Although adding oxaliplatin to fluorouracil and leucovorin in adjuvant chemotherapy for colon cancer may improve disease-free survival, grade 3-4 sensory neuropathy also increases. To determine whether oral N-acetylcysteine is neuroprotective against oxaliplatin-induced neuropathy, we did a pilot study. Fourteen stage III colon cancer patients with 4 or more regional lymph nodes metastasis (N2 disease) receiving adjuvant biweekly oxaliplatin (85 mg/m(2)) plus weekly fluorouracil boluses and low-dose leucovorin were randomized to oral N-acetylcysteine (1,200 mg) (arm A) or placebo (arm B). Clinical neurological and electrophysiological evaluations were performed at baseline and after 4, 8, and 12 treatment cycles. Treatment-related toxicity was evaluated based on National Cancer Institute (NCI) Criteria. After four cycles of chemotherapy, seven of nine patients in arm B and two of five in arm A experienced grade 1 sensory neuropathy. After eight cycles, five experienced sensory neuropathy (grade 2-4 toxicity) in arm B; none in arm A (p<0.05). After 12 cycles, grade 2-4 sensory neuropathy was observed in eight patients in arm B, one in arm A (p<0.05). There were no significant electrophysiological changes in arm A after 4, 8, or 12 cycles of chemotherapy. We concluded that oral N-acetylcysteine reduces the incidence of oxaliplatin-induced neuropathy in colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy.

OBJECTIVE

Factors limiting the accuracy of endorectal ultrasound in staging, locally advanced primary rectal cancer after preoperative neoadjuvant radiochemotherapy (RCT) were evaluated.

METHODS

Patients (n = 84) with initial locally advanced rectal cancer (uT3/uT4) undergoing R0 resection were investigated after preoperative treatment that combined radiotherapy up to 45 Gy with two cycles of chemotherapy (5-FU and leucovorin on d 1-5 and 22-28). At 4 to 6 weeks after completion of RCT and before tumor resection, preoperative endoluminal ultrasound was performed.

RESULTS

The accuracy to predict the depth of tumor infiltration (T-category) was found to correlate with downstaging. The T-category was correctly staged before surgery in 15 of the 51 responders (29%) and in 27 of 33 nonresponders (82%), whereas misinterpretation occurred in 36 of the responders (71%) and in 6 of the nonresponders (18%) (p < 0.001). Neither tumor distance from anal verge nor tumor location correlated with the staging accuracy. Lymph node involvement was correctly assessed in 48 patients (57%). Wall invasion was correctly ascertained in 42 patients (50%), with under estimation in 11 patients (13%) and overestimation in 31 patients (37%).

CONCLUSIONS

After radiochemotherapy, endosonography does not provide a satisfactory accuracy for preoperative staging of rectal cancer. New interpretation and diagnostic criteria are needed for the prediction of treatment response.

OBJECTIVE

Primary endpoints were 1. To determine if, in the context of postoperative adjuvant therapy of pancreatic and nonpancreatic periampullary adenocarcinoma, continuous infusion (C.I.) 5-fluorouracil (5-FU) and leucovorin (Lv), combined with continuous-course external-beam radiotherapy (EBRT) to liver (23.4-27.0 Gy), regional lymph nodes (50.4-54.0 Gy) and tumor bed (50.4-57.6 Gy), followed by 4 months of C.I. 5-FU/Lv without EBRT could be given with acceptable toxicity. 2. To determine an estimate of disease-free and overall survival (DFS, OS) with this treatment in this context. Secondary endpoints were 1. To observe the effects of therapy at two different dose levels of irradiation, and 2. To observe for correlations among DFS, OS and CA 19-9 levels during therapy.

METHODS

Patients received C.I. 5-FU 200 mg/m2 and Lv 5 mg/m2 Monday through Friday during EBRT, and 4 cycles of the same chemotherapy without EBRT were planned for each 2 weeks of 4, beginning 1 month following the completion of EBRT. Therapy was to begin within 10 weeks of surgery and patients were monitored for disease recurrence, toxicity, and CA 19-9 levels before the start of EBRT/5-FU/Lv, before each cycle of C.I. 5-FU/Lv, and periodically after the completion of therapy. There were two EBRT dosage groups: Low EBRT, 23.4 Gy to the whole liver, 50.4 Gy to regional nodes and 50.4 Gy to the tumor bed; High EBRT, 27.0 Gy to the whole liver, 54.0 Gy to regional nodes, and 57.6 Gy to the tumor bed.

RESULTS

29 patients were enrolled and treated (23 with pancreatic cancer, and 6 with nonpancreatic periampullary cancer). Of these, 18 had tumor sizes>> or = 3 cm and 23 had at least one histologically involved lymph node; 6 had histologically positive resection margins. Mean time to start of EBRT/5-FU/Lv was 53 +/- 2 days following surgery. The first 18 patients were in the Low EBRT Group and the last 11 in the High EBRT Group. Toxicity was moderate and manageable, including a possible case of late radiation hepatitis. Median DFS was 8.3 months (pancreatic cancer patients 8.5 months) and OS was 14.1 months (pancreatic cancer patients 15.9 months). Among patients with pancreatic cancer, results were similar for the Low and High EBRT Groups (DFS: 8.3 vs. 8.6 months; OS: 14.4 vs. 16.9 months, respectively). With a mean follow up of 2.6 +/- 0.3 years for the surviving patients and a minimal follow-up of 2.5 years, 27 of 29 pts have relapsed and 25 pts have died. A rise in CA 19-9 levels preceded clinical relapse by 9.1 +/- 1.5 months. Time to first relapse by site showed inverse correlation with dose of radiotherapy to that site: peritoneal (5 +/- 1 month), hepatic (7 +/- 0.9 months), regional nodes/tumor bed (9.6 +/- 1.8 months). Mean postresection CA 19-9 level was 63.3 +/- 16.2 U/ml. Postresection CA 19-9 values did not correlate with survival, margin status, or with the identification of metastatic carcinoma in resected lymph nodes. However, among patients with histologically involved nodes in the resected specimen, postresection CA 19-9 values did correlate with the number of positive nodes identified (p = 0.05).

CONCLUSIONS

Although toxicity was acceptable, survival results were not improved over those seen with standard adjuvant treatment. Most patients relapsed before the planned chemotherapy cycles were completed, or within 100 days thereof, suggesting disease resistance to C.I. 5-FU/Lv as used in this study. Although this regimen is not recommended for further study, the doses of EBRT utilized may be suitable for evaluation with other chemotherapy combinations. Postoperative CA 19-9 levels did not correlate with survival, but did correlate with the number of histologically involved lymph nodes found in the resected specimen among node-positive patients. Moreover, rising CA 19-9 levels anticipated ultimate clinical failure by 9 months.

Thirteen patients with primary lymphoma of the central nervous system (CNS) were treated with high-dose intravenous methotrexate (MTX), 3.5 gm/sq m, followed by calcium leucovorin rescue, at 3-week intervals, for three cycles. Eleven patients subsequently received radiation therapy to the whole brain, 30 to 44 Gy. Before radiation therapy, eight patients responded completely and four partially; there was one non-responder. The median Karnofsky score before high-dose MTX therapy was 60 and increased to 90 after treatment. Five of the eight complete responders reached a Karnofsky rating of 100. The three longest responders (one of whom received MTX only) were without recurrence of their disease at 29+, 32, and 32+ months posttherapy. The median response period is 9+ months. The median survival time from the date of the first MTX treatment is 9+ months, and the three longest survival times are 29+, 32+, and 54+ months. All patients received corticosteroids in either unchanging or diminishing dosages during therapy. It is concluded that primary CNS lymphoma is sensitive to high-dose MTX, which provides a safe and easily administered adjuvant to radiation therapy for this neoplasm.

Seventy-nine patients with advanced, measurable, metastatic colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either fluorouracil (FUra) administered intravenously at a dose of 370 mg/m2/d for 5 days or the combination of FUra in the same dose and schedule with high-dose continuous infusion leucovorin calcium (500 mg/m2/d) beginning 24 hours before the first dose of FUra and continuing for 12 hours after the completion of FUra therapy. Patients whose disease progressed on treatment with FUra alone were, if eligible, crossed over to receive leucovorin and FUra. Three patients on the FUra plus leucovorin arm of the study were excluded from the analysis because they did not meet eligibility requirements. The treatment arms were well balanced for prognostic criteria including performance status, age, prior radiotherapy, distribution of metastatic sites, and on-study carcinoembryonic antigen (CEA), lactic dehydrogenase, and serum albumin. FUra plus leucovorin was superior to FUra alone for response (P = .0019) and for time to progression or death (log-rank, P = .045). Response rates were 16 of 36 (44%) versus five of 40 (13%), and median time to progression or death was 164 versus 120 days in the two arms of the trial, respectively. Overall survival, however, while longer in the FUra and leucovorin arm was not significantly so. An analysis of the toxicities experienced by the patients in the two treatment groups showed that, except for significantly more stomatitis in the leucovorin arm of the study, the side effects experienced by patients treated with either regimen were comparable. These results suggest that the efficacy of FUra in patients with advanced, measurable, metastatic colorectal cancer can be enhanced significantly by administration of a continuous high-dose infusion of leucovorin calcium.

Mechanisms of resistance to 5-fluorouracil (FUra) were compared between a cell line resistant to a short-term exposure (4 h) to this agent (HCT-8/FU4hR) and a cell line resistant to a prolonged exposure (7 days) to the fluoropyrimidine (HCT-8/FU7dR). The two cell lines were obtained by repeatedly exposing 2 x 10(5) cells to a constant concentration of FUra (1000 microM for 4 h or 15 microM for 7 days), able to produce 3-4 logs of cell kill. HCT-8/FU4hR cells were still sensitive to FUra given as a 7-day exposure, suggesting different mechanisms of resistance. In addition, HCT-8/FU7dR cells were cross-resistant to fluorodeoxyuridine and, to a lesser degree, methotrexate; while HCT-8/FU4dR cells were not. Both HCT-8/FU4hR and HCT-8/FU7dR cells were similar to parental HCT-8 cells with regard to uptake of FUra as well as the pattern of FUra-metabolizing and FUra target enzymes. Although neither in situ thymidylate synthase (TS) activity nor the degree of its inhibition by FUra showed any evidence of alteration in HCT-8/FU7dR cells, a rapid recovery of TS activity after drug removal was evident in this cell line. The addition of as much as 100 microM leucovorin did not completely inhibit the recovery of thymidylate synthesis after FUra exposure. No differences were detected in the kinetic properties (Km for 2'-deoxyuridylate and 5,10-methylenetetrahydrofolate, concentration producing 50% inhibition for fluorodeoxyuridylate) or TS from HCT-8/FU7dR cells as compared to parental HCT-8 TS. Baseline levels of 5,10 methylenetetrahydrofolate were decreased in HCT-8/FU7dR cells, and analysis of the chain length distribution of the polyglutamylated form of the folate cofactor showed that in this cell line the defect in 5,10-methylenetetrahydrofolate levels is accompanied by, and possibly due to, a defect in the polyglutamylation of this cofactor. In contrast, HCT-8/FU4hR cells were similar to the parental cell line with regard to both the degree of in situ TS inhibition by FUra and duration of inhibition after FUra removal. Labeling studies with [3H-6]FUra (4 h exposure, 100 microM) showed that the incorporation of the fluoropyrimidine into RNA is significantly decreased in HCT-8/FU4hR cells as compared to parental HCT-8 cells.(ABSTRACT TRUNCATED AT 400 WORDS)

OBJECTIVE

To determine the feasibility, recommended doses, plasma pharmacokinetics, and antitumor activity of a biweekly chemotherapy regimen with oxaliplatin (L-OHP), irinotecan (CPT-11), infusional fluorouracil (5-FU), and leucovorin (LV) in metastatic colorectal cancer patients.

METHODS

Patients received CPT-11 followed by L-OHP and LV 200 mg/m(2) and followed by 5-FU 3,800 mg/m(2) as a 48-hour infusion, repeated every 2 weeks. In the first part of the study, an escalation of CPT-11 dose and/or a decrease of the L-OHP dose were planned. Once the recommended doses of CPT-11 and L-OHP were determined, all subsequent patients were treated at the recommended doses.

RESULTS

Forty-two patients entered the study. CPT-11 175 mg/m(2) and L-OHP 100 mg/m(2) in combination with LV 200 mg/m(2) and 5-FU 3,800 mg/m(2) could be administered with acceptable toxicities; 39 patients were treated at these dose levels. The pharmacokinetics parameters of the agents used and their metabolites did not seem to be influenced by the concomitant use of the other drugs. The most relevant toxicities were diarrhea and neutropenia, with 14% of patients experiencing one episode of febrile neutropenia. In five patients (11.9%) a complete and in 25 (59.5%) a partial response was demonstrated, for an objective response rate of 71.4% (95% confidence interval, 47% to 83%). In 11 patients (26%), a surgical resection of residual disease could be performed. Median progression-free and overall survival times were 10.4 and 26.5 months, respectively.

CONCLUSIONS

This biweekly regimen is feasible and has acceptable and manageable toxicities and no apparent relevant pharmacokinetics interactions. This combination is associated with a promising antitumor activity, time to progression, and survival. A phase III randomized trial in Italy planned by the Gruppo Oncologico Nord Ovest has just started.

Oxaliplatin (trans-L-diaminocyclohexane oxalatoplatinum, L-OHP) is a novel cisplatin derivative that can improve the side effects of cisplatin such as toxicity to the kidneys and peripheral nerve system. However, L-OHP is effective only when combined with 5-Fluorouracil (5-FU) and Leucovorin. The relatively low anti-tumor index of L-OHP alone is because low levels accumulate in tumor tissues due to high partitioning to erythrocytes in vivo. A successful outcome of cancer therapy using L-OHP requires the selective delivery of a relatively high concentration of the drug to tumors. The present study examines tumor-selective delivery of L-OHP using liposomes modified with transferrin-conjugated polyethyleneglycol (TF-PEG-liposomes). Delivery using these liposomes significantly reduced L-OHP partitioning to erythrocytes and improved the circulation time of L-OHP in vivo, resulting in enhanced extravasation of liposomes into tumors. The TF-PEG-liposomes maintained a high L-OHP concentration in tumors for over 72 h after intravenous injection, which was longer than that of the liposomes modified with PEG (PEG-liposomes). Intravenously administered L-OHP encapsulated within TF-PEG-liposomes (L-OHP: 5 mg/kg) suppressed tumor growth more effectively than PEG-liposomes, Bare-liposomes and free L-OHP. Although L-OHP is usually combined with 5-FU and Leucovorin, our results suggest that L-OHP encapsulated within TF-PEG-liposomes has potential for cancer therapy.

Our understanding of anticancer pharmacodynamics, and the relationships between pharmacologic measurements and clinical effects, has grown markedly in recent years due to advances in analytical and computational technology. Although methotrexate plasma levels have been empirically used to guide leucovorin dosing during high-dose methotrexate therapy, there has been no other standard use of therapeutic drug monitoring in oncology. More recently, investigators have attempted to titrate precisely the dose of antineoplastic agents based on previously derived models and real-time analysis of plasma drug or tissue concentrations. Studies have been completed or are in progress using hexamethylene bisacetamide, etoposide, teniposide, fluorouracil (FUra), and cytarabine (ara-C). Future studies will focus on optimal sampling strategies, analysis of intermediate biochemical end points, combination chemotherapy, modulation by colony-stimulating factors, and more sophisticated pharmacodynamic models.

Oxaliplatin is the first clinically available diaminocyclohexane platinum coordination complex. The drug is non-cross-resistant with cisplatin or carboplatin and is one of the few active drugs against human colorectal cancer. Its cytotoxicity is synergistic with fluorouracil and folinic acid (leucovorin), the reference treatment for this disease. The main cumulative dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy. The drug can also produce diarrhoea, vomiting and haematological suppression. Unlike cisplatin, no renal failure or peripheral motor neuropathy have been reported and the sensory neuropathy is partly reversible. Unlike carboplatin, oxaliplatin produces only mild to moderate haematological toxicity. Oxaliplatin undergoes biotransformation into aquated forms in the blood, where 3 species can be found: total platinum, ultrafilterable or 'free' platinum and erythrocyte platinum. Flameless atomic absorption (FAAS) is used for assaying platinum concentration in various tissues. Inductively-coupled plasma mass spectrometry (ICP-MS), with a >10-fold lower sensitivity threshold than FAAS, was also used for the determination of oxaliplatin pharmacokinetics. The pharmacokinetics of oxaliplatin are described by a 3-compartment model. The drug rapidly crosses the cellular membrane as a result of its lipophilicity. Hence, at the end of a 2-hour infusion, approximately 40% of the blood platinum is found in erythrocytes. The distribution half-life of ultrafiltrated plasma platinum ranges from 10 to 25 minutes and its terminal elimination half-life is 26 hours (determined with FAAS) or 270 hours (ICP-MS). The elimination half-life of erythrocytic platinum is 12 to 50 days, close to that of erythrocytes. 30 to 50% of the platinum is recovered in the urine within 2 to 5 days, with renal clearance accounting for half of the total clearance of ultrafiltrated platinum. The total clearance of this species is correlated with the glomerular filtration rate. No pharmacokinetic-pharmacodynamic relationship has been established for oxaliplatin. Pharmacokinetic alterations produced by fluorouracil + folinic acid or irinotecan were minimal if any. The prolonged stability of oxaliplatin makes it suitable for continuous infusions over 4 to 5 days, with a delivery rate which can be either constant or chronomodulated (peak rate at 1600h), using programmable ambulatory pumps. Chronomodulation significantly reduces toxicity and improves antitumour activity as compared with constant rate infusion. These differences in pharmacodynamic properties were paralleled by differences in plasma concentration time courses. The different drug concentration profiles achieved with different infusional modalities may be useful tools for understanding the relationship between the pharmacokinetics and pharmacodynamics of oxaliplatin and may lead to further optimisation of its administration schedule and its combination with other drugs.

BACKGROUND

Triplet chemotherapy has demonstrated manageable toxicities and a favorable response rate. The addition of cetuximab to chemotherapy can increase treatment efficacy. We evaluated the efficacy and safety of cetuximab plus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), the ERBIRINOX regimen, as first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC).

METHODS

In a phase II study, treatment consisted of weekly cetuximab plus biweekly. Treatment was continued for a maximum of 12 cycles and tumor response was evaluated every four cycles. The primary efficacy criterion was the complete response (CR) rate.

RESULTS

From April 2006 to April 2008, 42 patients were enrolled. The median age was 60 years (range, 32-76 years). The median duration of treatment was 5.2 months (range, 0.7-8.5 months), and a median of nine cycles was given per patient (range, 1-12 cycles). Five patients (11.9%) showed a CR, with a median duration of 23.1 months (95% confidence interval [CI], 10.8-39.7 months). The objective response rate was 80.9% (95% CI, 65.9%-91.4%). The median overall and progression-free survival times were 24.7 months (95% CI, 22.6 months to not reached) and 9.5 months (95% CI, 7.6-10.4 months), respectively. The most frequent grade 3-4 adverse events were diarrhea (52%), neutropenia (38%), and asthenia (32%).

CONCLUSIONS

The ERBIRINOX regimen appears to be effective and feasible in first-line treatment of mCRC patients. These promising results led us to initiate a multicenter, randomized, phase II trial ([Research Partnership for Digestive Oncology] PRODIGE 14) in patients with potentially resectable mCRC.

OBJECTIVE

To investigate the gefitinib, fluorouracil (FU), leucovorin, and oxaliplatin regimen (IFOX) in previously treated patients with metastatic colorectal cancer.

METHODS

Eligible patients had stage IV colorectal adenocarcinoma and had demonstrated progression or intolerance to a prior chemotherapy regimen not including oxaliplatin. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin 85 mg/m2 intravenously (IV) during 2 hours on day 1, hours 0 to 2; leucovorin 200 mg/m2 IV on days 1 and 2, hours 0 to 2; FU 400 mg/m2 IV push on days 1 and 2; and FU 600 mg/m2 IV on days 1 and 2, hours 2 to 24 (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg/d administered orally throughout the 14-day cycle.

RESULTS

Twenty-seven patients were enrolled onto the study. The median number of prior chemotherapy regimens was two, and 74% of all patients received prior irinotecan. Nine of the 27 patients (33%) and six of the 20 patients (30%) who had prior FU and irinotecan had a partial response by Response Evaluation Criteria in Solid Tumors Group criteria. Median overall survival was 12.0 months. Median event-free survival was 5.4 months. Grade 3 to 4 toxicities included neutropenia (48%), diarrhea (48%), nausea (22%), and vomiting (15%).

CONCLUSIONS

IFOX is an active regimen in patients with previously treated metastatic colorectal adenocarcinoma, demonstrating higher response rates than those reported with FOLFOX-4 alone in a similar patient population.

OBJECTIVE

The use of neoadjuvant chemotherapy can enable surgical resection of borderline resectable or unresectable pancreatic cancer (PC). The aim of this study was to evaluate the effectiveness of the multiagent 5-fluorouracil + oxaliplatin + irinotecan + leucovorin (FOLFIRINOX) regimen as a neoadjuvant treatment for PC.

METHODS

Studies in which FOLFIRINOX with or without radiotherapy was given before surgery to patients with borderline resectable or unresectable PC were analyzed using a meta-analytical approach. The primary outcomes were resection rate and radical (R0) resection rate. Data were expressed as weighted pooled proportions with 95% confidence intervals (CIs).

RESULTS

Thirteen studies, with a total of 253 patients, were included in this meta-analysis. After undergoing the treatment, 43% (95% CI, 32.8-53.8) of patients were resected and 39.4% (95% CI, 32.4-46.9) underwent R0 resection (85% of surgical specimens). In particular, among borderline resectable PCs, R0 resection was possible in 63.5% (95% CI, 49%-76%) of the cases. The rate of R0 resection in unresectable PCs was 22.5% (95% CI, 13.3-35.4).

CONCLUSIONS

This meta-analysis shows that down-staging after neoadjuvant FOLFIRINOX-based therapy is noticeable in patients with borderline resectable/unresectable PC, with a total R0 resection rate of 40%.

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5'UTR and 3'UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3-4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.

Pancreatic ductal adenocarcinoma is characterized by a poor prognosis and a low median survival, despite improvements observed for many other solid tumours. Intensive research efforts have been undertaken during the last decades to discover new prognostic and treatment predictive biomarkers for pancreatic ductal adenocarcinoma. The mainstay of medical treatment for the disease has been the well-tolerated nucleoside analogue, gemcitabine. The only targeted agent currently used in pancreatic ductal adenocarcinoma patients is the epithelial growth factor receptor inhibitor erlotinib in combination with gemcitabine. Recently, treatment regimens such as a combination of fluorouracil-leucovorin-irinotecan-oxaliplatin (FOLFIRINOX) and the combination of nab-paclitaxel with gemcitabine have been introduced for metastatic pancreatic ductal adenocarcinoma. Although these treatment regimens significantly improve survival of patients, there are no good predictive biomarkers available that can be used to identify who would benefit most from them. Therefore, the search for predictive biomarkers that would facilitate personalization of chemotherapy is highly relevant.

Pancreatic cancer is the fourth leading cause of cancer death in the US and is expected to become the second leading cause of cancer-related deaths in the next decade. Despite 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel significantly improving outcomes for metastatic cancer, refractory disease still poses significant challenges. Difficulties with early detection and the inherent chemo- and radio-resistant nature of this malignancy led to attempts to define the sequential biology of pancreatic cancer in order to improve survival outcomes. Pancreatic adenocarcinoma is characterized by several germline or acquired genetic mutations, the most common being KRAS (90%), CDK2NA (90%), TP53 (75%-90%), DPC4/SMAD4 (50%). In addition, the tumor microenvironment, chemoresistant cancer stem cells, and the desmoplastic stroma have been the target of some promising clinical investigations. Among the core pathways reproducibly shown to lead the development and progression of this disease, DNA repair, apoptosis, G1/S cell cycle transition, KRAS, Wnt, Notch, Hedgehog, TGF-beta, and other cell invasion pathways, have been the target of "precision therapeutics". No single molecularly targeted therapeutic though has been uniformly successful, probably due to the tumor heterogeneity, but biomarker research is evolving and it hopes to select more patients likely to benefit. Recent reports note activity with immunotherapies such as CD40 agonists, CCR2 inhibitors, cancer vaccines, and novel combinations against the immunosuppressive tumor milieu are ongoing. While many obstacles still exist, clearly we are making progress in deciphering the heterogeneity within pancreatic cancers. Integrating conventional and immunological targeting will be the key to effective treatment of this deadly disease.

The clinical relevance of circadian rhythm modifications in patients on chemotherapy is unknown. Even so, circadian parameter I<O before chemotherapy independently predicted overall survival. This study investigates the relevance of I<O measured during chemotherapy for survival and symptoms. The circadian rest-activity pattern was monitored for 3 days using a wristwatch actigraph while 77 patients were receiving a chemotherapy course within an international randomized Phase III trial. Treatment consisted of first-line chronomodulated or conventional delivery of 5-fluorouracil, <em>leucovorin</em> and oxaliplatin for metastatic colorectal cancer. I<O was computed as the percentage of minutes of activity counts in bed which were below the median of activity out of bed. Circadian disruption was defined by I<O equal to or less than 97.5%. Circadian disruption occurred in 39 patients (51%) on chemotherapy. It was associated with a significantly shorter overall survival, independently of other prognostic factors (multivariate Hazard Ratio: 2.12; p = 0.004). The median survival of patients with a robust circadian rhythm was 22.3 months as compared to 14.7 months in those with circadian disruption during chemotherapy. No toxicity was significantly associated with circadian disruption, but the incidence of grade ≥ 2 fatigue and of body weight loss ≥ 5% was two and threefold higher, respectively, in patients with disrupted circadian rhythm on chemotherapy. Chemotherapy disrupted circadian activity rhythm in nearly 50% of the patients. Circadian disruption on chemotherapy predicted for shorter overall survival. The prevention of chemotherapy-induced circadian disruption might reduce toxicity and improve efficacy in cancer patients.

OBJECTIVE

To evaluate the effect of adjuvant chemotherapy (ACT) in locally advanced rectal cancer (LARC) after neoadjuvant chemoradiation (NACT-RT). The study was funded by the Italian National Research Council (CNR).

METHODS

From September 1992 to January 2001, 655 patients with LARC (clinically T3-4, any N) treated with NACT-RT and surgery, were randomized in two arms: follow-up (Arm A) or 6 cycles of ACT with 5 fluorouracil (5FU)-Folinic Acid (Arm B). NACT-RT consisted of 45Gy/28/ff concurrent with 5FU (350mg/sqm) and Folinic Acid (20mg/sqm) on days 1-5 and 29-33; surgery was performed after 4-6weeks. Median follow up was 63·7months. Primary end point was overall survival (OS).

RESULTS

634/655 patients were evaluable (Arm A 310, Arm B 324); 92·5% of Arm A and 91% of Arm B patients received the preoperative treatment as in the protocol; 294 patients of Arm A (94·8%) and 296 of Arm B (91·3%) underwent a radical resection; complete pathologic response and overall downstaging rates did not show any significant difference in the two arms. 83/297 (28%) patients in Arm B, never started ACT. Five year OS and DFS did not show any significant difference in the two treatment arms. Distant metastases occurred in 62 patients (21%) in Arm A and in 58 (19·6%) in Arm B.

CONCLUSIONS

In patients with LARC treated with NACT-RT, the addition of ACT did not improve 5year OS and DFS and had no impact on the distant metastasis rate.

Gastric cancer (GC) is still the third leading cause of cancer death in both sexes worldwide. Helicobacter pylori infection is the most important risk factor for GC and, in spite of the consistent trend of a decreasing incidence, in 2015 approximately 4.4 billion individuals-more than half the world's population-were infected with H. pylori. The birth cohort pattern of decreased H. pylori infection reported in a systematic review contributes to explain the declining GC mortality in Japan. Current trends in estimated annual percentage change of GC incidence foreshadow expected reversals in both falling incidence and male predominance among US non-Hispanic whites. Combining serum pepsinogen 1 and H. pylori serology was shown to be useful for GC risk stratification in a Finnish population. Gastritis staging by operative link on gastritis assessment was confirmed to be reliable in predicting GC risk in a large prospective study. In a randomized trial from South Korea, H. pylori eradication therapy significantly reduced the rates of metachronous GC in patients who received curative endoscopic resection for early GC. A study based on a territory-wide health care database of the Hong Kong Hospital Authority showed that aspirin use is associated with a reduced GC risk. Another study based on the same database showed that proton pump inhibitors increase GC risk, but methodological biases have most likely acted as confounders. Confirmatory data on the role of endoscopic submucosal dissection in patients with early GC have been published. The phase III FLOT4 trial has shown that the FLOT triplet regimen (docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil) improves the outcome of patients with GC and locoregional disease as compared to the ECF triplet (epirubicin, cisplatin, and 5-fluorouracil). In the phase III ATTRACTION-2 trial, nivolumab was shown to be an effective treatment option with a relative safe profile for heavily pretreated patients with advanced GC.

Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance.

OBJECTIVE

To examine retrospectively whether levels of epidermal growth factor receptor (EGFR) expression can predict tumor downstaging after preoperative chemoradiotherapy in patients with locally advanced rectal cancer.

METHODS

A total of 183 patients with rectal cancer (cT3-T4 or N+) were enrolled in this study. Preoperative chemoradiotherapy consisted of 50.4 Gy of pelvic radiation with concurrent 5-fluorouracil and leucovorin bolus intravenous chemotherapy in 94 patients or oral capecitabine and leucovorin in 89 patients. EGFR expression in pretreatment paraffin-embedded tumor biopsy specimens was assessed by immunohistochemistry. EGFR expression was determined from the intensity and extent of staining. Tumor downstaging was defined as a reduction of at least one T-stage level.

RESULTS

Tumor downstaging occurred in 97 patients (53%), and the tumors showed a pathologic complete response in 27 patients (15%). Positive EGFR expression was observed in 140 (76%) of 183 patients. EGFR expression levels were low in 113 patients (62%) and high in 70 patients (38%). On logistic regression analysis, the significant predictive factor for increased tumor downstaging was a low level of EGFR expression and preoperative chemotherapy using oral capecitabine (odds ratio, 0.437; p = 0.012 vs. odds ratio, 3.235; p < 0.001, respectively).

CONCLUSIONS

A high level of EGFR expression may be a significant predictive molecular marker for decreased tumor downstaging after preoperative chemoradiotherapy in locally advanced rectal cancer.

To address the problem of historically poor results in the treatment of children with advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia (ALL), an intensive chemotherapy regimen was devised using the most effective single agents in high-dose short courses. Treatment commenced with a fractionated schedule of intravenous (IV) cyclophosphamide (300 mg/m2 every 12 hours for six doses) followed immediately by Adriamycin (50 mg/m2) and vincristine (1.5 mg/m2) with combined intrathecal (IT) methotrexate and cytarabine. Predictably, this treatment produced virtually complete disappearance of all tumor and profound myelosuppression. Immediately on hematologic recovery, IV high-dose methotrexate (1,000 mg/m2 over 24 hours) followed by IV cytarabine (400 mg/m2 over the next 48 hours) was administered with leucovorin rescue and repeated IT treatments. The treatment sequence described above is repeated four times, with the dose of cytarabine doubled in succeeding courses, up to 3,200 mg/m2. The entire planned therapy required approximately 24 weeks. Since 1981, we treated a total of 29 children with this approach, 19 of whom had massive unresectable intraabdominal tumor. According to initial extent of disease, 17 were classified as stage III, four as stage IV non-Hodgkin's lymphoma (NHL), and eight as B cell ALL. Eight of the 12 patients with stage IV NHL or B cell ALL had initial involvement of the CNS. Twenty-seven of 29 patients (93%) attained a complete remission. Fourteen of 17 stage III NHL patients remain disease free, for periods ranging from 3+ months to 4 1/2+ years. The actuarial estimate of the proportion of stage III patients remaining disease free at 2 years is 81%. Results in patients with initial involvement of the CNS and/or marrow are much less favorable, with only two of ten patients who attained remission apparently being cured. In addition to stage, the initial serum lactic dehydrogenase (LDH) level emerged as a prognostic indicator, higher levels (over 1,000 IU/L) being associated with the worst prognosis (P less than .05). Major toxicity consisted of severe hematopoietic suppression and febrile episodes associated with neutropenia. We conclude that this treatment is highly effective for advanced-stage Burkitt's tumors in children free of initial CNS involvement.

OBJECTIVE

A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial.

METHODS

Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined.

RESULTS

A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a>> or = 50% dose increase.

CONCLUSIONS

Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.

The effect of methotrexate (MTX) and leucovorin (LCV) on pentose cycle enzymes and the activity of enzymes involved in enzyme defence mechanisms against ROS in HeLa cells, were studied. The effect of MTX was also investigated on the cellular levels of glutathione. MTX inhibited the activity of glucose-6-phosphate and 6-phosphogluconate dehydrogenases. The activities of glutathione reductase and gamma-glutamylcysteine synthetase were also inhibited by the drug. No effect was observed on the activities of catalase, superoxide dismutase or transketolase. LCV had no effect on any of the enzymes studied. MTX decreased the cellular levels of glutathione (70 per cent), while the presence of LCV and glutamine did not interfere with the effect of MTX. The net results appear to show that the biological situation resulting from treatment with MTX leads to a reduction of effectiveness of the antioxidant enzyme defence system.