Cell-free DNA concentration and fragment size fraction correlate with FDG PET/CT-derived parameters in NSCLC patients.

PURPOSE: The aim of our study was to investigate the correlation between cfDNA concentration and fragment size fraction with FDG PET/CT- and CT-derived parameters in untreated NSCLC patient. METHODS: Fifty-three patients diagnosed of locally advanced or metastatic NSCLC who had undergone FDG PET/CT, CT and cfDNA analysis prior to any treatment were included in this retrospective study. CfDNA concentration was measured by fluorometry and fragment size fractions were determined by microchip electrophoresis. [18F]F-FDG PET/CT was performed and standardised uptake values (SUV), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were calculated for primary, extrapulmonary and total disease. CT scans were evaluated according to RECIST 1.1 criteria. RESULTS: CfDNA concentration showed a positive correlation with extrapulmonary MTV (r2 = 0.36, P = 0.009), and extrapulmonary TLG (r2 = 0.35, P = 0.009) and their whole-body (wb) ratios. Higher concentrations of total cfDNA were found in patients with liver lesions. Short fragments of cfDNA (100-250 bp) showed a positive correlation with extrapulmonary MTV (r2 = 0.49, P = 0.0005) and extrapulmonary TLG (r2 = 0.39, P = 0.006) and their respective wb ratios, and a negative correlation with SUVmean (r2 = -0.31, P = 0.03) and SUVmean/SUVmax ratio (r2 = -0.34, P = 0.02). A higher fraction of short cfDNA fragments was found in patients with liver and pleural lesions. CONCLUSIONS: This study supports the hypothesis that cfDNA concentration and short cfDNA fragment size fraction reflect the tumour burden as well as metabolic activity in advanced NSCLC patients. This suggests their suitability as complementary tests for a more accurate diagnosis of tumour metabolic behaviour and to allow personalised therapies.

Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions.

BACKGROUND: In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). PATIENTS AND METHODS: Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected. RESULTS: Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty-one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had <10 pg mutated genomes/µl with allelic fractions below 0.25%. Patients treated first line with TKIs based exclusively on EGFR positivity in blood had an ORR of 72% and a median PFS of 11 months. Of 105 patients screened after progression to EGFR-TKIs, sensitizing mutations were found in 56.2% and the p.T790M resistance mutation in 35.2%. CONCLUSIONS: Large-scale EGFR testing in the blood of unselected advanced NSCLC patients is feasible and can be used to select patients for targeted therapy when testing cannot be done in tissue. The characteristics and clinical outcomes to TKI treatment of the EGFR-mutated patients identified are undistinguishable from those positive in tumor.

Assessment of the psychosocial and economic impact according to sex in non-small cell lung cancer patients: an exploratory longitudinal study.

BACKGROUND: Little is known about the impact of sex on lung cancer patients from the psychological, economic and social perspectives. This study was designed to explore the psychosocial and economic impact according to sex of metastatic non-small cell lung cancer (mNSCLC) in patients and caregivers. METHODS: Exploratory study of two cohorts of patients starting first-line treatment for mNSCLC. The following questionnaires were administered at baseline, 4 months later and following the first and second disease progression: APGAR, relationship impact scale, DUKE-UNC scale, economic impact in patients and caregiver, and Zarit scale. It was planned to include 1250 patients to get an 80% possibility of detecting as significant (p < 0.05) effect sizes less than 0.19 between men and women. Univariate comparisons were made between the tests applied to men and women. Overall survival was estimated with Kaplan-Meier method. Cox analyses were done to estimate hazard ratios (HRs) with 95% CI. RESULTS: 333 patients were included. Most families reported to continue being functional despite the lung cancer diagnosis. Regardless of sex, they did not perceive changes in their partner relationship. Most patients felt their social support was normal. Roughly 25% of people reported a worsening in their economic situation, without remarkable differences by sex. Statistically significant differences were found between both groups regarding the caregiver's relationship to the patient (more parents were the caregiver in females than in males, p < 0.0001) and the caregiver's employment situation (more employed caregivers in females) (p < 0.0001). Most caregivers of both sexes considered that taking care of their relative did not pose a significant burden. CONCLUSIONS: This study provides a preliminary insight into sex-related characteristics in the management of advanced NSCLC and its impact on the emotional, social and economic burden of patients and their caregivers, and recall the high priority of researching in cancer from a sex perspective. Nevertheless, due to the low recruitment rate and the relevant loss of patients during the follow-up, it was difficult to find differences by sex. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02336061. ETHICS COMMITTEE: Comité Ético de Investigación Clínica del Hospital Clínic de Barcelona, Spain. Reference number: HCB/2014/0705.

Trained dogs can identify malignant solitary pulmonary nodules in exhaled gas.

OBJECTIVES: To investigate the capacity of a trained dog to identify LC in patients with malignant SPN. METHODS: We collected 90 exhaled gas samples from 30 patients with SPN (3 samples/patient). As controls we used 61 healthy volunteers and 18 COPD patients without SNP or LC, in each of whom we collected 5 exhaled gas samples (n = 395). The dog (Blat, a 4-year-old crossbreed between a Labrador Retriever and a Pitbull) and the methodology used were the same as previously reported by our group (see: https://drive.google.com/open?id=1R4mOtOtuZkTeb5iOEEv0K9r2kHKlPhWd). RESULTS: Of 30 patients with SPN, Blat recognized 27 of them as positive for LC and 3 as negative for LC. These results fully matched post-surgical pathological results. Sensibility was 0.97, Specificity 0.99, Positive Predictive value 0.97 and negative predictive value 0.99. The AUC of the ROC curve was 0.985. CONCLUSIONS: Trained dogs can identify accurately the malignant origin of SPN. It is now time to develop technology that can match canine olfaction and facilitate the implementation of this diagnostic approach in the clinic.

Efficacy of tyrosine kinase inhibitors in EGFR-mutant lung cancer women in a real-world setting: the WORLD07 database.

BACKGROUND: The WORLD07 project is a female specific database to assess the characteristics of women with lung cancer. METHODS: WORLD07 database sets up in 2007, and prospectively stores clinical characteristics, treatment, outcome, and follow-up of lung cancer women. All women with epidermal growth factor receptor (EGFR) mutation non-small cell lung cancer (NSCLC) were selected for this analysis. RESULTS: From October 2007 to December 2012, a total of 1775 NSCLC women were recruited. EGFR mutation was identified in 34.4% of patients. Upfront EGFR tyrosine kinase inhibitor (TKI) reported a response rate of 60%, a median progression-free survival of 11.7 months, and median overall survival of 23.0 months. EGFR TKI, EGFR-mutation type, and smoking status did not impact in the outcome of treated women. CONCLUSION: Prevalence of EGFR mutation in women with NSCLC is higher than overall population with NSCLC. Efficacy of EGFR TKI in this real-world setting is similar to that previously reported.

A consensus statement on the gender perspective in lung cancer.

Lung cancer is the most common cancer globally and has the highest mortality. Although this disease is not associated with a particular gender, its incidence is rising among women, who are diagnosed at an increasingly younger age compared with men. One of the main reasons for this rise is women taking up smoking. However, many non-smoking women also develop this disease. Other risk factors implicated in the differential development of lung cancer in women are genetic predisposition, tumour histology and molecular profile. Proportionally more women than men with lung cancer have a mutation in the EGFR gene. This consensus statement reviews the available evidence about the epidemiological, biological, diagnostic, therapeutic, social and psychological aspects of lung cancer in women.

Serum anti-p53 antibodies and prognosis of patients with small-cell lung cancer.

BACKGROUND: Some patients with cancer develop antibodies against the p53 tumor suppressor protein. The presence of these antibodies in serum has been associated with the expression of mutant p53 by the tumor and in some studies with a poorer survival. PURPOSE: The goals of this study were to determine the prevalence of anti-p53 antibodies in the serum of patients with newly diagnosed small-cell lung cancer (SCLC) and to assess the clinical relevance of the presence of these antibodies in the serum, particularly their relationship with tumor response to treatment and with patient survival. METHODS: In this prospective study, serum was obtained from 170 patients at the time of diagnosis of SCLC who were to subsequently receive platinum- or doxorubicin-based chemotherapy at any one of four hospitals in Barcelona, Spain, from October 1991 through June 1994. Normal human sera from blood bank donors (n = 50) served as controls. The presence of anti-p53 antibodies was determined by western blot analysis with the use of purified recombinant p53 protein. As of January 1996, 96.5% of the patients had been treated and observed in the study, for a median follow-up time of 33.5 months. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression and unconditional logistic regression analyses were conducted. All P values resulted from two-sided tests. RESULTS: Anti-p53 antibodies were detected in the serum of 27 (16%) of the 170 patients studied. None of 50 serum samples from normal individuals contained anti-p53 antibodies. Analysis of pretreatment clinical characteristics demonstrated that a weight loss of less than 5% (P = .025), a serum lactic acid dehydrogenase (LDH) level of less than 450 U/L (P = .002), and limited stage disease (i.e., tumor confined to one hemithorax, with local and regional lymph node positivity for tumor cells and/or ipsilateral pleural effusion allowed) (P < .001) were associated with a statistically significant complete response to therapy. The presence of serum anti-p53 antibodies was not associated with clinical characteristics, such as age (P = .622), functional status (P = 1.0), disease stage (P = .634), complete response to treatment (P = .572), and survival (P = .492) or with any laboratory parameters including known prognostic factors in SCLC, such as serum sodium or LDH concentration (P values of .731 and .246, respectively). CONCLUSIONS AND IMPLICATIONS: The presence of anti-p53 antibodies in the serum of patients with newly diagnosed SCLC was not associated with any clinical characteristics or prognostic markers, suggesting that, in this context, the measurement of anti-p53 antibodies is not a useful prognostic marker.

Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival.

PURPOSE: Anti-Hu antibodies (HuAb) recognize antigens expressed by neurons and small-cell lung cancer (SCLC). High titers of HuAb were initially reported in serum from patients with paraneoplastic encephalomyelitis/sensory neuropathy (PEM/SN) and SCLC. Preliminary studies have indicated that some SCLC patients without PEM/SN harbor low titer of HuAb in their serum, and that the SCLC of these patients may grow more indolently. Based on these observations, we conducted a multicenter prospective study of SCLC patients without PEM/SN to determine the incidence and prognostic implications of HuAb. METHODS: Serum samples were collected at diagnosis of SCLC in 196 patients without PEM/SN. HuAb were determined by immunoblot of purified recombinant HuD antigen. RESULTS: HuAb were detected in 32 (16%) of the 196 patients. Of the 170 patients who received treatment for the tumor, 27 (16%) were HuAb positive. HuAb was associated with limited disease stage (59.3% v 38.6%; P = .047), complete response to therapy (55.6% v 19.6%; P < .001), and longer survival (14.9 v 10.2 months; P = .018). In a logistic regression analysis, HuAb status was an independent predictor of complete response induction. The probability of achieving a complete response was more than five times higher in HuAb-positive than in HuAb-negative patients (odds ratio, 5.4; 95% confidence interval, 1.71 to 16.89; P = .004). Cox multivariate analysis indicated that HuAb status was not independently associated with survival. CONCLUSION: The presence of HuAb at diagnosis of SCLC is a strong and independent predictor of complete response to treatment. This feature accounts for the association between HuAb and longer survival.

SEOM clinical guidelines for the treatment of non-small cell lung cancer (NSCLC) 2015.

Lung cancer is the most common cancer worldwide as well as the leading cause of cancer related deaths as reported by Torre et al (CA Cancer J Clin 65:87-108, 2015]. Non-small cell lung cancer (NSCLC) accounts for up to 85 % of all lung cancers. Multiple advances in the staging, diagnostic procedures, therapeutic options, as well as molecular knowledge have been achieved during the past years, although the overall outlook has not greatly changed for the majority of patients with the overall 5-year survival having marginally increased over the last decade from 15.7 to 17.4 % as reported by Howlader et al. (SEER Cancer Statistics Review 2015).

Chronic oral etoposide in non-small cell lung carcinoma.

25 consecutive inoperable or extended non-small cell lung cancer (NSCLC) patients (19 non-chemotherapy pretreated, 6 non-heavily pretreated) were given oral etoposide, 50 mg/m2/day for 21 successive days, every 4 weeks. 5 partial responses (PR), 9 disease stabilizations were achieved; the overall response rate of 20% (95% confidence interval, 4% to 36%) or 26% in non-pretreated patients. Median survival and PR duration probabilities were 6.7 months and 6.3 months, respectively. Alopecia excepted (96% of patients), non-haematological toxicity was mild. Haematological toxicity WHO grade II+III mainly consisted of leukopenia (28%).

Efficacy of radiotherapy for malignant gliomas in elderly patients.

PURPOSE: Age above 65 years is a strong negative prognostic factor for survival in patients with malignant gliomas (MG) treated with radiotherapy (RT) and its value has been questioned. We analyzed the effect of RT on the survival of elderly patients with malignant gliomas. METHODS AND MATERIALS: We examined 85 consecutive elderly patients with a histological diagnosis of MG. Age ranged from 65 to 81 years (median 70 years). Glioblastoma multiforme (GBM) was diagnosed in 64 patients (75.3%). Surgical treatment included needle biopsy in 32 patients (37.6%). Median postoperative Karnofsky Performance Status (KPS) was 60 (range: 30-100). Survival probability was estimated using Kaplan-Meier method and compared with the log-rank test. Crude and adjusted hazard ratios (HR) were calculated using Cox's regression models. RESULTS: Median survival time for all patients was 18.1 weeks. In multivariate analysis, RT was the only independent prognostic variable for survival (HR: 9.1 [95% CI: 4.5-18.7]). Forty-two patients did not start RT mostly due to low KPS (<50). The median survival of the 43 patients who started RT was 45 weeks. In these patients, Cox multivariate analysis indicated that age was independently associated with prolonged survival (HR: 2.85 [95% CI 1.31-6.19]). Median survival of patients age 70 years and younger was 55 weeks compared with 34 weeks for patients older than 70 years. CONCLUSIONS: The overall survival for elderly patients with MG is poor. RT seems to improve survival in patients up to 70 years, but in older patients treated with RT the survival is significantly shorter.

Metastatic carcinoma of the breast resembling early gastric carcinoma.

We describe a case of gastric metastasis from a lobular carcinoma of the breast in a 45-year-old woman who had undergone a left mastectomy with axillary dissection 7 years earlier. At the current presentation, she had been experiencing progressive epigastric discomfort for 3 months. The initial diagnosis was early gastric carcinoma, diffuse type, based on gastric biopsy findings and ultrasonographic endoscopy. A definitive diagnosis of metastatic breast cancer was confirmed after subtotal gastrectomy of a presumed primary early gastric carcinoma. Although gastrointestinal metastases from breast cancer are not rare, the early stage of the gastric lesion and the absence of further disease dissemination make this case unusual. The onset of gastrointestinal symptoms in a patient with a history of breast carcinoma should prompt the physician to rule out the possibility of gastric metastases.

Integrating concurrent navelbine and cisplatin to hyperfractionated radiotherapy in locally advanced non-small cell lung cancer patients treated with induction and consolidation chemotherapy: feasibility and activity results.

OBJECTIVES: The purpose of this study was to determine the effectiveness and toxicity of a new combination schedule based on concurrent navelbine, cisplatin and hyperfractionated radiotherapy in patients with locally advanced NSCLC treated with platinum and gemcitabine induction and consolidation chemotherapy. MATERIALS AND METHODS: The 37 patients with pathological confirmed advanced NSCLC (non-surgical stages IIIA and IIIB) were included in the study. All of them were assessable for survival and 32 for response. The treatment schedule consisted of cisplatin (100 mg/m2) or carboplatin (400 mg/m2) on day 1 with gemcitabine (1000 mg/m2) on days 1, 8 and 15. Treatment was given every 28 days for two courses, followed by concurrent administration of accelerated modified hyperfractionated radiotherapy, with concomitant boost, with a total dose of 61.64 Gy administered for 5 weeks, with cisplatin and navelbine, for two courses, finally followed by two courses of the same initial chemotherapy. RESULTS: Four patients achieved complete response (12.5%) and 14 (44%) partial response, for an overall objective response rate of 56.5%. After a minimum follow-up duration of 35.5 months, median progression free survival was 12.2 months. The median survival was 15.4 months with actuarial 1-, 2- and 3-year survival of 67, 21 and 15%, respectively. The main toxicity was hematological. There was esophagitis (grades III and IV) in 30% of the patients and there were two treatment-related deaths. CONCLUSION: Combined treatment with concurrent radiotherapy and chemotherapy in non-surgical NSCLC is an acceptable treatment modality. However, the toxicity was not negligible.

Chronic oral etoposide in advanced breast cancer.

Chronic oral etoposide has shown activity in some metastatic refractory tumors. To test its activity in previously treated metastatic breast cancer patients, we started a study in 18 consecutive patients given etoposide orally at 50 mg/m2 daily for 21 days. A partial response was observed in 4 of 18 patients (22%); of the responding patients, 3 had visceral metastases and 1 had multiple bone metastases. Leukopenia of grade 3 or 4 was the main hematological toxic effect (23% of patients) and alopecia was the most important nonhematological toxicity. Chronic oral etoposide shows some activity in pretreated patients with metastatic breast cancer, with tolerance being good and toxicity, acceptable. Further studies of this drug given as first-line chemotherapy or in combination with other drugs can establish all its potential activity in this cancer.

"Smouldering" Chronic Lymphocytic Leukemia.

Although clinical staging systems are useful to assess the prognosis of chronic lymphocyctic leukemia (CLL), for the large majority (up to 60%) of patients in early clinical stage no system is able to predict those who will progress ("active" disease) and those who will remain at the same stage ("smouldering" disease). To identify the latter subset of patients is important since in these patients treatment should be withhold until progression occurs. In the past few years, there have been several attempts to define "smouldering" CLL. Basically, patients in early stage (Binet's A) with: (a) moderate bone marrow infiltration (non-diffuse pattern in the biopsy or less than 80% lymphocytes in bone marrow aspirate), (b) low blood lymphocyte count (<30 × 10(9)/L), (c) Hb level in a non-anemic range (> 12 or 13 g/dL), and d) prolonged lymphocyte doubling time (> 12 months) are not likely to progress and have a life-expectancy not different from matched controls. In three different series analyzed so far, disease-progression rate is approximately 15% to 5 yrs, and survival is not different from that of controls. Approximately, 20 to 30% of all CLL patients with CLL fulfill "smouldering" criteria. Besides the above criteria, there are others that merit consideration. Thus, Rai's substages (AO vs AI + II) have been found to predict different outcomes within Binet's stage A. On the other hand, chromosome abnormalities may be useful to further assess the prognosis. Finally, the contribution of phenotypic studies to the definition of "smouldering" CLL remains uncertain, and a female sex has been associated with a better outcome. Whether or not patients with "active" stage A (e.g., those not fulfilling "smouldering" CLL criteria) should be treated is unknown. The morbidity associated to treatment (e.g. increase number of second neoplasms) and the lack of survival advantage found in recent randomized trials cast doubts on the real benefit of treating patients in early stage (Binet's A; Rai's 0). To answer this question, the separate analysis of patients with "smouldering" stage A and patients with "active" stage A included in recent trials could be of help. Moreover, prospective studies of patients in early stage followed-up with no treatment could be useful to refine the definition of "smouldering" CLL.

Tumor markers in response monitoring and prognosis of non-small cell lung cancer: preliminary report.

BACKGROUND: The significance of tumor markers in lung cancer is not well established. PATIENTS AND METHODS: We analyzed level of serum markers as prognostic factor of response and survival in 46 evaluable patients with locally advanced or metastasic non small cell lung cancer. All patients were treated with cisplatin 120 mg/m2 or carboplatin 400 mg/m2 day 1, plus etoposide 80 mg/m2 days 1 to 3. RESULTS: Partial response was obtained in 11 patients (24%), stabilization in 18 and progression in 17. Tumor marker sensitivities were: CEA 37%, CA 125 54.5%, SCC 17.5%, NSE 30.5%, and CYFRA 52%. Higher levels of CEA and NSE correlated with more probability of response (p < 0.001 and p = 0.002). The survival probability of patients with normal pretreatment levels of NSE was significantly better than those with NSE over normal level (15.2 vs 7.2 months) p = 0.02. In patients who achieved partial response, CEA, CA 125 and CYFRA levels decreased significantly with respect to the pretreatment values. CONCLUSIONS: Patients with high CEA and NSE serum level have an increased probability of response than patients with low initial levels; however, patients with high initial level of NSE have poor survival. The decrease in CEA, CA 125 and CYFRA values at the moment of response evaluation could help in response assessment.

Phase II trial of carboplatin and etoposide activity in pretreated breast cancer patients.

Twenty-seven metastatic breast adenocarcinoma patients, pretreated with standard hormonotherapy or chemotherapy, received carboplatin 100 mg/m2/day x 3 intravenously (i.v.) plus etoposide 100 mg/m2/d x 3 i.v. repeated at 4-week intervals. There were five partial responses (18.5%), two minor responses, and 12 disease stabilizations. The dominant metastatic disease sites were soft tissue in three partially responding patients and visceral metastases in the two remaining responders. The median duration of response and time to progression were, respectively, 10 and 26 weeks. Major toxicity was myelosuppression with 85% of patients developing leukopenia; 48%, anemia; and 30%, thrombocytopenia. Carboplatin plus etoposide has shown antitumor activity in our group of pretreated patients. Based on the same schedule, a first-line carboplatin plus etoposide Phase II trial has been started.

Combination chemotherapy with oral etoposide plus intravenous cyclophosphamide in liver metastases of breast cancer.

Sixteen patients with hepatic metastases of histologically documented breast cancer were treated with etoposide (VP 16-213) and cyclophosphamide. Previously, 6 had shown relapse in the liver after adjuvant chemotherapy, 2 had failed to respond to another chemotherapy combination, and 8 had never undergone chemotherapy. Fifty percent responded to treatment, including 1 complete remission and 7 partial responses. Median survival was 16 months and median duration of response was 13 months. All patients showed alopecia and moderate leukopenia; 13 experienced moderate gastrointestinal toxicity; there was 1 mild case of anemia and 1 case of moderate hemorrhagic cystitis. This study suggests that the combination of VP 16-213 and cyclophosphamide is a well-tolerated and effective treatment in advanced breast cancer patients with liver metastases.