and 3 patients only conservative surgery. Overall, after completion of all therapy, 6/8 (75%) patients were rendered disease-free. Both induction chemotherapy and concomitant chemoradiotherapy resulted in significant toxicity, which consisted mainly of mucositis and thrombocytopenia. In conclusion, in the present study we have achieved a good clinical response and an optimal organ preservation, at the cost of a severe toxicity.

Assessment of the efficacy of two dosages and schedules of human recombinant erythropoietin in the prevention and correction of cisplatin-induced anemia in cancer patients.

Despite the numerous studies demonstrating the effectiveness of epoetin á (human recombinant erythropoietin) versus placebo in cisplatin-induced anemia of cancer patients, data are lacking on the most effective doses and schedules of administration of epoetin á in this setting. The aim of the present study was to assess the best dose and schedule of administration of epoetin á in cancer patients with cisplatin-induced anemia. This was an open, randomized, single-institution phase II study comparing the ability of two doses and schedules of epoetin á of preventing and/or correcting anemia, measured as the increase in hemoglobin level and decrease in transfusion requirements, in 20 chemotherapy-naive patients with advanced stage head and neck, esophageal, and lung cancer, treated with cisplatin at doses 80 mg/m2. The secondary endpoint of the study was to assess the serum levels of certain cytokines involved in cancer anorexia/cachexia syndrome. The eligible patients were randomly assigned to treatment with either: a) subcutaneous epoetin á 150 U/kg three times a week for up to 12 consecutive weeks (Group A); b) subcutaneous epoetin á 50 U/kg daily for up to 12 consecutive weeks (Group B). The following laboratory parameters were assessed before the study entry and during the study: hemoglobin (weekly); serum iron, transferrin and ferritin (before entry). The following immunological parameters were assessed before and after study end: Interleukin (IL)-1á, IL-1 , IL-6 and Tumor Necrosis Factor (TNF) á. Twenty patients were enrolled, data were available for 17. Nine patients were assigned to Group A and 8 to Group B. No statistically significant difference of hemoglobin level was found between the 2 groups at baseline, at month 1, 2 and 3, neither in the comparison of the change from baseline between the two groups. In Group A fewer transfusions were administered per patient per month after the first month of epoetin á therapy, compared to Group B. No significant difference was found as for transfusion requirements at month 1, 2 and 3 between Group A and B. The epoetin á dose administered was slightly higher than that projected. Epoetin á was well-tolerated. There was no statistically significant correlation between change in hemoglobin level and tumor response for either group, neither between change in hemoglobin level and change in ECOG score from baseline to final was observed. The changes from baseline of IL-1á and IL-1 , IL-6 and TNFá were not remarkable nor univocal in either group, there was not correlation between hemoglobin change and serum cytokine changes from baseline, except for IL-6 in Group A.

Relationships betxween Fas expression, activation molecule CD25, and functional activity of tumor-associated lymphomonocytes from neoplastic effusions.

Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas bearing cells. In the present study we assessed the expression of Fas, activation molecule interleukin (IL)-2 receptor alpha chain (CD25) and an index of functional activity such as thymidine uptake under mitogen stimulation of tumor associated lymphomonocytes (TALM) from 7 neoplastic effusions of advanced cancer patients. The same parameters were studied in peripheral blood mononuclear cells (PBMC) of 7 patients with cancer of different sites and in 7 normal subjects. The proliferative response to phytohemagglutinin (PHA), measured as [3H]-thymidine uptake, of TALM was significantly lower than that of PBMC of cancer patients. The expression of CD25 on unstimulated fresh TALM was slightly higher than that of PBMC from normal subjects: after 24 h of PHA stimulation the CD25 was expressed both on TALM and PBMC from normal subjects. The expression of Fas was assessed on unstimulated TALM, PBMC from cancer patients and normal subjects immediately after (by 2 h, t0) the cell separation, and at different times (24 h and 48 h) thereafter, and on PHA-stimulated TALM, PBMC from cancer patients and normal subjects after 24 h and 48 h of culture (in RPMI 1640). At all times (t0, 24 h and 48 h) the Fas expression by unstimulated TALM was significantly higher than that of PBMC from normal subjects: the Fas expression by PBMC from cancer patients was roughly in the same range as PBMC from normal subjects. At 24 h the Fas expression by PHA-stimulated TALM was significantly higher than that of PBMC from normal subjects, whereas at 48 h the difference was not significant. The TALM studied by us showed to be functionally defective and expressing relatively high levels of Fas showing the characteristics to be considered as a target for FasL expressing tumor cells, which in this way may escape immune control.

Prevention of nausea and vomiting (N&V) in cancer patients receiving high-dose cisplatin. Assessment of the potential antiemetic activity of transdermal fentanyl (TTS-F) compared to standard antiemetic treatment in acute and delayed N&V: first clinical report.

UNLABELLED: A single-institution, prospective, open crossover study was performed to compare the effectiveness and tolerability of transdermal fentanyl (TTS-F) vs intravenous (i.v.) ondansetron (OND), both combined with i.v. DEX, in the prevention of acute nausea and vomiting (N&V), and TTS-F vs metoclopramide (M), both combined with intramuscular (i.m.) DEX, in the prevention of delayed N&V in patients with advanced stage head and neck squamous cell carcinoma receiving high-dose (> or = 100 mg/m2) cisplatin. This is the first report on the clinical use of TTS-F in this setting. PATIENTS AND METHODS: All patients were adequately informed of the study characteristics and gave their written informed consent before study entry. The antiemetic treatment for acute N&V consisted of A) OND 8 mg plus DEX 20 mg (i.v.) or B) TTS-F 75 micrograms/h plus DEX 20 mg i.v. For prevention of delayed N&V, patients receiving TTS-F for acute N&V were given TTS-F at the same dosage (75 micrograms/h) on days 2-5, whereas patients receiving OND for acute N&V were treated with M 20 mg orally every 6 h on days 2-5, starting 24 h after CDDP. All patients received DEX 8 mg i.m. every 12 h on days 2 and 3, 4 mg i.m. every 12 h on days 4 and 5, starting 24 h after CDDP. From November 1997 to April 1998, 15 consecutive patients entered the study and were assigned to one of the two alternative treatments for acute N&V. All of them were evaluable. Twelve patients were evaluable for delayed N&V. Seven patients were assigned to Group 1 starting with treatment A (OND + DEX) and 8 patients were assigned to Group 2 starting with treatment B (TTS-F + DEX). In the prevention of acute N&V, the overall efficacy of OND + DEX was statistically significantly higher than that of TTS-F + DEX in achieving Complete Response (CR) and Major Efficacy (ME = CR + Major Response, MaR). As for delayed N&V, the overall efficacy of M + DEX, both in achieving CR and ME, although higher, was statistically not significantly different from that of TTS-F + DEX. Unfortunately, due to the small number of patients included in the study, the sophisticated criteria for evaluating response in antiemetic research, such as the persistence of efficacy, the response after crossing-over, did not make it possible for us to draw additional conclusions, although the trend was in favor of "standard" treatments, particularly in acute N&V. The 'response to treatment A (OND + DEX) in the prevention of acute N&V was in the same range as the response to treatment A (M + DEX) for delayed N&V. The response to treatment B (TTS-F) for acute N&V was lower than the response to the same treatment for delayed N&V. The TTS-F treatment was well-tolerated with no significant side-effects including the well-known opioid-related symptoms. Our study confirms that the currently available standard antiemetic treatments both for acute and delayed N&V must be considered by far the most effective ones for clinical use.

Clinical evaluation of two dosages and schedules of ifosfamide in combination with cisplatin in neo-adjuvant chemotherapy of patients with advanced (stage III-IV) head and neck squamous cell carcinoma: a phase II randomized study.

The aims of the present open, randomized, single-blind (patient), single institution, phase II study were: i) to compare the therapeutic effectiveness and toxicity of two dosages and schedules of ifosfamide (IFO) in combination with cisplatin (CDDP) mainly in the neo-adjuvant setting of patients (pts) with locally advanced (stage III-IV) head and neck squamous cell cancer (HNSCC) (primary endpoint); ii) to assess the quality of life (QL) of pts included in the study before and after treatment (secondary endpoint). From July 1996 to June 1997, 28 pts, all males (mean age 56.79 years, range 37-72), hospitalized in the Department of Medical Oncology, University of Cagliari, were enrolled in the study. Twenty pts (M/F 20/0, mean age 53.6, range 37-71 years; stage III 1 pt, stage IV 19 pts) were evaluable for response and all 28 pts enrolled were evaluable for toxicity. Arm A: IFO 2.2 g/m2 i.v. as a 4 h infusion on days 1-5, Mesna 600 mg i.v. as push injection at 0 h, 4 h, 8 h on days 1-5, CDDP 20 mg i.v. as a 60 min infusion on days 1-5. The regimen was repeated every 28 days for 2 cycles. Fifteen pts (11 of whom were evaluable) were enrolled in this Arm. Arm B: IFO 1.5 g/m2 i.v. as a 4 h infusion on days 1-5, Mesna 600 mg i.v. as push injection at 0 h, 4 h, 8 h on days 1-5, CDDP 20 mg i.v. as a 60 min infusion on days 1-5. The regimen was repeated every 28 days for 3 cycles. Thirteen pts (9 of whom were evaluable) were enrolled in this Arm. The two Arms were well-balanced for sex, age, site of primary, ECOG PS and clinical stage. After completion of 2 (Arm A) or 3 (Arm B) cycles of chemotherapy, the pts were assessed for response. All evaluable pts received treatment as planned. Six pts (54.5%) of Arm A and 4 pts (44.5%) of Arm B had partial response (PR) with an overall response rate (ORR) of 54.5% and 44.5%, respectively: it is worth noting that all (100%) pts who had PR in Arm B achieved a high-grade PR, i.e. >/=70%, whereas only one pt (16.7%) who had PR in Arm A achieved a high-grade PR. Three pts (27.3%) in Arm A and 2 pts (22.2%) in Arm B had stable disease (SD); 2 pts (18.2%) in Arm A and 3 pts (33.3%) in Arm B had progressive disease (PD). The actual dose intensity was over 80% of the projected dose intensity for both drugs and for both Arms. Over a total of 59 cycles administered, the total number of episodes of toxicity was 24 for Arm A and 17 for Arm B. Three pts out of 28 evaluable for toxicity (10.8%) died for Grade 5 hematological toxicity: all pts were included in Arm A. In Arm A, 2 pts (13.3%) experienced hematological Grade 3 toxicity and 2 pts (13.3%) hematological Grade 4 toxicity. In Arm B no pt experienced Grade 3-4 hematological toxicity. No Grade 3-4 toxicity of any other type was found in either Arm. The QL evaluation, using the Cella's FACT-G scale supplemented with disease-specific scale (FACT-H&N scale), did not show significant beneficial effect of neo-adjuvant chemotherapy treatment.

High serum levels of soluble IL-2 receptor, cytokines, and C reactive protein correlate with impairment of T cell response in patients with advanced epithelial ovarian cancer.

The serum levels of interleukin-(IL-)1 alpha, IL-1 beta, IL-2, IL-6, TNF alpha, and sIL-2R and the proliferative response of peripheral blood mononuclear cells (PBMC) to phytohemagglutinin (PHA), anti-CD3 monoclonal antibody (mAb), recombinant IL-2 (rIL-2), and the combination of PHA or anti-CD3 mAb with rIL-2 were studied and correlated with serum levels of C-reactive protein (CRP) in women with advanced epithelial ovarian cancer. The expression of CD25 and CD122 subunities of membrane-bound IL-2R on PHA- or anti-CD3 mAb-stimulated PBMC was also studied. In comparisons with the controls, PBMC response to PHA, anti-CD3 mAb, and rIL-2 was significantly lower in the cancer patients. The addition of exogenous rIL-2 to the PBMC cultures increased response in both controls and patients but did not modify the significance of the differences. After stimulation with PHA or anti-CD3 mAb, the percentage of PBMC CD25+ or CD122+ was significantly lower in patients. The serum levels of IL-1 alpha, IL-1 beta, IL-6, TNF alpha, sIL-2R, and CRP were significantly increased in patients compared to the controls. Instead, no differences were observed for serum levels of IL-2. A strong association was found between high serum levels of the above-mentioned cytokines, sIL-2R, and CRP. The results of our study on advanced stage (IIIb-IV) ovarian cancer patients are consistent with the previously reported hypothesis that high IL-6 and/or CRP serum levels may represent an important and independent prognostic factor of the likely outcome in cancer patients.