Saro Oriana

A Randomized Trial Comparing Axillary Dissection to No Axillary Dissection in Older Patients With T1N0 Breast Cancer: Results After 5 Years of Follow-up

Summary Background Data:Axillary dissection, an invasive procedure that may adversely affect quality of life, used to obtain prognostic information in breast cancer, is being supplanted by sentinel node biopsy. In older women with early breast cancer and no palpable axillary nodes, it may be safe to give no axillary treatment. We addressed this issue in a randomized trial comparing axillary dissection with no axillary dissection in older patients with T1N0 breast cancer. Methods:From 1996 to 2000, 219 women, 65 to 80 years of age, with early breast cancer and clinically negative axillary nodes were randomized to conservative breast surgery with or without axillary dissection. Tamoxifen was prescribed to all patients for 5 years. The primary endpoints were axillary events in the no axillary dissection arm, comparison of overall mortality (by log rank test), breast cancer mortality, and breast events (by Gray test). Results:Considering a follow-up of 60 months, there were no significant differences in overall or breast cancer mortality, or crude cumulative incidence of breast events, between the 2 groups. Only 2 patients in the no axillary dissection arm (8 and 40 months after surgery) developed overt axillary involvement during follow-up. Conclusions:Older patients with T1N0 breast cancer can be treated by conservative breast surgery and no axillary dissection without adversely affecting breast cancer mortality or overall survival. The very low cumulative incidence of axillary events suggests that even sentinel node biopsy is unnecessary in these patients. Axillary dissection should be reserved for the small proportion of patients who later develop overt axillary disease.

Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer

SummaryRecent efforts to improve the response rates in advanced ovarian cancer with the use of high-dose cisplatin have been limited by unacceptable toxicity. Based on experimental and clinical studies indicating that reduced glutathione (GSH) is a protective agent against cisplatin-induced toxicity, a new high-dose regimen including GSH as a chemoprotector was designed in an attempt to improve the efficacy and therapeutic index of cisplatin. A total of 40 consecutive patients with stage III (bulky) and IV ovarian carcinoma were treated with cisplatin (40 mg/m2 daily for 4 consecutive days) and cyclophosphamide (600 mg/m2 i. v. on day 4). The treatment was repeated every 3–4 weeks for five courses unless progression or severe toxicity occurred. Before each cisplatin administration, patients received GSH (1,500 mg/m2) i. v. over 15 min, with a standard i. v. hydration (2,000 ml fluid) without diuretics. Debulking surgery was initially attempted in 18 patients and, after 2–3 courses, in 16 patients; it could not be carried out in 6 patients. Three patients were not evaluable for response because they prematurely discontinued their treatment. In all, 23 patients (62%) achieved complete clinical remission (negative second-look laparotomy in 16), with an overall (complete + partial) response rate of 86%; 2 patients achieved disease-free status following second surgery. Nausea/vomiting was the most severe acute toxic effect; myelosup-pression was acceptable. Renal impairment was effectively prevented by GSH. Neurotoxicity that was not associated with motor dysfunction was the most significant cumulative toxicity in patients (24/32) receiving 4–5 courses. The results of this study indicate that the use of GSH is a safe new method for high-dose cisplatin administration. This regimen is well-tolerated and very effective in ovarian cancer patients with bulky disease and warrants further evaluation.

Dose Intensification of Platinum Compounds with Glutathione Protection as Induction Chemotherapy for Advanced Ovarian Carcinoma

Based on previous clinical experience indicating the tolerability and efficacy of high-dose cisplatin with glutathione protection in the treatment of advanced ovarian cancer, this study was undertaken to explore the efficacy and feasibility of an alternative high-dose, platinum-based approach including a combination of high-dose cisplatin plus carboplatin as induction chemotherapy of advanced ovarian carcinoma and intervention surgery. Fifty consecutive eligible patients with untreated stage III or IV epithelial ovarian cancer received 40 mg/m2 cisplatin daily on days 1–4 and 160 mg/m2 carboplatin on day 5. The cycle was repeated after 28 days. Patients received glutathione (2,500 mg) before each cisplatin or carboplatin administration and standard intravenous hydration. After 2 courses of induction chemotherapy, the patients underwent surgical reevaluation with debulking, when possible, followed by a further 3 cycles of 120 mg/m2 cisplatin (i.e. 40 mg/m2 daily for 3 consecutive days plus 600 mg/m2 cyclophosphamide on day 3) except in instances of lack of response. All eligible patients were assessed for response and toxicity. The toxicity was moderate with lack of significant nephrotoxicity. Neurotoxicity and ototoxicity were acceptable and in no patient was treatment discontinued for those toxic effects. Myelotoxicity was somewhat more severe than that observed with our previous study with high-dose cisplatin and probably related to the addition of carboplatin. Of the 40 responsive patients, 23 (46%) had a pathological complete response and 4 (8%) had a clinical complete response (without second-look laparotomy). The efficacy of the present protocol was also documented by overall survival (median survival >48 months), which appeared to be better than expected with the current therapy in this group with advanced/bulky disease. The impressive efficacy suggests a possible contribution of reduced glutathione itself in improving the outcome, as supported by preclinical studies. The results of this study should be placed in context with current platinum-based therapy including paclitaxel.

Glutathione and detoxification

Cisplatin is recognized as one of the most effective drugs in the treatment of a variety of solid tumors. Its therapeutic usefulness has been limited by acute and cumulative nephrotoxicity ( 13). This side-effect is dose-dependent and requires adequate protective measures. The identification of dose intensity of cisplatin as an important factor in achieving optimal therapeutic results has stimulated attempts to improve the therapeutic index of cisplatin. The administration of cisplatin in hypertonic saline has allowed the delivery of 200 mg/m*, an approximate doubling of the maximum tolerated dose per treatment course (13). This strategy has proved successful in preventing severe renal damage. However, new sideeffects (myelosuppression, ototoxicity and disabling peripheral neuropathy) are emerging as dose-limiting (13). The severity of these side-effects remains a major obstacle to widespread use of high-dose cisplatin. In an attempt to identify safer methods of cisplatin dose escalation, the use of promising chemoprotectors has been explored as a potentially useful method to deliver high-dose cisplatin (5). The rational basis for the use of nucleophilic sulfur-containing compounds as antidotal agents is the high affinity of sulfur ligands for platinum complexes. Cisplatin is known to undergo nucleophilic substitution of one or both chloride ligands. The major problem in their use remains the questionable selectivity of the protective action, since reaction with cisplatin could also inhibit cytotoxic activity. Thus, an improvement in the therapeutic index of cisplatin in combination with these exogenous protectors remains to be clearly documented (1). Among nucleophilic agents, the natural tripeptide thiol glutathione (GSH) fulfills the fundamental requirements for an antidote. GSH is known to participate in the natural defenses against the toxicity of alkylating and platinating agents (3).

Gene expression of DNA topoisomerases I, IIα and IIβ and response to cisplatin-based chemotherapy in advanced ovarian carcinoma

DNA topoisomerases, nuclear enzymes that regulate DNA topology, are recognized as the primary targets of effective anti‐tumor drugs. These enzymes may also have a role in the repair of DNA damage induced by alkylating agents and platinum compounds; therefore, their expression may be a determinant of tumor response to chemotherapy. Our study was undertaken in an attempt to establish a correlation between the enzyme expression and response of ovarian cancer to cisplatin‐based chemotherapy. The expression of topoisomerase I, IIα and IIβ genes was assessed by RNase protection assay in tumor specimens obtained from 37 untreated patients with advanced epithelial ovarian cancer at initial surgery and from 13 pre‐treated patients at subsequent laparotomy. The expression levels were compared with those found in 5 specimens from benign ovarian tissue and 5 specimens from normal ovarian tissue. The expression levels in untreated patients were used to establish a correlation with response to high‐dose cisplatin therapy. A significant intertumor variability of mRNA expression was noted for all the genes examined. However, a comparison of median values indicated a remarkable increase of expression in malignant tumors over benign or normal tissues only for topoisomerase IIα. This change is not related to alterations or amplification of topoisomerase IIα gene. Interestingly, a correlation was found between tumor response to chemotherapy and the expression level of the isoform α (but not of topoisomerase IIβ and topoisomerase I). The observed correlation suggests a contribution of the enzyme in determining tumor sensitivity. Alternatively, increased expression levels of the α isoenzyme gene in responsive tumors might reflect higher fractions of proliferating tumor cells that may be more drug‐sensitive than resting cells.

PERIPHERAL NEUROTOXICITY FOLLOWING HIGH-DOSE CISPLATIN WITH GLUTATHIONE : CLINICAL AND NEUROPHYSIOLOGICAL ASSESSMENT

The use of high-dose cisplatin is limited by development of severe peripheral neurotoxicity and gradual worsening of renal function. In an ongoing study of high-dose cisplatin glutathione has been employed with the aim of preventing major cisplatin-induced toxicities. Neurotoxicity was examined in detail in 32 patients with ovarian cancer treated with cisplatin (160 mg/m2) and cyclophosphamide (600 mg/m2) every 3-4 weeks for five courses. In addition to serial complete neurological examination, sensory action potentials (SAPs) and motor conduction velocities (MCVs) were also assessed. We confirmed the development of a predominant sensory involvement, characterized by mild distal paresthesias and decrease in vibratory sensibility and in deep tendon reflexes, with a slight reduction of SAPs, observed after three courses of treatment. After five courses, distal paresthesias and disesthesias, decreased proprioception and loss of vibratory sensibility with ataxic signs, absence of deep tendon reflexes, unobtainable SAPs and only moderately reduced MCVs were seen. We did not observe any case of disabling neuropathy. There was a tendency to a more severe involvement of peripheral nerves in patients aged more than fifty. The 3 patients presenting the most serious neuropathy were the oldest in the whole group. Low degree of neurotoxicity observed in this study supports a glutathione protection against cisplatin-induced neurotoxicity. As the urinary excretion of platinum indicated no changes in the renal clearance of cisplatin following repeated courses, the lack of drug accumulation and high plasma peak due to preserved renal function might explain the reduced neurotoxicity observed.

An I.T.M.O. group study on second-line treatment in advanced epithelial ovarian cancer: an attempt to identify clinical and biological factors determining prognosis

The aim of the present study was to determine the activity of a combined regimen of mitoxantrone (DHAD) and ifosfamide (IFO) and identify clinical and biological factors with prognostic importance for the second-line treatment of ovarian cancer. The following factors were investigated for their prognostic importance: age, disease sites, platinum responsiveness, histological grade, the presence of clinically/radiologically detectable versus not detectable disease, residual disease volume after first surgery, p53 protein, c-erbB-2 oncoprotein and laminin receptor. 72 patients entered the trial. DHAD and IFO therapy led to a 15% response rate among the 47 cases with clinically/radiologically detectable disease (1 complete and 6 partial responses), with a median response duration of 4 months. The response rate was significantly different according to platinum responsiveness (4% objective responses in platinum-resistant versus 27% in platinum-sensitive disease). The time to treatment failure (TTF) and overall survival (OS) were affected by the presence of clinically detectable disease at study entry (median TTF 4 months in the presence of clinically/radiologically detectable disease versus 9 months if the disease was not similarly detectable, P = 0.02; median OS 10 months versus 21 months, P = 0.01). Initially overexpressed in only a few tumours, the c-erbB-2 oncoprotein became overexpressed in 36% of platinum-resistant tumours; this modulation did not occur in platinum-sensitive tumours. Furthermore, laminin receptor was expressed in 77% of platinum-sensitive versus 39% of platinum-resistant patients. There were no differences in p53 protein expression according to drug responsiveness.

Bilateral ovariectomy in premenopausal patients with advanced breast cancer, after the evaluation of estrogen receptors and urinary androgen excretion

SummaryEighty premenopausal patients with advanced breast cancer underwent bilateral ovariectomy. Clinical response was evaluated at 6 months from the operation and correlated with the presence or absence both of estrogen receptors and of elevated urinary androgen excretion. The results obtained show that both parameters considered are actually significant to predict the clinical response to ovariectomy, especially when both of them are concordant.

Urinary testosterone as a marker of risk of recurrence in operable breast cancer

SummaryWe investigated the role of urinary testosterone levels as a marker of risk of recurrent disease in 113 operable breast cancer patients (70 premenopausal, 43 postmenopausal). Twenty-four-hour urine collections for testosterone measurement were obtained before surgical treatment, between 20–40 days thereafter, and then every 6 months for 5 years. The cutoff values to separate ‘high testosterone (A+)’ from ‘normal testosterone (A−)’ were 8.0µg/24h in premenopause and 4.9µg/24h in postmenopause. Urinary testosterone levels were considered high when they exceeded the cutoff value in at least 2 of the first 3 measurements (pretreatment, post-treatment, 6 months) of each patient. According to the aforementioned criterion, 33 patients (29.2%) had high testosterone levels, which were associated to axillary node involvement in 16 patients. Thirteen of the latter relapsed during the 5-year follow-up period (5/7 in premenopause, 8/9 in postmenopause). Relapse-free survival (RFS) curves were drawn only for node-positive patients owning to the small number of recurrences observed in the node-negative group. In premenopausal node-positive patients, RFS was significantly different for patients presenting high and normal urinary testosterone levels (77% vs 28%, respectively; logrank test, p< 0.006). In postmenopausal node-positive patients, RFS was also different between the two groups (54% vs 11% in ‘high’ and ‘normal’ excretors, respectively) but the difference was not statistically significant. The present findings suggest that urinary testosterone is a prognostic indicator of early breast cancer recurrence in node-positive patients.

A Clinical Study of Reduced Glutathione as a Protective Agent Against Cisplatin-Induced Toxicity

Cisplatin is one of the most effective anticancer drugs available for the treatment of ovarian cancer, and a dose-dependent response has been documented (1,2). However, the effectiveness of high-dose cisplatin is limited by the overall (renal and nonrenal) toxicity (1). In particular, nephrotoxicity is a major dose-limiting side effect in the high-dose regimen, since at doses higher than 120 mg/m2 there is an unacceptable incidence of renal impairment even in the presence of adequate hydration and forced diuresis (1,3). High-level hydration and hypertonic saline provide partial protection and have been included in most clinical protocols with high-dose cisplatin (1). In an attempt to improve the therapeutic index of the drug, efforts to explore methods of reducing its toxicity have continued. A variety of drug manipulations and strategies have been proposed for protecting the kidney, including protection with sulfur-containing nucleophilic compounds (4). Several thiol compounds have been shown to be effective in blocking or reducing cisplatin toxicity in experimental models (5).