Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial.

BACKGROUND: Several studies show the importance of accurately quantifying not only KRAS and other low-abundant mutations because benefits of anti-EGFR therapies may depend on certain sensitivity thresholds. We assessed whether ultra-selection of patients using a high-sensitive digital PCR (dPCR) to determine KRAS, NRAS, BRAF and PIK3CA status can improve clinical outcomes of panitumumab plus FOLFIRI. PATIENTS AND METHODS: This was a single-arm phase II trial that analysed 38 KRAS, NRAS, BRAF and PIK3CA hotspots in tumour tissues of irinotecan-resistant metastatic colorectal cancer patients who received panitumumab plus FOLFIRI until disease progression or early withdrawal. Mutation profiles were identified by nanofluidic dPCR and correlated with clinical outcomes (ORR, overall response rate; PFS, progression-free survival; OS, overall survival) using cut-offs from 0% to 5%. A quantitative PCR (qPCR) analysis was also performed. RESULTS: Seventy-two evaluable patients were enrolled. RAS (KRAS/NRAS) mutations were detected in 23 (32%) patients and RAS/BRAF mutations in 25 (35%) by dPCR, while they were detected in 7 (10%) and 11 (15%) patients, respectively, by qPCR. PIK3CA mutations were not considered in the analyses as they were only detected in 2 (3%) patients by dPCR and in 1 (1%) patient by qPCR. The use of different dPCR cut-offs for RAS (KRAS/NRAS) and RAS/BRAF analyses translated into differential clinical outcomes. The highest ORR, PFS and OS in wild-type patients with their lowest values in patients with mutations were achieved with a 5% cut-off. We observed similar outcomes in RAS/BRAF wild-type and mutant patients defined by qPCR. CONCLUSIONS: High-sensitive dPCR accurately identified patients with KRAS, NRAS, BRAF and PIK3CA mutations. The optimal RAS/BRAF mutational cut-off for outcome prediction is 5%, which explains that the predictive performance of qPCR was not improved by dPCR. The biological and clinical implications of low-frequent mutated alleles warrant further investigations. CLINICALTRIALS.GOV NUMBER: NCT01704703. EUDRACT NUMBER: 2012-001955-38.

Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy.

BACKGROUND: Extended RAS analysis is mandatory in metastatic colorectal cancer (mCRC) patients. The optimal threshold of RAS mutated subclones to identify patients most likely to benefit from antiepidermal growth factor receptor (EGFR) therapy is controversial. Our aim was to assess the clinical impact of detecting mutations in RAS, BRAF, PIK3CA and EGFRS492R in basal tissue tumour samples by using a highly sensitive next-generation sequencing (NGS) technology in mCRC patients treated with chemotherapy plus anti-EGFR or anti-vascular endothelial growth factor. PATIENTS AND METHODS: Five hundred and eighty-one tumour samples from untreated mCRC patients from 7 clinical studies were collected. Mutational analysis was carried out by standard-of-care (therascreen pyro) with a sensitivity detection of 5% mutant allele fraction (MAF), and compared with NGS technology using 454GS Junior platform (Roche Applied Science, Germany) with a sensitivity of 1%. Molecular results were correlated with clinical outcomes. RESULTS: After quality assessment, 380 samples were evaluable for molecular analysis. Standard-of-care mutational analysis detected RAS, BRAFV600E or PIK3CA mutations in 56.05% of samples compared with 69.21% by NGS (P = 0.00018). NGS identified coexistence of multiple low-frequency mutant alleles in 96 of the 263 mutated cases (36.5%; range 2-7). Response rate (RR), progression-free survival (PFS) and overall survival (OS) were increasingly improved in patients with RAS wild-type, RAS/BRAF wild-type or quadruple (KRAS/NRAS/BRAF/PIK3CA) wild-type tumours treated with anti-EGFR, assessed by standard-of-care. No additional benefit in RR, PFS or OS was observed by increasing the detection threshold to 1% by NGS. An inverse correlation between the MAF of the most prevalent mutation detected by NGS and anti-EGFR response was observed (P = 0.039). EGFRS492Rmutation was not detected in untreated samples. CONCLUSIONS: No improvement in the selection of patients for anti-EGFR therapy was obtained by adjusting the mutation detection threshold in tissue samples from 5% to 1% MAF. Response to anti-EGFR was significantly better in patients with quadruple wild-type tumours.

First-line single-agent regorafenib in frail patients with metastatic colorectal cancer: a pilot phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD).

BACKGROUND: Treatment of frail patients with advanced colorectal cancer (CRC) is controversial. This pilot phase II trial aimed to assess the efficacy and safety of regorafenib when administered in first-line to frail patients with advanced CRC. METHODS: Frail patients without prior advanced colorectal cancer treatment were included in the study. Definition of frailty was defined per protocol based on dependency criteria, presence of chronic comorbid pathologies and/or geriatric features. MAIN OBJECTIVE: to assess progression-free survival (PFS) rate at 6 months. Treatment consisted of 28-day cycles of orally administered regorafenib 160 mg/day (3 weeks followed by 1 week rest). RESULTS: Forty-seven patients were included in the study. Median age was 81 years (range 63-89). Frailty criteria: dependency was observed in 26 patients (55%), comorbidities in 27 (57%) and geriatric features in 18 (38%). PFS rate at 6 months was 45% (95% confidence interval [CI] 30-60]. Median PFS was 5.6 months (95%CI 2.7-8.4). Median overall survival (OS) was 16 months (95%CI 7.8-24). Complete response, partial response and stable disease were observed in one, two and 21 patients respectively (objective response rate 6.4%; disease control rate 51%). Thirty-nine patients (83%) experienced grade 3-4 adverse events (AEs). The most common grade 3-4 AEs were hypertension (15 patients; 32%), asthenia (14; 30%), hypophosphatemia (6; 13%); diarrhea (4; 8%), hand-foot-skin reaction (4; 8%). There were two toxic deaths (4.2%) (grade 5 rectal bleeding and death not further specified). Dose reduction was required in 26 patients (55%) and dose-delays in 13 patients (28%). CONCLUSIONS: The study did not meet the pre-specified boundary of 55% PFS rate at 6 months. Toxicity observed (83% patients experienced grade 3 and 4 AEs) preclude its current use in clinical practice on this setting. Disease control rate and overall survival results are interesting and might warrant further investigation to identify those who benefit from this approach. TRIAL REGISTRATION: This trial was prospectively registered at EudraCT ( 2013-000236-94 ). Date of trial registration: April 9th, 2013.

Genotype-based selection of treatment of patients with advanced colorectal cancer (SETICC): a pharmacogenetic-based randomized phase II trial.

Background: There has been little progress toward personalized therapy for patients with metastatic colorectal cancer (mCRC). TYMS-3' untranslated region (UTR) 6 bp ins/del and ERCC1-118C/T polymorphisms were previously reported to facilitate selecting patients for fluoropyrimidine-based treatment in combination with oxaliplatin as first-line therapy. We assessed the utility of these markers in selecting therapy for patients with mCRC. Patients and methods: This randomized, open-label phase II trial compared bevacizumab plus XELOX (control) versus treatment tailored according to TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T polymorphisms. Patients randomized to the experimental treatment received bevacizumab plus FUOX, FUIRI, XELIRI, or XELOX depending on their combination of favorable polymorphisms for FUOX treatment (TYMS-3'UTR ins/del or del/del; ERCC1-118T/T). Progression-free survival (PFS) was the primary end point. Results: Overall, 195 patients were randomized (control n = 65; experimental n = 130). The primary objective was not met: median PFS was 9.4 months in the control group and 10.1 months in the experimental group (P = 0.745). Median overall survival was similar in both groups (16.5 versus 19.1 months, respectively; P = 0.797). Patients in the experimental group had a significantly higher overall response rate (ORR; 65% versus 47% in the control group; P = 0.042) and R0 resection rate (86% versus 44%, respectively; P = 0.018). Neuropathy, hand-foot syndrome, thrombocytopenia, and dysesthesia were significantly less common in the experimental group. Conclusions: This study did not show survival benefits after treatment personalization based on polymorphisms in mCRC. However, the improved ORR and R0 resection rate and fewer disabling toxicities suggest that tailoring therapy by TYMS-3'UTR and ERCC1-118 polymorphisms warrants further investigation in patients with mCRC. ClinicalTrials.gov: NCT01071655.

Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy. PATIENTS AND METHODS: A prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue. RESULTS: ctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71 - 0.90) and BEAMing in tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74 - 0.92). Fifteen cases (10.3%) showed discordant tissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possibly due to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explained by low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second- or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allele fractions in plasma below 1%. CONCLUSIONS: Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection.

Role of circulating tumor cells as prognostic marker in resected stage III colorectal cancer.

BACKGROUND: The prognostic role of circulating tumor cells (CTC) in early colorectal cancer (CRC) has not been determined yet. We evaluated the potential prognostic value of CTC in stage III CRC patients. PATIENTS AND METHODS: Prospective multicenter study of 519 patients with stage III CRC recruited between January 2009 and June 2010. CTC were enumerated with the CellSearch System after primary tumor resection and before the start of adjuvant therapy. A total of 472 patients were included in the analysis. RESULTS: CTC ≥1, ≥2, ≥3 and ≥5 were detected in 166 (35%), 93 (20%), 57 (12%) and 34 (7%) patients, respectively. Median follow-up was 40 months. In the overall population, CTC ≥1 (disease-free survival (DFS): HR 0.97, P = 0.85; overall survival (OS): HR 1.03, P = 0.89), ≥2 (DFS: HR 1.07, P = 0.76; OS: HR 1.02, P = 0.95), ≥3 (DFS: HR 0.96, P = 0.87; OS: HR 0.74, P = 0.41) and ≥5 (DFS: HR 0.72, P = 0.39; OS: HR 0.48, P = 0.21) were not associated with worse DFS and OS. No clinicopathological characteristics were significantly associated with the presence of CTC. In patients with disease relapse, the proportion with CTC ≥1 was not significantly different between those with single versus multiple metastatic locations (37.9% versus 31.4%, P = 0.761). In the multivariate analysis, CTC ≥1 was not an independent prognostic factor for DFS (HR 0.97, P = 0.87) and OS (HR 0.96, P = 0.89). CONCLUSION: CTC detection was not associated with worse DFS and OS in patients with stage III CRC. Given the scarcity of CTC in these patients, it is likely that CTC determined by CellSearch system does not have a prognostic role in this setting. However, a longer follow-up is needed.

Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.

BACKGROUND: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. RESULTS: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. CONCLUSIONS: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.

Author Correction: Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study.

PURPOSE: To compare the efficacy and safety of orally administered capecitabine (Xeloda; Roche Laboratories, Inc, Nutley, NJ), a novel fluoropyrimidine carbamate designed to mimic continuous fluorouracil (5-FU) infusion but with preferential activation at the tumor site, with that of intravenous (IV) 5-FU plus leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer. PATIENTS AND METHODS: We prospectively randomized 602 patients to treatment with capecitabine 1,250 mg/m(2) administered twice daily days 1 to 14 every 3 weeks, or to the 4-weekly Mayo Clinic regimen (5-FU/LV) until disease progression or unacceptable toxicity. RESULTS: The primary objective, to demonstrate at least equivalent response rates in the two treatment groups, was met. The overall response rate was 18.9% for capecitabine and 15.0% for 5-FU/LV. In the capecitabine and 5-FU/LV groups, respectively, median time to disease progression was 5.2 and 4.7 months (log-rank P =.65); median time to treatment failure was 4.2 and 4.0 months (log-rank P =.89); and median overall survival was 13.2 and 12.1 months (log-rank P =.33). The toxicity profiles of both treatments were typical of fluoropyrimidines. However, capecitabine led to significantly lower incidences (P <.00001) of stomatitis and alopecia, but a higher incidence of cutaneous hand-foot syndrome (P <.00001). Capecitabine also resulted in lower incidences (P <.00001) of grade 3/4 stomatitis and neutropenia, leading to a lower incidence of grade 3/4 neutropenic fever and sepsis. Only grade 3 hand-foot syndrome (P <.00001) and uncomplicated grade 3/4 hyperbilirubinemia (P <.0001) were reported more frequently with capecitabine. CONCLUSION: Oral capecitabine achieved an at least equivalent efficacy compared with IV 5-FU/LV. Capecitabine demonstrated clinically meaningful safety advantages and the convenience of an oral agent.

The macroinfauna of the Galician sandy beaches (NW Spain) affected by the Prestige oil-spill.

Eighteen sandy beaches were sampled along the 1659 km of the Galician coast (NW Spain) six months after the Prestige oil-spill to study the impact of the fuel and the clean-up activities on the macroinfauna community. A transect was extended at each beach, from above the drift line to below the swash line at five sampled levels; at each level six 0.05 m2 replicates were taken to a depth of 30 cm and sieved through a 1mm mesh, and the organisms collected and preserved. Results were compared with previous data obtained using the same procedures. The macroinfauna was numerically dominated by the amphipod Pontocrates arenarius, the isopod genus Eurydice, the polychaete Scolelepis squamata, and the amphipod Talitrus saltator. As a result of the Prestige oil-spill and the clean-up activities, beach populations were reduced, with Eurydice and S. squamata as the most affected taxa.

SEOM clinical guidelines for diagnosis and treatment of metastatic colorectal cancer 2015.

Colorectal cancer (CRC) is the second leading cause of cancer dead in Spain. About half the patients will eventually develop distant metastases. However, as treatment options are expanding, prognosis has steadily improved over the last decades. Management of advanced CRC should be discussed within an experienced multidisciplinary team to select the most appropriate systemic treatment (chemotherapy and targeted agents) and to integrate surgical or ablative procedures when indicated. Disease site and extent, resectability, tumor biology and gene mutations, clinical presentation, patient preferences, and comorbidities are key factors to design a customized treatment plan. The aim of these guidelines is to provide synthetic recommendations for managing advanced CRC patients.

Gemcitabine plus capecitabine (Gem-Cape) biweekly in chemorefractory metastatic colorectal cancer.

PURPOSE: A proportion of patients with metastatic colorectal cancer (mCRC) are still able to continue with active therapy after their progression to fluoropyrimidines, oxaliplatin, and irinotecan regimens. Studies suggest that gemcitabine and fluoropyrimidines are synergic antimetabolites. The purpose was to evaluate gemcitabine-capecitabine (Gem-Cape) in heavily pretreated mCRC and to thus assess possible predictive factors for progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: This analysis was performed on 119 evaluable patients pretreated with fluoropyrimidines, oxaliplatin, irinotecan, and biological agents between June 2001 and July 2011. Patients received gemcitabine 1,000 mg/m(2) day 1 and capecitabine 1,000 mg/m(2) bid for 7 days every 2 weeks. RESULTS: The general characteristics were ECOG 0-1, 89 %; male, 68 %, and median age 63 years. In total, 61 % had received two chemotherapy lines, while 39 % had received three or more. Objective response rates and stable disease rates at 3 months were 6.72 and 37.81 %, equalling a clinical benefit of 44.53 %. The median PFS and OS were 2.87 months [95 % confidence interval (CI) 2.53-3.17 months] and 6.53 months (95 % CI 5.33-8.77), respectively. The most frequent toxicities were grades 1-2, anemia (22 %), thrombocytopenia (10 %), and hand-foot syndrome (9 %); grade ≥3, diarrhea (2 %), with no treatment-related discontinuations. No treatment-related deaths were reported. Statistical significance was obtained by subgroups, assessing clinical benefits and objective responses for PFS and OS. Moreover, patients under 65 tended to have a better PFS. CONCLUSION: These data suggest that Gem-Cape is a tolerable and feasible regimen, associated with clinical benefit in non-selected, heavily pretreated, mCRC patients.

Phase II study of carboplatin and 1-h intravenous etoposide and paclitaxel in a novel sequence as first-line treatment of patients with small-cell lung cancer.

PURPOSE: To evaluate the efficacy and tolerability of paclitaxel, carboplatin and etoposide when administered in combination to previously-untreated small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS: Patients (n=95) with limited-stage disease (LSD; n=45) or extensive-stage disease (ESD; n=50) from 14 Spanish hospitals were entered into the study. Etoposide was administered 80 mg/m(2)/day intravenous (i.v.) on days 1, 2 and 3, paclitaxel 175 mg/m(2) i.v. on day 3 and carboplatin area-under-the-concentration-time-curve=6; i.v. on day 3, of a 3-week cycle, and repeated for up to 6 cycles. RESULTS: The overall response (OR) rate was 74% (n=70; 32 complete, 38 partial). Although the OR in LSD and ESD patients was similar (73 vs 74%, respectively), the percentage complete response was significantly higher among the former (49 vs 20%). The main toxicities were grade 3-4 neutropenia and febrile neutropenia (62 and 18%, respectively) and there were 3 toxic deaths. Other toxicities were rare or easily manageable. Disease-free survival and overall survival rates at 1 year were 53 and 70% in LSD and 18 and 39% in ESD patients, respectively. CONCLUSION: The results indicate that the combination of paclitaxel, etoposide and carboplatin has an anti-tumour activity in SCLC that is comparable to other combination regimens, and is well tolerated.

High-dose BCNU and autologous progenitor cell transplantation given with intra-arterial cisplatinum and simultaneous radiotherapy in the treatment of high-grade gliomas: benefit for selected patients.

A phase II study of postoperative high-dose carmustine (HDBCNU), intracarotid cisplatin (CDDP), and radical radiotherapy in patients with high-grade glioma was performed. Patients underwent 4-6 consecutive days of blood hematopoietic progenitor cell (HPC) apheresis without prior mobilization. Chemotherapy included intracarotid CDDP, 60 mg/m2, and BCNU, 900 mg/m2. HPC were infused 48 h after HDBCNU. Whole brain irradiation, up to 50 Gy, was started on the 8th day after HPC infusion. With a median follow-up time of 44 months, median overall survival was 15.5 months. Eight patients (23.5%) are alive free of disease 2-6 years after treatment (seven out of 25 patients with glioblastoma multiforme and one out of nine patients with anaplastic astrocytoma). Survival was influenced by young age, good performance and complete surgical resection. Two patients (5.8%) died of therapy-related complications. Acute hematological toxicity of HDBCNU was moderate, with a full recovery on day 26. No acute pulmonary or hepatic toxicity was found. Late severe neurological toxicity was observed in one third of patients surviving beyond 2 years. We conclude that HDBCNU, 900 mg/m2, intracarotid CDDP and radical radiotherapy appear to benefit some patients with high-grade gliomas, and phase III studies should preferentially select young patients with resectable tumors.

Intra-arterial hepatic treatment with carboplatin (CBDCA) and 5-fluorouracil (5-FU) in metastases from colorectal carcinoma.

Thirty-one patients with hepatic metastases from colorectal carcinoma were treated with carboplatin (CBDCA), 55 mg/m2, given in a 4-hour intra-arterial infusion daily for 5 days, and 5-fluorouracil, 900 mg/m2, given in a 20-hour intra-arterial infusion daily for 5 days. Cycles were administered every 5 weeks. Objective responses were observed in 16 (51.6%) patients (5 complete and 11 partial responses). Another 13 patients maintained stable disease, and 2 patients rapidly progressed. The overall median survival was 23.5 months. The 16 patients with objective response had a median survival of 26.5 months. In this series, no evidence of biliary sclerosis, cholecystitis, chemical hepatitis, or myelosuppression was observed. Complications of drug delivery system were observed in 14 (45.16%) patients. In conclusion, intra-arterial hepatic chemotherapy with CBDCA-5FU was associated with a modest benefit, expressed in good quality responses and extended survival of approximately 2 years in about half of the treated patients.

Phase II evaluation of doxorubicin, ifosfamide, and dacarbazine plus amphotericin B in the treatment of metastatic soft tissue sarcomas. A pilot study.

Amphotericin B enhances the cytotoxicity of certain antineoplastic agents in vitro and in vivo. A phase II study was designed to evaluate whether this effect can be produced in the treatment of metastatic soft-tissue sarcomas (STS). The program AIDAB consisted of ADM 50 mg/m2 i.v. bolus at day 1; ifosfamide (IFX) 1.5 g/m2 in 1 hour i.v. infusion/day x 3 days; mesna 300 mg/m2 i.v. bolus before and 4 and 8 hours after IFX; dacarbazine (DTIC) 400 mg/m2 i.v. in 6 hours infusion/day x 3 days; and amphotericin B 25 mg/m2 i.v. in 6 hours infusion/day x 3 days; repeated every 4 weeks. There were 25 patients evaluable for response and toxicity, 22 with no previous chemotherapy. The median age was 44, (range: 16-64); 14 males, 11 females with a Karnofsky range of 40 to 90%. The response rate was 48% (4% complete response and 44% partial response). The median duration of response was 6.6 months. Of these 25 patients, 17 (68%) have died; the median survival was 12 months (range: 3-51 months). A total of 175 cycles were given to the 25 patients, with a mean of 7 cycles per patient. Toxicities encountered were leukopenia and/or thrombocytopenia, grade IV (WHO), in 9 patients (36%); fever and chills during amphotericin B infusion in 40%; vomiting, grade III (WHO), in 56%; mild mucositis in 12%, and a symptomatic decrease in cardiac ejection fraction in one patient. There was one toxic death due to severe thrombocytopenia. We can conclude that AIDAB is effective in the treatment of metastatic soft-tissue sarcoma. The addition of amphotericin B did not improve the response rate or survival above what is expected from chemotherapy alone.

Neoadjuvant intra-arterial chemotherapy in inflammatory carcinoma of the breast.

From 1982 to 1989, 18 eligible patients (median age 50.5 years, range 30-72 years) with inflammatory breast carcinoma have been treated with neoadjuvant intra-arterial (IA) chemotherapy. The treatment regimen includes IA cisplatin, adriamycin, mytomycin C and thiotepa on Day 1 and intravenous 5-fluorouracil on Days 1 and 2. An objective clinical response rate of 100% (eight complete and 10 partial) has been observed. The median disease-free and overall survivals are 27 months (range 5-85+ months) and 33 months (range 8-85+ months), respectively. With a median follow-up of 21.5 months, six (33.3%) patients remain alive and free of disease and 12 patients have died because of distant metastases. No local recurrences have been observed. Intra-arterial chemotherapy is an attractive technique for the treatment of locally advanced breast carcinoma with mild toxicity and high local control rate.

Spionidae (Annelida: Polychaeta) from the Parque Nacional Morrocoy, Falcón, Venezuela.

Five species of polychaetes (Spionidae) were found associated to Thalassia testudinum meadows in Parque Nacional Morrocoy, Venezuela. We included a guide for their identification and present range extensions for the Venezuelan coasts and Southern Caribbean Sea. The species are: Dipolydora socialis, Prionospio (Minuspio) cirrifera, P. (Prionospio) fallax, P. (P.) steenstrupi, and Spio pettiboneae.

[Complementary chemotherapy of breast cancer; experience at the University Clinic of Navarra]. / Quimioterapia complementaria del cáncer de mama; experiencia de la Clínica Universitaria de Navarra.

From 1982 to 1989, 68 patients were treated with the diagnosis of breast cancer. 57 were premenopausal and 11 postmenopausal. The most frequent stage was T2N1 (44.1%) followed by T1N1 (20.6%). The mean dosage of chemotherapy given were 91.2% for cyclophosphamide, 88% for methotrexate and 94% for 5-fluorouracil. The treatment was well tolerated and the most frequent toxicity encountered was leukopenia. The disease free survival were 89.4% at 96 month for premenopausal and 63.3% at 68 month for postmenopausal. We have not seen any differences in the disease free survival in relation to the size of the tumor or the status of the hormonal receptors of the tumor. The most important prognostic factor were the number of positive axilar nodes affected and the dosage of chemotherapy.