[Radically resected pancreatic cancer and adjuvant treatment. A review of the literature]. / Carcinoma del pancreas resecato radicalmente e terapia adiuvante. Revisione della letteratura.

Adjuvant therapy represents the gold standard treatment for radically resected pancreatic cancer. Results from randomized clinical trials confirmed the efficacy of adjuvant therapy for pancreatic cancer but did not define what is the "right choice" in terms of type of antiblastic drug (among gemcitabine, 5-fluorouracil or other drugs), role of polychemotherapy and chemoradiotherapy. The objective of our study was to evaluate the efficacy and toxicity of adjuvant chemotherapy and chemoradiotherapy for radically resected pancreatic cancer through a systematic review of literature data, emphasizing the benefits regarding overall survival, disease-free survival and toxicity.

Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study.

This multicenter phase II trial was designed to evaluate the activity of lapatinib in metastatic breast cancer patients with HER2-negative primary tumors and HER2-positive circulating tumor cells (CTCs). In this study MBC patients with HER2-negative primary tumors and HER2-positive CTCs previously treated with at least a first-line therapy for metastatic disease received lapatinib 1500 mg/day. The CellSearch System® was used for CTCs isolation and bio-characterization. HER2 status was assessed on CTCs by immunofluorescence. A case was defined as CTCs positive if ≥2 CTC/7.5 ml of blood were isolated and HER2-positive if ≥50% of CTCs were HER2-positive. 139 HER2-negative patients were screened, 96 patients were positive for CTCs (mean number of CTCs: 85; median number of CTCs: 19; range 2-1637). Seven of the 96 patients (7%) had ≥50% HER2-positive CTCs and were eligible for treatment with lapatinib. No objective tumor responses occurred in this population. In one patient, disease stabilization lasting 254 days (8.5 months) was observed. From the findings of this study, we concluded that a subset of patients with a HER2-negative primary tumor presents HER2-positive CTCs during disease progression, although the HER2 shift rate seems to be lower than previously reported. Despite the lack of objective response, the durable disease stabilization observed in one patient cannot rule out the hypothesis that lapatinib may have some activity in this patient population. However, considering that only 1/139 screened patients may potentially have derived benefit from this approach, future trials designed according to the presented strategy cannot be recommended.

Toxic encephalopathy in elderly patients during treatment with capecitabine: literature review and a case report.

Capecitabine is now-a-days rapidly replacing 5-Fluorouracil in daily clinical practice. Neurologic toxicity during a treatment with fluoropyrimidines, as 5-fluorouracil, represents a well-known side-effect, largely described in literature. Central nervous system (CNS) toxicity, mainly encephalopathy with or without seizures, occurs occasionally even when conventional doses are used. CNS toxicity incidence increases markedly when the blood-brain barrier is either overwhelmed or bypassed (Hildebrand J. Neurological complications of cancer chemotherapy. Curr Opin Oncol 2006; 18: 321-324). Peripheral nervous system (PNS) toxicity is more common because proximal and distal extremities of the peripheral nerves are not protected by a blood-brain like barrier and peripheral neuropathy remains a major limiting factor for the administration of conventional doses of several agents (Saif W, Wood TE, McGee PJ and Diasio RB. Peripheral neuropathy associated with capecitabine, Anticancer Drugs 2004;15: 767-771). Capecitabine is a prodrug of 5-fluorouracil, more easily administered by mouth; its transformation in 5-fluorouracil is performed in the liver. There are only a few reports on the toxic neurological side-effects of capecitabine. We describe in our report a rare case of toxic encephalopathy in a 82-year-old female, with a brief review of literature. In the literature reviewed, we found 12 neurologic episodes due to capecitabine lasting between a few days till some months. All clinical symptoms of the cases described in literature, obtained a complete regression with the discontinuation of capecitabine. A relation was not found with dihydropyrimidine dehydrogenase (DPD) mutation, also if pharmacologic and pharmacogenetic assessment should be done for this drug, especially in old patients. Toxic encephalopathy represents a rare event during capecitabine treatment and on the bases of the data found, is fairly managed in the clinical setting. The knowledge of the natural history of the toxic effect allows the use of the drug also in old patients.

[Role of sequential chemotherapy in the treatment of metastatic colorectal cancer]. / Ruolo dei trattamenti chemioterapici sequenziali nella terapia delle neoplasie metastatiche del colon-retto.

BACKGROUND: Aim of our work was to assess the role of prognostic and predictive factors in patients to be treated with II and III line chemotherapy in metastatic colorectal cancer. METHODS: All the patients with metastatic colorectal cancer treated with at least one line of chemotherapy for metastatic disease and progressed after I line chemotherapy were considered eligible and enrolled into the trial. RESULTS: Twenty-six out of 51 consecutive, and potentially eligible patients (51%) were considered eligible and included into the analysis. The median time to progression to I line chemotherapy was 6.7 months with no significant differences between FOLFOX and FOLFIRI (respectively 10 and 6.7 months, p = 0.71). The I line response rate was 57.7% with no significant differences between FOLFOX and FOLFIRI (respectively 46.1% vs 70%, p = 0.4). A significant improve in overall survival was observed for I line responder patients (respectively, 60 and 12 months for responder and non-responder patients, p = 0.0037), with a significant correlation with the time to progression to I line chemotherapy (p = 0.041). No statistical difference was observed for the number of lines of treatment (3 vs 2, p = 0.3), the treatment sequence (FOLFOX-->FOLFIRI vs FOLFIRI-->FOLFOX, p = 0.94), patient's age (p = 0.105), patient sex (p = 0.055), II line response rate (p = 0.987) and time to progression to II line chemotherapy (p = 0.151) in multivariate analysis. CONCLUSIONS: Our data seem to suggest a prognostic significance of I line response rate and time to progression in patients with metastatic colorectal cancer.

[Preoperative chemotherapy in locally advanced rectal cancer: systematic review of literature]. / Chemioterapia preoperatoria nelle neoplasie del retto localmente avanzate.

Nowadays, neoadjuvant radiotherapy represents the gold standard in the treatment of locally-advanced rectal cancer. Likewise, a lot of evidences seems to suggest that preoperative chemotherapy could improve the local control of the disease, favour the downstaging of the tumor, and make possible an higher number of conservative, sphincter-sparing surgical approaches. In our paper we systematically reviewed the evidences of literature to detect both the main benefits and the limits of pre-operative chemotherapy in the treatment of locally advanced rectal cancer. Moreover, we critically reviewed both the main outcomes of preoperative chemotherapy (overall survival, disease-free interval, number of conservative, sphincter-sparing surgical approaches) and its safety (acute and chronic safety), to give clinicians an evidence-based support for their clinical practice.

Risk of cancer of the prostate and of the kidney parenchyma following bladder cancer.

AIMS AND BACKGROUND: A registry-based cohort study of male patients with bladder cancer was conducted to determine the relative risk of second primary cancer of the prostate and kidney, the uni-/multivariate differences in relative risk according to patient characteristics, the cumulative risk by duration of the follow-up, and the prevalence:incidence ratio of prostate and kidney cancer cases detected in the first 6 months after the diagnosis of bladder cancer. METHODS: The complete case records of all male patients (n = 2025) diagnosed with bladder cancer between 1986 and 2002 were extracted from the database of the Romagna Cancer Registry: 1539 patients were eligible for analysis of the incidence of following prostate and kidney cancers, of the relative risk and the standardized incidence ratio specific for the time interval of follow-up. RESULTS: A total of 108 prostate cancer cases and 23 kidney cancer cases were observed during the follow-up. The relative risk of second primary cancer of the prostate and kidney was respectively 3.52 (95% CI, 2.89-4.25) and 3.90 (95% CI, 2.47-5.85). The absolute excess risk was 11.8 x 1000 for prostate cancer and 2.5 x 1000 for kidney cancer. The number of prevalent cases of prostate and kidney cancer detected was approximately 10 times greater than the expected number based on incidence rates from the general population. During the follow-up, incidence of prostate cancer stabilized at a level that was 3- to 4-fold greater than that expected. Despite fluctuations, a decrease was also observed for incidence of kidney cancer. CONCLUSIONS: In summary, our study showed the relatively constant high incidence of prostate and kidney cancers in bladder cancer patients over time. The possibility of subsequent cancer implies that an appropriate long surveillance is required. The pertinence depends on the duration of the follow-up as well as the degree of surveillance.

Quality of life assessment of randomized controlled trials.

AIMS AND BACKGROUND: According to the USA Food and Drug Administration, quality of life (QOL) and/or survival are a priority for new anticancer drug approval. This study was performed to review approaches to QOL in randomized controlled clinical trials (RCCTs) and to survey the use of such measures in trials. MATERIAL AND METHODS: A literature survey was carried out using the Medline/Medscape, Embase, Cochrane Library, and Ovid databases. Included in the survey were all publications in the set period (from 1966 to June 2005) with "quality of life" in the title or in the abstract in the field of "randomized, controlled clinical trials". Each trial was evaluated according to the level of importance of QOL as a measure of outcome (primary, important and secondary) and was analyzed using the quality scoring system reported by Nicolucci et al. with some items regarding QOL. RESULTS: Four hundred and five RCCT articles in the oncology setting were found. Fifty-six of the 405 (13.8%) publications had QOL as primary end point. The overall quality score of these trials ranged from 40% to 100%, with a median overall score of 80%. The overall score was correlated with the year of publication (P = 0.007), the type of journal (P = 0.05), the presence of a biostatistician among the authors (P = 0.001), and the number of participating institutions (P = 0.009). CONCLUSIONS: More attention to QOL in all components of RCCTs (design, choice of instruments, data management and processing) is required from both clinicians and statisticians.

Bolus fluorouracil and leucovorin with oxaliplatin as first-line treatment in metastatic colorectal cancer.

PURPOSE: A phase II trial investigated the activity and toxicity of a bolus administration schedule of oxaliplatin, fluorouracil (5-FU), and leucovorin (LV) therapy in patients with untreated advanced colorectal cancer. PATIENTS AND METHODS: Forty-five patients in this multicenter, open, nonrandomized study received oxaliplatin 130 mg/m(2) on the first day of each course and 5-FU and LV 350 mg/m(2) and 20 mg/m(2), respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses. RESULTS: Partial responses occurred in 18 patients, giving an intent-to-treat response rate of 40.0%. Median time to response was 12.7 weeks; median duration of response was 18.4 weeks. Median progression-free survival was 5.9 months; median survival was 14 months. The independent prognostic factors for improved overall survival were good performance status and negative carcino-embryonic antigen blood level. Incidences of adverse effects were reduced after the 5-FU dose was reduced to 300 mg/m(2). Reversible neurologic toxicity occurred in 44.4% of patients. CONCLUSION: Bolus administration of oxaliplatin, 5-FU, and LV as first-line therapy for untreated advanced colorectal cancer is efficacious and safe. In addition to a more favorable safety profile, the 300 mg/m(2) dosage offered improved dose-intensity compared with the initial dosage.

Malignant pericardial mesothelioma. Report of two cases, review of the literature and differential diagnosis.

Malignant pericardial mesothelioma is an uncommon variety of a primary malignant cardio-pericardial tumor and it is a highly lethal and fortunately rare cardiac neoplasm. The presentation of pericardial mesothelioma is aspecific and pathologically mesothelioma is not the most common among primary tumors of the pericardium. It is characterized by atypical solid growth of mesothelium with formation of atypical cavities surrounded by fibrous stroma. Antemortem diagnosis is difficult and distant metastases are extremely rare. Radical surgery can be used to treat localized mesothelioma. The treatment for advanced primary pericardial mesothelioma is usually palliative because the tumor is resistant to radiotherapy and chemotherapy. The prognosis is unfavorable. The median survival from the onset of symptoms is six months. In this paper we report two cases of patients with primary mesothelioma of the pericardium without a definite history of asbestos exposure.

Relevance of urine telomerase in the diagnosis of bladder cancer.

CONTEXT: The identification of new molecular markers is one of the most challenging goals for the early detection of bladder cancer because available noninvasive methods have neither sufficient sensitivity nor specificity to be acceptable for routine use. OBJECTIVE: To develop a relatively simple, inexpensive, and accurate test that measures telomerase activity in voided urine to apply to large-scale screening programs for bladder cancer detection. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted in 218 men (84 healthy individuals and 134 patients at first diagnosis of histologically confirmed bladder cancer), frequency matched by age and recruited between March 2003 and November 2004 in Italy. Urine telomerase activity was determined using a highly sensitive telomeric repeat amplification protocol (TRAP) assay. Urine samples were processed for cytological diagnosis and TRAP assay. The diagnosis of bladder cancer was based on bioptic and cystoscopic examinations. The performance of the TRAP assay to detect urine telomerase activity was compared with urine cytology as an aid to early cancer detection. Quantification of urine telomerase activity was conducted in a blinded manner. MAIN OUTCOME MEASURE: Sensitivity and specificity of TRAP to detect bladder cancer. RESULTS: Using a 50 arbitrary enzymatic unit cutoff value, we validated the results obtained in the pilot study. In the overall series, sensitivity was 90% (95% confidence interval [CI], 83%-94%) and specificity was 88% (95% CI, 79%-93%). Specificity increased to 94% (95% CI, 85%-98%) for individuals aged 75 years or younger. The same predictive capacity of telomerase activity levels was observed for patients with low-grade tumors or with negative cytology results. CONCLUSIONS: The present validation study demonstrated the ability of urine telomerase activity levels to accurately detect the presence of bladder tumors in men. This test represents a potentially useful noninvasive diagnostic innovation for bladder cancer detection in high-risk groups such as habitual smokers or in symptomatic patients.

[Chemotherapy in extended small-cell lung cancer. Retrospective analysis of two different series of patients treated with carboplatin and etoposide or ciclophosphamide-epidoxorubicin and etoposide]. / La chemioterapia del microcitoma disseminato. Confronto tra carboplatino-etoposide e ciclofosfamide-epirubicina-etoposide.

Although cisplatin and etoposide seem to represent the treatment of choice in Small-Cell Lung Cancer, a lot of data exist in literature supporting both the use of anthracycline-containing regimens and the use of alternating regimens where platinum-containing regimens and anthracycline-containing regimens are alternatively used as first line in the same patient. In our paper we review the outcomes of two different series of patients treated with ciclophosphamide-epidoxorubicin-etoposide (CEVP16) or carboplatin-etoposide (CBE) for extended Small-Cell Lung Cancer. Sixty-three patients (53.4%) were treated with CEVP16 and 55 patients (46.6%) with CBE. Response Rate (complete plus partial responses) was greater in patients treated with CEVP16 (49.2%) when compared with the response rate in patients treated with CBE (30.9%) (p=0.04 using the Chi-Square test); no differences were observed in the median time to progression (235 vs 199 days, using the Log-Rank test). Overall survival was greater in the CEVP16 group when compared with the CBE one (281 vs 208 days and 35.6% vs 16.3% of patients alive after 2 years of follow up for CEVP16 and CBE respectively, p=0.02 using the Log-Rank test). Although our data present all the methodological limits of the "case-series", it is interesting to observe how an anthracycline-containing regimen seems to be more effective than a platinum-containing one and how it could still play a role in the treatment of extended Small-Cell Lung Cancer.

Urine telomerase: an important marker in the diagnosis of bladder cancer.

Telomerase activity is present in most human malignant tumors, whereas it is generally not detectable, with some exceptions, in normal cells. Therefore, it represents a potential tool for tumor detection. In the present study, telomerase activity was determined in urine from 79 healthy individuals and 121 previously untreated bladder cancer patients using a highly sensitive telomeric repeat amplification protocol (TRAP) assay and the results were expressed as arbitrary enzymatic units (AEU). This approach enabled us to identify cutoff values characterized by high sensitivity (from 75% to 93%) and specificity (from 72% to 92%). Moreover, analysis as a function of gender showed a higher accuracy of TRAP assay in males (93% sensitivity and 90% specificity at the cutoff of 50 AEU) than in females. This sensitivity was confirmed in patients with nonassessable or negative cytology. In women, morphological and immunocytochemical determinations using a monoclonal antibody (anti-hTERT) recently developed in our laboratory showed a large fraction of immunoreactive inflammatory or nonbladder cells, which may justify the false-positive TRAP results. In conclusion, this assay represents an important noninvasive diagnostic tool to detect bladder cancer also in patients with negative or nonassessable urine cytology and with low-grade and early-stage lesions.

Detection of colorectal cancer by a quantitative fluorescence determination of DNA amplification in stool.

DNA amplification of exfoliated cells in stool represents an inexpensive and rapid test, but has only 50% to 60% sensitivity. A new quantitative method, called fluorescence long DNA, was developed and validated in our laboratory on stool obtained from 86 patients with primary colorectal cancer and from 62 healthy individuals. It consists of the amplification of stool DNA with fluorescence primers and the quantification of the amplification using a standard curve. Results are arbitrarily expressed in nanograms. The potential of the new method compared to the conventional approach was analyzed in a subgroup of 94 individuals (56 patients and 38 healthy volunteers). In the present series, DNA amplification analysis showed a specificity of 97% and a sensitivity of only 50%. Conversely, fluorescence DNA evaluation, using the best cutoff of 25 ng, showed a sensitivity of about 76% and a specificity of 93%. Similar sensitivity was observed regardless of Dukes stage, tumor location, and size, thus also permitting the detection of early-stage tumors. The present study seems to indicate that quantitative fluorescence DNA determination in stool successfully identifies colorectal cancer patients with a sensitivity comparable, if not superior, to that of multiple gene analysis but at a lower cost and in a shorter time.

Rapid progression of advanced "hormone-resistant" prostate cancer during palliative treatment with progestins for cancer cachexia.

We report three patients with advanced "hormone-resistant" prostate cancer, each of whom had rapid progression of the disease during treatment with megestrol acetate for cancer cachexia. All patients had been previously treated with total androgenic deprivation. With progression of the disease, megestrol acetate was given to palliate the cancer-related wasting syndrome. No other antineoplastic drugs were contemporaneously given, and no concomitant condition that could favor the progression of the disease was present. The worsening observed while receiving megestrol acetate, and the atypical withdrawal syndrome occurring after the treatment was stopped, seem to suggest a promoting role of megestrol acetate in advanced "hormone-resistant" prostate cancer. The risk of rapid disease progression overwhelming the anti-cachectic palliative effect should be kept in mind when progestins are administered as a palliative treatment of cancer cachexia in patients with advanced "hormone-resistant" prostate cancer.

Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and a comparison with previous meta-analyses.

AIMS AND BACKGROUND: Up to now adjuvant chemotherapy after curative resection for gastric cancer (GC) has been considered an experimental approach. The results of existing phase III randomized trials comparing chemotherapy with control after surgery are controversial. Three meta-analyses have been published in recent years. It is likely that each of them presents a theoretical bias, mainly as regards the inclusion criteria of the trials. In this article we re-examine this potential bias, highlighting the differences between the present and past meta-analyses on adjuvant chemotherapy for GC. METHODS: Only randomized controlled clinical trials comparing systemic adjuvant chemotherapy with control after radical resection of GC were eligible. Total mortality was assessed as outcome measure of the treatment effect and a pooled odds ratio was calculated using the Peto-Mantel-Haenszel method. RESULTS: After the selection process 17 papers (18 comparisons) proved eligible for inclusion in the meta-analysis with a total of 3118 patients, of whom 1546 randomized to the treatment arms and 1572 to the control arms; 762 and 871 deaths occurred in the treatment and control arms, respectively. Statistical analysis suggests an absence of significant heterogeneity between the trials and a significant advantage in survival for adjuvant chemotherapy (pooled odds ratio, 0.72, 95% Cl, 0.62-0.84). CONCLUSIONS: Our meta-analysis would seem to indicate that adjuvant chemotherapy results in a significant survival advantage in patients with GC. However, this observation undoubtedly requires confirmation in large randomized controlled trials including cisplatin before adjuvant chemotherapy after curative resection for GC can be proposed for use in clinical practice.

Carboplatin and gemcitabine in the palliative treatment of stage IV non-small cell lung cancer: definitive results of a phase II trial.

BACKGROUND: Cisplatin-containing regimens represent the gold standard in the treatment of advanced non-small cell lung cancer, but carboplatin is often preferred for its better toxic profile when palliation is the aim of the treatment. The synergistic effect and tolerability of carboplatin-gemcitabine combination are well known. In this phase II trial, we evaluated the activity and safety of a schedule with carboplatin and gemcitabine, defined in our previous phase I trial. METHODS: Thirty-seven patients with measurable stage IV non-small cell lung cancer were treated with carboplatin, AUC 4.5 mg/ml/min on day 1, and gemcitabine, 800 mg/m2 on days 1 and 8, every 21 days. All patients were treated until disease progression or intractable toxicity and were evaluated before each course of chemotherapy for toxicity and after every 3 courses for response. RESULTS: After a median follow-up of over 10 months, complete response, partial response, and stabilization of the disease were observed in 3 (8.1%), 9 (24.3%), and 15 patients (40.5%), respectively. Median time to progression was 7 months. At this writing, 27 patients have died, with a median survival of 10 months, and 29 (78.3%), 16 (43.2%), and 11 (29.7%) patients are alive after 6, 12, and 15 months of follow-up, respectively. Toxicity was mild, and mainly hematological, with a significant correlation with the number of courses of chemotherapy (P = 0.0003). CONCLUSIONS: Our results are comparable with those reported in the literature and confirm the good activity and tolerability of the carboplatin-gemcitabine combination. Up to 4 courses of chemotherapy with carboplatin and gemcitabine may represent an interesting option in the palliative treatment of non-small cell lung cancer.

Chemotherapy-induced nausea and vomiting in Italian cancer centers: results of CINVDAY, a prospective, multicenter study.

PURPOSE: Guideline consistency in the prevention of chemotherapy-induced nausea and vomiting (CINV) remains low (29% in the Pan European Emesis Registry study) and very low (11%) in regimens with a high emetogenic risk. The aim of this study was to evaluate the guideline consistency of CINV prophylaxis for acute emesis in daily clinical practice in Italy. METHODS: This was a prospective, observational, multicenter study. Patients scheduled to receive antitumor treatment on a single prespecified day were included. Data on patient characteristics (demographic and clinical), type of anticancer therapy, and type of antiemetic therapy prescribed for acute emesis were collected on electronic data capture forms. Chemotherapy regimens and antiemetic prophylaxis were categorized according to the MASCC 2011 guidelines. The study was approved by the local ethics committees. RESULTS: From July 2013 to February 2014, a total of 502 patients were enrolled at 26 study sites. Median age was 62 years (range 27-87 years). Colorectal cancer and breast cancer were the most common malignancies. The emetogenic potential of the chemotherapy regimens used was high (HEC) (23.7%), moderate (MEC) (40.6%), low (31.3%) or minimal (4.4%). Overall, guideline consistency was 19.3%. Consistency reached 45% when the various 5HT3 receptor antagonists were considered equivalent and interchangeable in MEC regimens. Adherence to guidelines was lowest for MEC and Minimal risk groups. Ten percent of patients in HEC and MEC regimens did not receive any 5HT3 receptor antagonists. NK1 receptor antagonists were used in 8% of all regimens. CONCLUSIONS: Our study indicates that antiemetic guideline inconsistency remains an issue in daily clinical oncology practice in Italy.

Long lasting clinical response to chemotherapy for advanced uterine leiomyosarcoma: a case report.

INTRODUCTION: Uterine leiomyosarcoma is one of the most frequent uterine sarcomas. In the metastatic setting it is sensitive to doxorubicin, ifosfamide, gemcitabine, docetaxel and a few other drugs, but time to progression is generally short. For this reason prognosis is often poor and there are few reports in the literature of long responders. CASE PRESENTATION: We report a case of a 40-year-old Caucasian woman with metastatic uterine leiomyosarcoma who began treatment six years before the presentation of this case report and for the following six years underwent ten lines of chemotherapy, achieving excellent results and a good quality of life. Among the treatments administered we observed a long response to temolozomide, an unconventional drug for this kind of disease. CONCLUSION: Although there are few chemotherapeutic options for the management of metastatic uterine leiomyosarcoma, a small number of patients have an unexpected long lasting response to treatment. For this reason further research is needed to identify new therapeutic agents and the predictive factors for the achievement of response.

Prediction of nodal metastasis and prognosis of breast cancer by ANN-based assessment of tumour size and p53, Ki-67 and steroid receptor expression.

BACKGROUND: Tumour stage and the appropriate course of treatment in patients with breast cancer are primarily characterized by the state of metastasis in the axillary lymph nodes. In recent years, substantial research has focused on the prediction of lymph node status based on various pathological and molecular markers in order to obviate the necessity to carry out axillary dissection. In the present study, artificial neural network (ANN) is employed as the analysis platform to examine the prognostic significance of a group of well-established prognostic markers for breast cancer outcome prediction in terms of nodal status. Furthermore, we investigated existing interactions between these markers. PATIENTS AND METHODS: The data set contained 66 patient records, where 5 pathological and molecular markers including tumour size, oestrogen receptor status (ER), progesterone receptor status (PR), Ki-67 and p53 expression had been assessed for each patient. The spread of metastasis to the axillary lymph nodes was clinically diagnosed and patients were accordingly categorized into node-positive and node-negative groups. The aforementioned markers were analyzed using a probabilistic neural network (PNN) for nodal status prediction which was considered as the network output. Furthermore, the interactions between these markers were evaluated using different marker combinations as the network input for finding the best marker arrangement for nodal predication. RESULTS: The best prediction accuracy was obtained by a 3-marker combination including tumour size, PR and p53 with 71% accuracy for nodal prediction. Leaving out ER and PR from the full marker set showed approximately the same variations in the results, which is an indication of the direct correlation of these two markers. Furthermore, tumour size was proved to be the most significant individual marker for predicting nodal metastasis. However, when used in combination with Ki-67 the prediction results drop significantly. CONCLUSION: The results presented here indicate that molecular and pathological markers can provide useful information for early-stage prognosis. However, the interactions between these markers must be considered in order to achieve accurate and reliable prediction.

Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study.

PURPOSE: This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) -positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes). PATIENTS AND METHODS: In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m(2)) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily. RESULTS: A total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P = .019). CONCLUSION: The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer.