Andrés García-Palomo

A Phase II Study of Weekly Vinorelbine and Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer

BACKGROUND Trastuzumab combined with cytotoxic agents presents encouraging results in metastatic breast cancer (MBC), but cardiac toxicity limits some combinations. The synergism shown with trastuzumab and the favorable tolerability profile of vinorelbine provided the rationale for investigating this combination. PATIENTS AND METHODS Patients with HER2-positive MBC who had received <2 lines of chemotherapy for metastatic disease were included. Vinorelbine (25 mg/m2 on day 2, then weekly on day 1) and trastuzumab (4 mg/kg on day 1, then 2 mg/kg weekly) were administered for a maximum of 6 cycles (1 cycle=3 weeks). RESULTS A total of 52 patients were enrolled. The median age was 50 years (range, 26-79 years). Ninety percent of the patients had received adjuvant chemotherapy, 42% received a first line of chemotherapy for MBC, and 69% had disease at visceral sites. The overall response rate was 58% (95% CI, 43%-71%). The median time to progression and overall survival were 7 months (95% CI, 5-9 months) and 26 months (95% CI, 20-32 months), respectively. Grade 4 neutropenia was present in 3 courses; neutropenic fever was not reported. The main grade 3 nonhematologic toxicities were asthenia, neuropathy, diarrhea, alopecia, and nausea/vomiting. No patients experienced serious cardiac toxicity. CONCLUSION These results confirm that weekly vinorelbine/trastuzumab is an active and safe regimen in patients with HER2-positive MBC with an unfavorable prognosis.

A dose-dense schedule of docetaxel followed by doxorubicin and cyclophosphamide as neoadjuvant treatment for breast cancer: results from a phase II study

IntroductionThe objective was to evaluate a dose-dense schedule of docetaxel followed by doxorubicin and cyclophosphamide (AC) as neoadjuvant treatment for patients with locally advanced breast cancer.Patients and methodsNinety-nine patients were included and received 100 mg/m2 of docetaxel every two weeks for four cycles followed by 60 mg/m2 of doxorubicin and 600 mg/m2 of cyclophosphamide every two weeks for four cycles. Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was administered systematically to all patients.ResultsEfficacy and toxicity analyses were carried out on an intention-to-treat basis. After treatment, complete pathological response in the breast and lymph nodes was confirmed in 15 patients (15%, 95% confidence interval [CI]: 8.4–22.9). Clinical response rate was 74% (95% CI: 65–82), of which 19% were complete responses. Breastconserving surgery could be performed in 41% of patients. The dose-dense schedule was generally well tolerated. The most important grade 3/4 toxicities per patient were cutaneous toxicity (12.1%) and hepatic dysfunction (9.1%) during docetaxel administration, and neutropenia (28.1%) and leucopenia (8.3%) with AC.ConclusionA dose-dense schedule of docetaxel followed by AC as neoadjuvant treatment is an effective and safe treatment for locally advanced breast cancer. Primary prophylaxis with G-CSF, and possibly the change in the sequence of drug administration, appears to play a major role in avoiding the excessive toxicity of dose-dense schedules.

Mecanismo de acción y desarrollo preclínico de afatinib

Afatinib, together with gefitinib and erlotinib, is approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). This is an irreversible inhibitor of the ErbB family, acting on EGFR (HER1, ErbB1), ErbB2 (HER2) and ErbB4 (HER4). Covalent attachment to cysteine residues in the catalytic domain of EGFR, HER2 and ErbB4 inhibits the tyrosine kinase activity (TKIs) of these receptors, decreasing auto- and transphosphorylation between ErbB dimers, and thus blocking the activity of downstream signalling pathways related to growth and apoptosis suppression. In preclinical models, this has resulted in a reduction in tumour size. Furthermore, due to its mechanism of action, afatinib may be more potent than the first-generation EGFR TKIs (gefitinib and erlotinib) and may even be able to overcome acquired resistance to such treatments. Finally, because of the demonstrated synergism with other chemotherapeutic and target agents, it could be interesting to enhance its clinical development in combination with other drugs.Afatinib, together with gefitinib and erlotinib, is approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). This is an irreversible inhibitor of the ErbB family, acting on EGFR (HER1, ErbB1), ErbB2 (HER2) and ErbB4 (HER4). Covalent attachment to cysteine residues in the catalytic domain of EGFR, HER2 and ErbB4 inhibits the tyrosine kinase activity (TKIs) of these receptors, decreasing auto- and transphosphorylation between ErbB dimers, and thus blocking the activity of downstream signalling pathways related to growth and apoptosis suppression. In preclinical models, this has resulted in a reduction in tumour size. Furthermore, due to its mechanism of action, afatinib may be more potent than the first-generation EGFR TKIs (gefitinib and erlotinib) and may even be able to overcome acquired resistance to such treatments. Finally, because of the demonstrated synergism with other chemotherapeutic and target agents, it could be interesting to enhance its clinical development in combination with other drugs.

Neoadyuvant therapy with dose-dense (DD) docetaxel (T) and doxorubicin/cyclophosphamide (AC) in locally advanced breast cancer (LABC)

11514 Background: Systemic and local therapy is the standard care in the management of LABC. T, A and C have proven efficacy in BC treatment. DD chemotherapy has shown improvement in clinical outcomes for BC. This study was designed to evaluate the efficacy of DD therapy with T × 4 followed by AC × 4. Main objective is pathologic complete response rate. Methods: Women with histologic confirmation of LABC, ECOG PS ≤ 2, age ≥ 18 years and adequate bone marrow, renal, hepatic and cardiac functions were included. Treatment: T 100 mg/m2 iv and prophylactic G-CSF, every 2 weeks × 4 cycles followed by A 60 mg/m2 iv and C 600 mg/m2 iv, every 2 weeks × 4 cycles. Response was evaluated every 4 cycles according to RECIST criteria. Results: Ninety-nine patients (pt) were enrolled, with a median age of 50 years (29–80), ECOG PS was 0/1 86.2/13.8%. Breast locations were left 51.5%, right 46.5% and both 2.0%. Forty-three pt (43.4%) presented stage III breast cancer, 83% had infiltrating ductal carcinoma and 50% were pre...

SUSPECTED EXTRAGONADAL GERM-CELL CANCER SYNDROME PRESENTING WITH AN ORBITAL MASS AND ELEVATION OF SERUM CEA, CA19-9 AND CA50 LEVELS

Patients with extragonadal germ-cell cancer syndrome (EGCCS) represent a subgroup of patients with poorly differentiated carcinoma or adenocarcinoma of an unknown primary site for whom potentially curative therapy is available. We report the case of a young man presenting an orbital tumor and high serum levels of CEA, CA19-9 and CA50 for whom an initial diagnosis of metastatic poorly differentiated carcinoma was made. Suspecting EGCCS, he was treated as for a germ-cell tumor. While in treatment, he underwent residual orbital mass resection, and the histologic diagnosis was embryonal carcinoma based on alphafetoprotein immunoperoxidase staining. We discuss the rare location at diagnosis, the impressive increase in the commonly considered gastrointestinal markers that he showed, and the potential utility of these markers for such patients.