Giuseppe Capri

Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study.

PURPOSE To define the maximum-tolerated dose (MTD) and better tolerated sequence of paclitaxel by 3-hour infusion plus bolus doxorubicin (DOX) and to evaluate antitumor efficacy. PATIENTS AND METHODS Thirty-five women with metastatic breast cancer (dominant visceral metastases in 56%, and involvement of > or = three sites in 67%) who never received chemotherapy of any type were studied. Paclitaxel every 3 weeks (125 mg/m2 starting dose) was increased by 25-mg/m2 steps in subsequent cohorts of patients. DOX (60 mg/m2 fixed dose) was administered 15 minutes before the start of or after the end of paclitaxel for a maximum of eight cycles. Subsequently, patients in continuous response could receive single-agent paclitaxel (175 to 200 mg/m2 every 3 weeks). The drug sequence was alternated in consecutive patients and in the first two cycles. RESULTS Severe neutropenia that lasted greater than 7 days (n = 4), febrile neutropenia (n = 7) and grade III oral mucositis (n = 6) defined the MTD of paclitaxel at 200 mg/m2 in 34 assessable patients. Grade II peripheral neuropathy occurred in 33% of patients. Six women (18%) developed clinically reversible congestive heart failure (CHF) after a median of 480 mg/m2 total DOX. Drug sequence had no effect on toxicities. High efficacy on all metastatic sites in 32 assessable patients accounted for a 41% complete response (CR) rate (95% confidence interval [CI], 24% to 59%) and 94% overall-response rate (95% CI, 79% to 99%). After a median follow-up of 12 months (range 3 to 18), the median response duration is 8 months (range, 2+ to 18+) for complete responders and 11 months (range 1+ to 15+) for partial responders. CONCLUSION The rate of CR and incidence of CHF may be an expression of therapeutic and toxic enhancement due to the schedule used in this trial. Until clarification of this possibility, this promising combination should be used in investigational trials.

Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans.

PURPOSE To characterize and model the disposition of paclitaxel in humans and define a pharmacodynamic relationships between paclitaxel disposition and its toxicity and efficacy. PATIENTS AND METHODS Paclitaxel pharmacokinetics were studied in 55 courses of therapy in 30 patients. Paclitaxel was administered at 135 mg/m2 or 175 mg/m2 by either a 3- or a 24-hour infusion schedule to patients with advanced ovarian cancer (n = 15), or at 225 mg/m2 by 3-hour infusion to patients with advanced breast cancer (n = 15). Paclitaxel and 6 alpha-hydroxylpaclitaxel were quantified by high-performance liquid chromatography (HPLC). Pharmacokinetics were assessed by noncompartmental and model-dependent methods. Pharmacodynamic correlations were evaluated statistically and by regression models. RESULTS Paclitaxel disposition is nonlinear in humans and, on the 3-hour schedule, 6 alpha-hydroxylpaclitaxel was identified in the plasma of all patients treated. The plasma disposition of paclitaxel and 6 alpha-hydroxylpaclitaxel was well described by a model that featured multiple nonlinear processes. Neutropenia was not related to the areas under the curves (AUCs) of paclitaxel or 6 alpha-hydroxylpaclitaxel, or to palitaxel peak concentrations (Cmax). Neutropenia was related to the duration that plasma concentrations were > or = 0.05 mumol/L, a relationship that is well described by a sigmoid maximum response (Emax) model. CONCLUSION The disposition of paclitaxel in humans is nonlinear. Paclitaxel metabolism to 6 alpha-hydroxylpaclitaxel is likely an important detoxification pathway. Myelosuppression is related to the duration that plasma paclitaxel concentrations are > or = 0.05 mumol/L. Trials of new doses and schedules of paclitaxel should take into account its nonlinear disposition to rule out adverse clinical consequences, especially if the drug is administered by short infusion. Our pharmacokinetic model should prove to be a powerful tool in predicting paclitaxel disposition, regardless of dose and schedule, and should facilitate further pharmacodynamic investigations.

Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer.

PURPOSE We performed a pharmacologic investigation of paclitaxel (PTX) infused over 3 hours and bolus doxorubicin (DOX) to assess the role of sequence, interval between drugs, and duration of doxorubicin infusion on paclitaxel and anthracycline plasma disposition. We also explored possible mechanisms of pharmacokinetic interference involving the physiologic role of the multidrug resistance phenotype in anthracycline and taxane biliary excretion. PATIENTS AND METHODS Pharmacokinetics was performed in 80 cycles and 36 women with previously untreated metastatic breast cancer. PTX, DOX, and their metabolites 6 alpha-hydroxyl-PTX (6 alpha OH-PTX) and doxorubicinol (DOL) were measured by high-pressure liquid chromatography (HPLC). Human breast cancer MCF-7 wild-type (WT) and resistant (TH) cell lines were cultured in whole human plasma to study anthracycline retention after treatment with different combinations of PTX, Cremophor EL (CEL) (PEG35 castor oil; BASF, Parsippany, NJ), and DOX. RESULTS Pharmacokinetic interference between PTX and DOX was responsible for nonlinearity of DOX plasma disposition and increased concentrations of DOX and DOL. These effects were PTX dose-dependent, DOX concentration-dependent, and likely a result of interference at the level of liver elimination. In view of the physiologic role of P-glycoproteins (P-gp) in xenobiotic biliary excretion, retention of DOX was assessed in MCF-7 WT and MCF-7 TH cells. Intracellular was significantly higher in MCF-7 WT than MCF-7 TH (P < .05). However, concomitant exposure to DOX, PTX, and CEL caused similar DOX retention in both MCF-7 WT and TH cells. CONCLUSION PTX, as clinically formulated in CEL, is responsible for a nonlinear disposition of DOX and DOL. Nonlinearity is PTX- and DOX-dependent, and possibly caused by competition for biliary excretion of taxanes and anthracyclines mediated by P-gp. Nonlinearity indicates that even minor modifications of dose and infusion duration of DOX and PTX may lead to unpredictable pharmacodynamic consequences. The postulated role of P-gp suggests that CEL is clinically active, and advises caution in designing combinations of PTX with other drugs that are substrate for P-gp.

Clinical and pharmacological phase I evaluation of Exherin™ (ADH-1), a selective anti-N-cadherin peptide in patients with N-cadherin-expressing solid tumours

BACKGROUND Upregulation of N-cadherin promotes dysregulated cell growth, motility, invasiveness, plus maintenance of vascular stability and is associated with cancer progression in several human tumour types. N-cadherin is expressed also on tumour cells and the anti-N-cadherin cyclic pentapeptide ADH-1, tested in the present study, can exert a direct antitumour effect. PATIENTS AND METHODS Adult patients with advanced solid malignancies expressing N-cadherin on tumour biopsies carried out in the previous 12 months received escalating i.v. doses of ADH-1 given weekly (initially for 3 of 4 weeks, then every week). Plasma pharmacokinetics (PK) was studied at cycle 1. Blood flow changes were assessed after first dosing in all patients treated in the initial regimen. RESULTS In all, 129 patients were screened, 65 (50%) were N-cadherin positive, and 30 were enrolled. The doses ranged from 150 to 2400 mg/m(2); no maximum tolerated dose was reached. Treatment was well tolerated with asthenia as the most frequent adverse event. Two patients with ovarian cancer showed prolonged disease stabilisation while one patient with fallopian tube carcinoma achieved a mixed response. PK was linear in the range of doses tested. CONCLUSION ADH-1 is the first anti-N-cadherin compound tested in humans. In N-cadherin-positive patients, ADH-1 showed an acceptable toxicity profile, linear PK and hints of antitumour activity in gynaecological cancers.

Phase IB Study of the mTOR Inhibitor Ridaforolimus With Capecitabine

PURPOSE Synergistic/additive cytotoxicity in tumor models and widespread applicability of fluoropyrimidines in solid tumors prompted the study of the combination of the mammalian target of rapamycin (mTOR) inhibitor, non-prodrug rapamycin analog ridaforolimus, with capecitabine. PATIENTS AND METHODS Thirty-two adult patients were treated. Intravenous ridaforolimus was given once weekly for 3 weeks and capecitabine was given from days 1 to 14 every 4 weeks. Ridaforolimus was given at 25, 37.5, 50, or 75 mg with capecitabine at 1,650 mg/m(2) or 1,800 mg/m(2) divided into two daily doses. Pharmacokinetics of both drugs were determined during cycles 1 and 2. Pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) and wound tissue of the skin characterized pathways associated with the metabolism or disposition of fluoropyrimidines and mTOR and ERK signaling. RESULTS Two recommended doses (RDs) were defined: 75 mg ridaforolimus/1,650 mg/m(2) capecitabine and 50 mg ridaforolimus/1,800 mg/m(2) capecitabine. Dose-limiting toxicities were stomatitis and skin rash. One patient achieved a partial response lasting 10 months and 10 of 29 evaluable patients had stable disease for ≥ 6 months. The only pharmacokinetic interaction was a ridaforolimus-induced increase in plasma exposure to fluorouracil. PBMC data suggested that prolonged exposure to capecitabine reduced the ridaforolimus inhibition of mTOR. Ridaforolimus influenced the metabolism of fluoropyrimidines and inhibited dihydropyrimidine dehydrogenase, behavior similar to that of rapamycin. Inhibition of the target thymidylate synthase by capecitabine was unaffected. mTOR and ERK signaling was inhibited in proliferating endothelial cells and was more pronounced at the RD with the larger amount of ridaforolimus. CONCLUSION Good tolerability, feasibility of prolonged treatment, antitumor activity, and favorable pharmacologic profile support further investigation of this combination.

Clinical and Pharmacologic Study of the Epirubicin and Paclitaxel Combination in Women With Metastatic Breast Cancer

PURPOSE A pharmacokinetic interaction may cause increased cardiotoxicity of paclitaxel (PTX) and high cumulative dose of doxorubicin. We tested antitumor activity, tolerability, and pharmacokinetics of the lesser cardiotoxic epirubicin (EPI) and PTX (ET combination). PATIENTS AND METHODS Twenty-seven women with untreated metastatic breast cancer, median age of 56 years, and prominent visceral involvement (74%) were studied. Three-weekly EPI (90 mg/m(2)) and PTX (200 mg/m(2) over 3 hours) were given for a maximum nine cycles. EPI was administered 24 hours before PTX (E --> T) in cycle 1, and 15 minutes before PTX (ET) thereafter. EPI, epirubicinol (EOL), EPI-glucuronide (EPI-glu), EOL-glucuronide (EOL-glu), PTX, and 6alpha-OH-PTX were measured in plasma and urine in 14 women. RESULTS Patients received 205 cycles of ET and a median EPI dose of 720 mg/m(2). Grade 4 neutropenia (49% of cycles) was the most frequent toxicity. Cardiac contractility was decreased in five patients. Mild congestive heart failure occurred in two (7.4%). Response rate was 76% (28% complete). Median overall survival was 29 months. On the basis of intrapatient comparison in the first 24 hours of E --> T and ET cycles, PTX did not affect EPI disposition, but significantly increased plasma exposure to EOL (by 137%), EPI-glu (threefold) and EOL-glu (twofold). Urinary excretion of EPI dose went from 8.2% in E --> T to 11.8% in ET cycles. Clearance of PTX was 30% slower in ET than E --> T. ET cycles caused lower neutrophil nadir than E --> T (644 +/- 327 v 195 +/- 91, P <.05) CONCLUSION ET is feasible, devoid of excessive cardiac toxicity, and active. A reciprocal pharmacokinetic interference between the two drugs has pharmacodynamic consequences, and suggests a direct effect of PTX on EPI metabolism requiring ad hoc investigation.

Adjuvant and neoadjuvant treatment of breast cancer

Treatment of early breast cancer has been revolutionized during the past 30 years and new data continue to refine our knowledge of systemic treatments for this stage of disease. The updated worldwide overview has confirmed that, in terms of recurrence and survival, the balance of the known long-term benefits and risk favors some months of adjuvant polychemotherapy and/or a few years of tamoxifen for a wide range of patients. Both the overview and individual trials have shown that anthracycline-containing regimens can achieve additional reduction of the risk of disease relapse and death over cyclophosphamide, methotrexate, and fluorouracil (CMF)-like regimens. Paclitaxel-containing regimens appear promising, but require additional confirmation with longer follow-up. By contrast, controversy still exists on the role of high-dose chemotherapy in high-risk patients. Primary (neoadjuvant) chemotherapy is a new modality to treat large operable breast cancers and offers the possibility of breast conservation with treatment results at least similar to those achieved with classical adjuvant regimens. In the near future, newer agents and information gained on the role of prognostic and predictive factors will probably increase the effectiveness of adjuvant and neoadjuvant treatments.

Cardiotoxic effects of anthracycline-taxane combinations

The association of doxorubicin (DOX) and paclitaxel (PTX) is very active in breast cancer. Unfortunately, PTX may potentiate the cardiotoxic effects of anthracyclines: it causes nonlinear disposition of DOX and its metabolites, leading to persistant of elevated plasma concentrations of the anthracyclines. However, this pharmacokinetic interference is not sufficient to explain the enhanced cardiotoxicity of the combination. Recent data suggest that PTX stimulates the conversion of DOX to cardiotoxic metabolites (namely doxorubicinol) inside cardiomyocytes. Docetaxel (DTX) does not have a major influence on DOX plasma concentration because it does not interfere with its elimination. Clinical data suggest that DTX may not enhance anthracycline cardiotoxicity, but patients seldom received a total anthracycline dose compatible with increased risk. Furthermore, there are experimental data indicating that DTX can also stimulate the metabolism of DOX to toxic species in human heart.

The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict efficacy of platinum-based chemotherapy in patients with metastatic triple negative breast cancer

Platinum salts are active against metastatic triple negative breast cancer (mTNBC), and biomarkers to predict their effectiveness are urgently needed. In recent years, the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have emerged as prognostic biomarkers in many malignancies, but their predictive role in platinum-treated mTNBC patients remains unexplored. We performed a retrospective, single centre study to evaluate the association between baseline NLR or PLR and progression free survival (PFS) of mTNBC patients treated with platinum-based chemotherapy. As a control population, we analysed data from patients with hormone receptor-positive HER2-negative (HR+ HER2−) metastatic breast cancer. Among 57 mTNBC patients treated with the carboplatin-paclitaxel or carboplatin-gemcitabine combination, high NLR and PLR were associated with significantly lower PFS at both univariate and multivariable analysis. Conversely, we did not find a significant association between NLR or PLR and the PFS of 148 patients in the control population. Our findings suggest that the NLR and PLR are predictive of benefit from platinum-containing chemotherapy specifically in mTNBC patients. If validated in larger prospective studies, these easy-to-measure parameters could be combined with emerging predictive biomarkers, such as BRCA 1/2 mutations, to improve the selection of mTNBC patients more likely to benefit from platinum-based chemotherapy.

EFFICACIA DELLA COMBINAZIONE LAPATINIB-CAPECITABINA IN UNA PAZIENTE CON CARCINOMA MAMMARIO HER2-POSITIVO METASTATICO E CON RESISTENZA PRIMARIA A DUE LINEE DI TERAPIA CON AGENTI ANTI-HER2

La sovraespressione dell’oncoproteina HER2 (human epidermal growth factor receptor 2), spesso sostenuta dall’amplificazione del corrispondente oncogene HER2, si verifica in circa il 15-20% dei carcinomi mammari ed e associata a una rapida crescita tumorale e a un comportamento clinico aggressivo. L’introduzione di farmaci capaci di inibire l’attivita biologica di HER2, come trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) e lapatinib, ha drasticamente migliorato la prognosi delle pazienti affette da questo tipo di neoplasia. La combinazione dei due inibitori di HER2, trastuzumab e pertuzumab, insieme con un taxano (paclitaxel o docetaxel), e attualmente considerato il trattamento di prima scelta per pazienti affette da carcinoma mammario metastatico HER2-positivo, mentre il T-DM1 viene ritenuto il trattamento da preferire dopo il fallimento della terapia di I linea. Viene qui presentato il caso di una donna di 56 anni affetta da carcinoma mammario HER2-positivo con secondarismi ossei ed encefalici, resistente sia al doppio blocco trastuzumab-pertuzumab che a T-DM1, ma sensibile alla combinazione lapatinib-capecitabina in III linea e a vinorelbina-trastuzumab in IV linea. (Oncology)