Circulating tumour cell gene expression and chemosensitivity analyses: predictive accuracy for response to multidisciplinary treatment of patients with unresectable refractory recurrent rectal cancer or unresectable refractory colorectal cancer liver metastases.

BACKGROUND: Patients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs). METHODS: In this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected. RESULTS: Our analyses resulted in evaluations of 94.12% (95% CI 0.71-0.99) for sensitivity, 5.26% (95% CI 0.01-0.26) for specificity, a predictive value of 47.06% (95% CI 0.29-0.65) for a positive response, a predictive value of 50% (95% CI 0.01-0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30-0.64). CONCLUSIONS: This is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials.

A Prospective Study of Intraarterial Infusion Chemotherapy in Advanced Wild-Type BRAF Melanoma Patients.

BACKGROUND: Treatment strategies for advanced cutaneous melanoma (CM) patients, resistant or not treatable with novel target and immunotherapeutic drugs, remain a significant challenge, particularly for patients with unresectable stage IIIC/D disease localized to inferior limbs and pelvis, for whom specific outcomes are rarely considered. MATERIALS AND METHODS: This is a prospective study of multidisciplinary treatments, including locoregional melphalan chemotherapy, in 62 BRAF wild-type CM patients with locoregional metastases in the inferior limbs and pelvis, including inguinal regions. Patients were either in progression following or ineligible for, or not treatable with novel immunotherapy. For exclusively inferior limb-localised disease, patients received locoregional melphalan chemotherapy performed by hyperthermic isolated limb perfusion (n = 19) or isolated limb infusion (n = 19), and for synchronous lesions localised to inferior limbs and pelvis, received hypoxic pelvic and limb perfusion (n = 24). Additional multidisciplinary therapy included local, locoregional and systemic treatments and the primary endpoint was tumour response. RESULTS: The objective response rate following first cycle of locoregional chemotherapy was 37.1% at 3 mo and median progression-free survival was 4-mo, with 12.9% procedure-related complications, 30.6% low-grade haematological toxicity and 11.3% severe limb toxic tissue reactions. Multivariate logistic regression showed that the odds of response were significantly higher for patients ≤ 75 y of age and for patients with locoregional metastases exclusively located in the inferior limbs. CONCLUSION: In this subgroup of CM patients with BRAF wild-type status, locoregional metastases localized to inferior limbs and pelvis, in progression following or ineligible for immunotherapy, melphalan locoregional chemotherapy demonstrated a safe and effective profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01920516; date of trial registration: August 6, 2013.

Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6-7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A.

Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6-7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L'Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6-7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6-7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6-7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6-7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6-7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study.

A Pilot Study of the Predictive Potential of Chemosensitivity and Gene Expression Assays Using Circulating Tumour Cells from Patients with Recurrent Ovarian Cancer.

Circulating tumour cells (CTCs) from liquid biopsies are under current investigation in several cancers, including epithelial ovarian cancer (EOC) but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic EOC CTCs, from 10 patients, nine with stage IIIC and one with stage IV disease, in progression after systemic chemotherapy, submitted for hypoxic isolated abdominal perfusion (HAP), are both feasible and useful in predicting response to therapy. Viable metastatic EOC CTCs (>5 cells/mL for all 10 blood samples), enriched by transient culture and identified by reverse transcription polymerase chain reaction (RT-PCR) and indirect immunofluorescence (IF), were subjected to flow cytometry-based Annexin V-PE assays for chemosensitivity to several chemotherapeutic agents and by RT-PCR for tumour gene expression profiling. Using a cut-off value of >80% cell death, CTC chemosensitivity tests were predictive of patient RECIST 1.1 responses to HAP therapy associated with 100% sensitivity, 50% specificity, 33% positive predictive, 100% negative predictive and 60% accuracy values. We propose that the methodology employed in this study is feasible and has the potential to predict response to therapy, setting the stage for a larger study.

A review discussing the use of polyethylene glycol microspheres in the treatment of hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is indicated in unresectable hepatocellular carcinoma and allows the delivery of embolics inside tumor vascularization to reduce blood supply and release gradually the drug. This lowers the systemic exposure to chemotherapeutics, while increasing their local concentration and tissue necrosis that is higher than conventional TACE. The technology of TACE has seen the introduction of several types of embolics that are made of different materials. Available embolics for TACE include: drug-eluting beads (DC beads), acrylic copolymer, tris-acrylic microspheres and polyethylene glycol (PEG) microspheres. Few studies are available on PEG embolics and their use for TACE. This review focuses on the efficacy and safety of TACE performed with PEG microspheres for the treatment of hepatocellular carcinoma and discusses future therapeutic advantages.

Chemoembolization in Conjunction with Bevacizumab: Preliminary Results.

Transarterial chemoembolization is an effective, minimally invasive therapy that is widely used for treatment of unresectable colorectal cancer liver metastases (CRC-LM). However, chemoembolization induces a hypoxic microenvironment, which increases neoangiogenesis and may promote early progression. For this reason, transarterial chemoembolization efficacy may be improved by combining it with an angiogenesis inhibitor, such as bevacizumab. This report shows that transarterial chemoembolization with irinotecan-loaded polyethylene glycol embolics and bevacizumab therapy was effective and well tolerated by 6 patients with CRC-LM, resulting in a disease control rate of 83% and an overall improvement in quality of life.

Melphalan hypoxic perfusion with hemofiltration for melanoma locoregional metastases in the pelvis.

BACKGROUND: For patients with melanoma metastases in the pelvic and groin regions, the median survival time (MST) was 8 mo with old treatments, whereas today is approximately 20 mo with new target therapy and novel immunotherapy. Unfortunately, approximately 30% of patients are nonresponsive to these new drugs. MATERIALS AND METHODS: Thirty-six patients, previously progressing after standard treatments, collectively received 146 melphalan (30 mg/m2) hypoxic pelvic perfusions with hemofiltration, in association with palliative excision in most cases. RESULTS: The median follow-up time was 15 mo. Among 36 patients, three patients were alive without evidence of disease after 62, 95, and 118 mo, respectively. Thirty-three patients died of melanoma. The overall MST was 15 mo. The 5-y survival rate was 8%. The MST was 37 mo for stage IIIB; 19 mo for stage IIIC; and 6 mo for stage IV. The MST was 11 mo for patients with ≥1 mitosis per mm2 and 20 mo for patients with <1 mitosis per mm2; 17 mo for patients who received excision and 7 mo for patients who did not receive excision; and 19.5 mo for patients who received >2 treatments and 7.5 mo for patients who received ≤2 treatments. CONCLUSIONS: Pelvic/inguinal perfusion is a safe and feasible treatment for patients with advanced melanoma. Further studies are necessary to establish if it may play a role in patients who fail current systemic therapies.

Chemoembolization Adopting Polyethylene Glycol Drug-Eluting Embolics Loaded With Doxorubicin for the Treatment of Hepatocellular Carcinoma.

OBJECTIVE: The purpose of this study is to determine the efficacy and tolerability of transarterial chemoembolization (TACE) using polyethylene glycol (PEG) drug-elutable microspheres loaded with doxorubicin for treatment of hepatocellular carcinoma (HCC). SUBJECTS AND METHODS: Forty-two patients with unresectable HCC, as determined by a tumor board, were assigned to undergo TACE and were treated with PEG drug-elutable embolics loaded with doxorubicin. Patients were prospectively enrolled and included 32 (76%) men and 10 (24%) women. Their median age was 65 years (range, 42-83 years). Patients were treated with 50 mg of doxorubicin loaded in 2 mL of PEG embolics (mean [± SD] diameter, 100 ± 25 µm) that were infused via a chemoembolization method. Data collected included previous cancer therapy, tumor size, number of lesions, history of TACE, tumor response (at 1, 3, and 6 months), type and intensity of adverse events, and quality of life (QOL) analysis. RESULTS: One month after TACE, the overall tumor response rate was 79% (50% complete response, 29% partial response, 17% stable disease, and 5% progressive disease). At 3 months, the rates were 48% for complete response, 24% for partial response, 24% for stable disease, and 3% for progressive disease. At 6 months, the rates were 43% for complete response, 19% for partial response, 29% for stable disease, and 10% for progressive disease. TACE was well tolerated by all patients, with no evidence of procedure-related complications or systemic drug-related adverse events. Fever (33%), increase in transaminase level (17%), and pain (33%) were the most frequent adverse events, and their intensity was mostly mild (grades 1 and 2). The QOL scores were 80 at 1 month, 81 at 3 months, and 82 at 6 months after TACE. CONCLUSION: These data suggest that PEG embolics are efficacious and safe for the treatment of HCC, as indicated by their good tolerability, QOL scores, and high tumor response.

Transarterial chemoembolization with DC Bead LUMI™ radiopaque beads for primary liver cancer treatment: preliminary experience.

AIM: Primary objectives of the study were to assess the safety of transarterial chemoembolization (TACE) using DC Bead LUMI™ for the treatment of hepatocellular carcinoma and beads distribution after TACE. PATIENTS/METHODS: This was a prospective observational cohort study. The study included 44 hepatocellular carcinoma patients who were treated with TACE using DC Bead LUMI. Beads distribution was monitored 1 h after TACE by CT scan. RESULTS: TACE had no intraprocedural complications. Observed side effects were of mild intensity and included pain in 5 (11%), fever in 4 (9%) and vomiting in 2 (5%) patients. Most patients (89%) reported no adverse event. Non-target distribution was observed in only two cases (5%). CONCLUSION: DC Bead LUMI allowed assessing in real time their distribution. This could prevent non-target infusion and reduce toxicity.

Does Locoregional Chemotherapy Still Matter in the Treatment of Advanced Pelvic Melanoma?

Pelvic Melanoma relapse occurs in 15% of patients with loco regional metastases, and 25% of cases do not respond to new target-therapy and/or immunotherapy. Melphalan hypoxic pelvic perfusion may, therefore, be an option for these non-responsive patients. Overall median survival time (MST), stratified for variables, including BRAF V600E mutation and eligibility for treatments with new immunotherapy drugs, was retrospectively assessed in 41 patients with pelvic melanoma loco regional metastases. They had received a total of 175 treatments with Melphalan hypoxic perfusion and cytoreductive excision. Among the 41 patients, 22 (53.7%) patients exhibited a wild-type BRAF genotype, 11 of which were not eligible for immunotherapy. The first treatment resulted in a 97.5% response-rate in the full cohort and a 100% response-rate in the 22 wild-type BRAF patients. MST was 18 months in the full sample, 20 months for the 22 wild-type BRAF patients and 21 months for the 11 wild-type BRAF patients not eligible for immunotherapy. Melphalan hypoxic perfusion is a potentially effective treatment for patients with pelvic melanoma loco regional metastases that requires confirmation in a larger multicenter study.

Genetic modulation of the interleukin 6 (IL-6) system in patients with advanced gastric cancer: a background for an alternative target therapy.

BACKGROUND: IL-6 triggers oncogenic/angiogenic signals and the cytokine-dependent pro-cachexia cascade. The prognostic role of the functional IL-6 (promoter) rs1800795 and the IL-6R (receptor) rs8192284 single nucleotide polymorphisms (SNP) was studied in patients with advanced gastric cancer treated with palliative chemotherapy. METHODS: One-hundred-sixty-one patients were genotyped for rs1800795 and rs8192284 SNPs using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) analysis assay. These results were studied for association with overall survival (OS). RESULTS: In 161 assessable patients, frequencies of rs1800795 G/G, G/C and C/C genotypes were 46%, 42% and 12%, respectively. Frequencies of rs8192284 A/A, A/C and C/C genotypes were 36%, 45% and 19%, respectively. Carriers of the rs1800795 G/G and rs8192284 C/C genotypes showed the worst OS. In the multivariate model, rs1800795 G/G (1.69 hazard ratio; 95% confidence interval 1.18-2.42), and rs8192284 C/C (1.78 hazard ratio; 95% confidence interval 1.12-2.83) confirmed an adverse prognostic impact. CONCLUSIONS: In this population, genetic variants that up-regulate the IL-6 system showed impact on OS. This findings sustain the hypothesis that anti-IL-6 compounds deserve clinical studies as novel therapeutics in the palliative treatment of cancer patients.

A phase II study of modified FOLFOX as first-line chemotherapy for metastatic gastric cancer in elderly patients with associated diseases.

BACKGROUND: Elderly patients are generally underrepresented in the study populations of combination chemotherapy trials. This study evaluates the efficacy and safety of a modified FOLFOX regimen in elderly patients with metastatic gastric cancer and presenting associated disease(s). METHODS: A total of 43 patients aged ≥70 years received oxaliplatin 85 mg/m(2) together with 6S-leucovorin 200 mg/m(2) on day 1, followed by a 46-h infusion of 5-fluorouracil 2,400 mg/m(2), every 2 weeks. Assessment of response was performed every four cycles according to RECIST criteria. RESULTS: Median patient age was 74 years (range, 70-83 years). Overall response rate was 34.9% [95% confidence interval (CI), 20.6-49.1, with 3 complete responses and 12 partial responses. Grade 3 neutropenia occurred in 4 patients (9.3%), fatigue in 3 patients (7.0%), and vomiting in 2 patients (4.6%). Grade 2 and 3 peripheral neuropathy was observed in 5 patients (11.6%) and 1 patient (2.3%), respectively. No treatment-related death was observed. Median progression-free and overall survival were 6.8 and 10.5 months, respectively. CONCLUSIONS: This modified FOLFOX regimen is an active and well-tolerated treatment for elderly patients with metastatic gastric cancer and also represents a good therapeutic option in patients with associated disease(s).

Meta-Analysis of Modulated Electro-Hyperthermia and Tumor Treating Fields in the Treatment of Glioblastomas.

BACKGROUND: Glioblastoma is one of the most difficult to treat and most aggressive brain tumors, having a poor survival rate. The use of non-invasive modulated electro-hyperthermia (mEHT) and Tumor Treating Fields (TTF) devices has been introduced in the last few decades, both of which having proven anti-tumor effects. METHODS: A meta-analysis of randomized and observational studies about mEHT and TTF was conducted. RESULTS: A total of seven and fourteen studies about mEHT and TTF were included, with a total number of 450 and 1309 cases, respectively. A 42% [95% confidence interval (95% CI): 25-59%] 1-year survival rate was found for mEHT, which was raised to 61% (95% CI: 32-89%) if only the studies conducted after 2008 were investigated. In the case of TTF, 1-year survival was 67% (95% CI: 53-81%). Subgroup analyses revealed that newly diagnosed patients might get extra benefits from the early introduction of the devices (mEHT all studies: 73% vs. 37%, p = 0.0021; mEHT studies after 2008: 73% vs. 54%, p = 0.4214; TTF studies: 83% vs. 52%, p = 0.0083), compared with recurrent glioblastoma. CONCLUSIONS: Our meta-analysis showed that both mEHT and TTF can improve glioblastoma survival, and the most benefit may be achieved in newly diagnosed cases.

Diagnostic and Therapeutic Algorithm for Appendiceal Tumors and Pseudomyxoma Peritonei: A Consensus of the Peritoneal Malignancies Oncoteam of the Italian Society of Surgical Oncology (SICO).

Aim: Pseudomyxoma peritonei (PMP) is an uncommon pathology, and its rarity causes a lack of scientific evidence, precluding the design of a prospective trial. A diagnostic and therapeutic algorithm (DTA) is necessary in order to standardize the disease treatment while balancing optimal patient management and the correct use of resources. The Consensus of the Italian Society of Surgical Oncology (SICO) Oncoteam aims at defining a diagnostic and therapeutic pathway for PMP and appendiceal primary tumors applicable in Italian healthcare. Method: The consensus panel included 10 delegated representatives of oncological referral centers for Peritoneal Surface Malignancies (PSM) affiliated to the SICO PSM Oncoteam. A list of statements regarding the DTA of patients with PMP was prepared according to recommendations based on the review of the literature and expert opinion. Results: A consensus was obtained on 33 of the 34 statements linked to the DTA; two flowcharts regarding the management of primary appendiceal cancer and peritoneal disease were approved. Conclusion: Currently, consensus has been reached on pathological classification, preoperative evaluation, cytoreductive surgery technical detail, and systemic treatment; some controversies still exist regarding the exclusion criteria for HIPEC treatment. A shared Italian model of DTA is an essential tool to ensure the appropriateness and equity of treatment for these patients.

Hyperthermia combined with chemotherapy vs chemotherapy in patients with advanced pancreatic cancer: A multicenter retrospective observational comparative study.

BACKGROUND: Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electro-hyperthermia (mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer. AIM: To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer. METHODS: This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer (stage III and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128 (59%) of them were treated with CHT (no-mEHT) and 89 (41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT. RESULTS: Median patients' age was 67 years (range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group (20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses (45% vs 24%, P = 0.0018) and a lower number of progressions (4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions. CONCLUSION: mEHT seems safe and has beneficial effects on survival and tumor response of stage III-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results.

High let-7a microRNA levels in KRAS-mutated colorectal carcinomas may rescue anti-EGFR therapy effects in patients with chemotherapy-refractory metastatic disease.

Preclinical and experimental data in vivo indicate that Lethal-7 (Let-7) microRNA downregulates KRAS with antitumor effects in the presence of activating KRAS mutations. We quantified the Let-7a isoform in KRAS-mutated colorectal carcinomas from patients who received salvage cetuximab plus irinotecan. The study population was retrospectively identified among metastatic colorectal cancer patients who underwent third-line therapy with cetuximab plus irinotecan in a period when only epidermal growth factor receptor (EGFR) expression was required for anti-EGFR therapy. In 59 patients harboring KRAS mutations, Let-7a levels were analyzed for association with overall survival (OS) and progression-free survival (PFS) times. An exploratory subgroup analysis was performed using the rs61764370 (LCS6 T>G) polymorphism that experimentally impairs Let-7 binding to KRAS mRNA. In the whole group, higher Let-7a levels were significantly associated with better survival outcomes. For the primary OS endpoint, the multivariate hazard ratio was 0.82 (95% confidence interval, 0.73-0.91; p = .01). The same findings with an accentuated positive effect of high Let-7a levels on both OS and PFS times were observed in an exploratory analysis of the 45 wild-type LCS6 patients (excluding 14 carriers of the LCS6 G allele variant). All survival associations were confirmed after excluding patients with KRAS codon 13 mutations. Among the clinicopathologic features, high Let-7a levels were associated with grade 2-3 skin toxicity (p = .002). In patients with KRAS mutations, Let-7a analysis may serve to identify subgroups of patients who may still benefit from EGFR inhibition and this may open up new perspectives for alternative treatment strategies.

Adding a combination of hydroxycitrate and lipoic acid (METABLOC™) to chemotherapy improves effectiveness against tumor development: experimental results and case report.

Altered metabolism of cancer first highlighted by Otto Warburg has a long history. Although ignored for a considerable amount of time, it is now receiving substantial attention. We recently published results obtained with a combination of two drugs, lipoic acid and hydroxycitrate, targeting metabolic enzymes particularly affected in cancer: ATP citrate lyase and pyruvate dehydrogenase kinase. This treatment was as efficient as chemotherapy in the three mouse cancer models that were tested. In this work, we asked if our drug combination could be used in conjunction with standard cytotoxic chemotherapy, in particular cisplatin, to improve basic protocol efficacy. A combination of lipoic acid and hydroxycitrate was administered to mice implanted with syngeneic cancer cells, LL/2 lung carcinoma and MBT-2 bladder carcinoma, concommitantly with classical chemotherapy (cisplatin or methotrexate). We demonstrate that the triple combination lipoic acid + hydroxycitrate + cisplatin or methotrexate is more efficient than cisplatin or methotrexate used individually or the combination of lipoic acid and hydroxycitrate administered alone. Of particular note are the results obtained in the treatment of an 80 year-old female who presented with ductal adenocarcinoma of the pancreas accompanied by liver metastases. A treatment course using gemcitabine plus α-lipoic acid and hydroxycitrate gave highly promising results. The in vivo data, coupled with the case study results, suggest a possible advantage in using a treatment targeted at cancer metabolism in association with classical chemotherapy.

Screening of well-established drugs targeting cancer metabolism: reproducibility of the efficacy of a highly effective drug combination in mice.

Alterations in metabolic pathways are known to characterize cancer. In order to suppress cancer growth, however, multiple proteins involved in these pathways have to be targeted simultaneously. We have developed a screening method to assess the best drug combination for cancer treatment based on targeting several factors implicated in tumor specific metabolism. Following a review of the literature, we identified those enzymes known to be deregulated in cancer and established a list of sixty-two drugs targeting them. These molecules are used routinely in clinical settings for diseases other than cancer. We screened a first library in vitro against four cell lines and then evaluated the most promising binary combinations in vivo against three murine syngeneic cancer models, (LL/2, Lewis lung carcinoma; B16-F10, melanoma; and MBT-2, bladder cancer). The optimum result was obtained using a combination of α-lipoic acid and hydroxycitrate (METABLOC(TM)). In this study, a third agent was added by in vivo evaluation of a large number of combinations. The addition of octreotide strongly reduced tumor development (T/C% value of 30.2 to 34.5%; P < 0.001) in the same models and prolonged animal survival (P < 0.001) as compared to cisplatin. These results were confirmed in a different laboratory setting using a human xenograft model (NCI-H69, small cell lung cancer). None of these three molecules are known to target DNA. The effectiveness of this combination in several animal models, as well as the low toxicity of these inexpensive drugs, emphasizes the necessity of rapidly setting up a clinical trial.

Sequential chemotherapy with cisplatin, leucovorin, and 5-fluorouracil followed by docetaxel in previously untreated patients with metastatic gastric cancer: a phase II study.

BACKGROUND: The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients. METHODS: Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50 mg/m(2) as a 30-min infusion on day 1, leucovorin 200 mg/m(2) in a 2-h infusion, and 5-FU 2,800 mg/m(2) in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75 mg/m(2), every 3 weeks). RESULTS: Thirty-four patients were enrolled, with an average age of 64 years (range 34-69). The main cumulative grade 3-4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9-54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6 months, respectively. CONCLUSIONS: For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.

Immune response and locoregional treatments for peritoneal carcinomatosis.

Peritoneal Carcinomatosis (PC) is considered as a terminal disease with short survival. It is treated with palliative therapies, consisting of repeated drainages and sometimes instillation of chemotherapy. Since the nineties, surgery has been combined with more effective systemic chemotherapy, intraperitoneal chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC. This combination therapy significantly increases the overall survival of selected PC patients. The understanding of how intraperitoneal chemotherapy and HIPEC can cure patients is still unclear. Experts hypothesized that the efficacy is obtained by the ability of high peritoneal drug exposure and hyperthermia to directly kill cancer cells. Several studies indicate that cancer cells death directly influences the response of the immune system. For this reason, the protective effect of intraperitoneal chemotherapy and HIPEC could be mediated by its ability to kill cancer cells in an immuno-genic way, causing an efficient anticancer immune response. In this review, we investigate the role of the innate peritoneal or locoregional therapy-induced immune response in PC therapy.