5-fluorouracil Therapy Research Articles

PS02.189: A STUDY ON PRETREATMENT NUTRITIONAL SCORE OF ESOPHAGEAL CANCER PATIENTS WHO UNDERWENT PREOPERATIVE TREATMENT

Abstract Background Esophageal cancer tends to be malnourished due to anorexia, transit disorder, so it is important to conduct sufficient nutritional assessment and treatment. For standard treatment of neoadjuvant chemotherapy for esophageal cancer, Cisplatin + 5-fluorouracil (FP) therapy is common, but sufficient therapeutic effect has not been obtained. As a more powerful regimen, DCF therapy with Docetaxel added to FP therapy and chemoradiotherapy have been introduced. In this study, we examined pretreatment nutritional score of esophageal cancer patients who underwent neoadjuvant therapy. Methods We studied 105 patients undergoing preoperative treatment diagnosed as esophageal cancer or esophagogastric junctional carcinoma from July 2012 to August 2017. Esophagectomy with lymph node dissection after neoadjuvant therapy. Relationship between Glassgow Prognostic Score (GPS) and Controlling Nutrition Status Score (CONUT) score, sex, age, staging, main tumor location, adverse event, postoperative complication and tube feeding nutrition are examined. Results Median age was 66 years, male/female = 92/13, and cases requiring tube feeding were 29 cases. The breakdown of the clinical stage is Stage IA, B/IIA, B/IIIA, B, C/IV = 9/34/50/12. The breakdown of neoadjuvant therapy is FP/DCF/FPRT/DCFRT/other = 9/27/26/39/4. The incidences of grade 3/4 adverse events during preoperative treatment were 66 cases (63%) in 105 patients. The treatment effect is CR/PR/SD/PD = 6/41/50/8. Histopathological result is Grade 0/1a/1b/2/3 = 3/52/13/6/31. Postoperative complications were Clavien-Dindo classification Grade IIIa or more in 20 cases, in-hospital death was 1 case.CONUT score was judged to be cut-off by more than 2, there was a significant relationship between presence of tube nutrition and treatment result (P = 0.0376, 0.0231). GPS was judged to be 1 or more cutoff, there was a significant association with tube nutrition availability and histopathological result (P = 0.0019, 0.0083). There was no significant difference between occurrence of adverse events and occurrence of postoperative complications. Conclusion It was suggested that CONUTscore and GPS at hospitalization are useful as predictors of treatment result and histopathological result in esophageal cancer patients who undergo neoadjuvant therapy. Disclosure All authors have declared no conflicts of interest.

PS02.122: PREOPERATIVE CHEMOTHERAPY WITH BIWEEKLY DOCETAXEL, CISPLATIN, AND 5-FLUOROURACIL FOR ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy can have severe adverse events, including neutropenia and febrile neutropenia. Feasibility of DCF is a concern especially for elderly patients, patients with moderate organ disorder, and those with dysphagia or insufficient oral intake causing malnutrition. We introduced biweekly DCF therapy (bDCF) for the purpose of reducing severe adverse events for these fragile patients. This study investigated the feasibility and efficacy of bDCF therapy for patients with advanced esophageal squamous cell carcinoma who underwent radical esophagectomy after chemotherapy. Methods The parent DCF regimen consisted of 60–70 mg/m2 of docetaxel on day 1, administered intravenously for 2 h; 80 mg/m2 of cisplatin on day 1, administered intravenously for 2 h; and 5-fluorouracil administered by continuous infusion at a dose of 800 mg/m2 on days 1–5. The DCF regimen was repeated every 3–4 weeks. The bDCF regimen consisted of docetaxel (30 mg/m2) on days 1 and 15 in combination with cisplatin (80 mg/m2 on day 1) and 5-fluorouracil (800 mg/m2 on days 1–5), repeated every 4 weeks. Results Thirty-seven patients were treated with the DCF regimen (DCF group) and 22 patients were treated with the bDCF regimen (bDCF group). The age of patients was significantly higher in the bDCF group than in the DCF group. The bDCF group had more patients with heart and pulmonary comorbidities. Biweekly DCF group was significantly higher in the clinical response rate (DCF group 62.2% vs. bDCF group 86.4%, P = 0.0472). Grade 3 or 4 neutropenia was less frequent in the bDCF group (40.9%) than in the pDCF group (81.1%) (P = 0.0016). Among non-hematologic toxicities, anorexia was less frequent in the bDCF group (0%) than in the pDCF group (18.9%) (P = 0.0298). There were no significant differences between the groups in postoperative morbidity rate (bDCF group 45.5% vs. pDCF group 32.4%). Conclusion Preoperative bDCF therapy was feasible and safety without reduction of the efficacy of DCF therapy for fragile patients such as elderly patients, patients with moderate functional disorder, and that with malnutrition caused by dysphagia or insufficient oral intake. Disclosure All authors have declared no conflicts of interest.

Outcomes of esophagectomy after chemotherapy with biweekly docetaxel plus cisplatin and fluorouracil for advanced esophageal cancer: a retrospective cohort analysis

BackgroundDocetaxel, cisplatin, and 5-fluorouracil (DCF) therapy can cause severe adverse events, including neutropenia and febrile neutropenia. The feasibility of DCF therapy is a concern, particularly for elderly patients, patients with moderate organ disorders, and patients suffering from malnutrition caused by dysphagia or insufficient oral intake. We introduced a biweekly DCF therapy (bDCF) for the purpose of reducing severe adverse events for these fragile patients. This study investigated the feasibility and outcome of an esophagectomy after bDCF therapy for patients with advanced esophageal squamous cell carcinoma.MethodsFifty-nine patients with esophageal carcinoma underwent an esophagectomy after DCF or bDCF therapy as primary chemotherapy. DCF was administered to 37 patients in the DCF group, whereas bDCF was administered to 22 patients in the bDCF group.ResultsPatients in the bDCF group were significantly older than those in the DCF group (p = 0.016). Heart and pulmonary comorbidities were significantly more common in the bDCF than in the DCF group (p < 0.001 and p = 0.039, respectively). Grade 3 or 4 neutropenia was less frequent in the bDCF than in the DCF group (40.9 vs. 81.1%, p = 0.002). Anorexia was more frequent in the DCF group than in the bDCF group (18.9 vs. 0%, p = 0.030). The clinical response rate of the bDCF group was significantly higher than that of the DCF group (86.4 vs. 62.2%, p = 0.047). There was no significant between-group difference in the postoperative morbidity rate (bDCF 45.5% vs. DCF 32.4%) or in the histological therapeutic effect.ConclusionThe results demonstrate that primary bDCF therapy for high-risk patients with advanced esophageal cancer is feasible and safe in both chemotherapeutic and perioperative periods without a reduction in the efficacy of DCF therapy.

Highlights of This Issue

Actinic keratoses (AK) are very common premalignant skin lesions (presquamous cell carcinoma) in patients with chronic sun damage. Recently, physicians have been empirically combining two treatment approaches, topical 5-fluorouracil (5FU) and photodynamic therapy (PDT), but without any scientific basis. In a mechanistic clinical study using surface fluorimetry and skin biopsies, Maytin and colleagues show that sequential 5FU and PDT improves AK clearance by upregulating mitochondrial heme enzymes, increasing target photosensitizer (protoporphyrin IX) expression, and increasing proapoptotic p53. The results provide a scientific rationale for combining two FDA-approved treatments in an effective, practical approach that reduces cutaneous precancer burden.Besides therapeutically targetable mutations in signal transduction pathways, mutations related to the KEAP1/NRF2-pathway are involved in malignant transformation in various cancers, including lung cancer. Based on the NGS-analysis of a large cohort of NSCLC patients, Frank and colleagues show that mutations in KEAP1 and NRF2 occurred nearly mutually exclusive even though strongly linked functionally. They are also associated with different histologies, clinical characteristics, and co-occurring molecular aberrations. Thus, patients with KEAP1- or NRF2-mutations are a heterogenous group. This work argues against a driver function of these mutations but suggests a pivotal role in chemotherapy resistance.Around 50% of non-small cell lung cancer (NSCLC) patients receiving first-generation EGFR inhibitors develop resistance by T790M mutation. Osimertinib has proven effective in overcoming T790M mutation; however, resistance inevitably develops. Yang and colleagues surveyed 416 cancer-related genes in 93 NSCLC patients who progressed on osimertinib by next-generation sequencing (NGS). EGFR mutation on G796/C797, L792 or L718/G719 residues were identified in approximately 1/3 of the patients; further, resistance mechanisms were functionally studied in vitro. In EGFR nonmutated patients, MET, KRAS, and PIK3CA mutations were discovered. This study uncovers novel osimertinib-resistant mechanisms using cell-free DNA-based liquid biopsy and provides grounds for future therapeutic strategies.Dysregulated zinc transport is involved in many malignancies, including pancreatic cancer, and it promotes tumor growth. To further understand the mechanism of zinc transporter-mediated cancer progression, Liu and colleagues used genetic inactivation and rescue assays in human pancreatic cancer cells and mouse models to demonstrate that a zinc importer ZIP4 promotes pancreatic cancer migration and invasion through decreasing ZO-1 and claudin-1 via activation of ZEB1, leading to upregulation of their targets FAK and Paxillin. These findings suggest a novel signaling pathway initiated by ZIP4 controlling pancreatic cancer invasiveness and metastasis, and may be a new therapeutic target for this devastating disease.

Regulation of transforming growth factor is involved in the efficacy of combined 5-fluorouracil and interferon alpha-2b therapy of advanced hepatocellular carcinoma

Transforming growth factor-beta (TGF-β) is critical in cancer cell invasion and metastasis. The effects of a treatment that targets TGF-β using the combination of interferon alpha (IFNα)-2b and 5-fluorouracil (5-FU) are unknown. Here, we show that the serum levels of TGF-β1 prior to the therapy correlate with increased maximum tumor diameter, which is significantly (p < 0.01) decreased after the combination therapy. 5-FU increased both the expression and secretion levels of TGF-β1 in hepatoma cells, but not in normal hepatocytes. The combination of 5-FU and IFNα-2b synergistically affected cell death. However, a TGF-β1 specific inhibitor did not affect the anti-tumor activity of 5-FU. 5-FU inhibited the phosphorylation of SMAD2 and reduced the total protein levels of SMAD2, SMAD4, and pINK4b. Conversely, 5-FU stimulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2. Accordingly, the protein levels of E-cadherin and claudin-1 were reduced in 5-FU-treated cells. The combination of 5-FU and IFNα-2b, and the inhibition of ERK1/2 by a specific inhibitor neutralized the effects of 5-FU on TGF-β-related signaling molecules and restored their protein levels to those observed in the control. Interestingly, the phosphorylated protein levels of SMAD2 and the total protein levels of E-cadherin and p15INK4b were increased in 5-FU-stimulated HuH-7 cells, but not in Hep G2 cells. Our data suggest that the higher efficacy of the 5-FU and IFNα-2b combination therapy was associated with the regulation of TGF-β expression, secretion, and the signals mediated by it.

Regorafenib tolerance and outcomes in inner-city minority colorectal cancer population.

722 Background: Regorafenib (REG) is an oral multikinase inhibitor used for treatment of metastatic colon cancer after progression on fluorouracil, oxaliplatin and irinotecan therapy. The FDA approval was based on CORRECT trial showing improvements in progression-free survival (PFS) and overall survival (OS). Another trial (CONCUR) showed similar results. However, these trials included predominantly Whites and Asians. Our study aimed to evaluate treatment outcomes in the underserved, mainly African Americans and Hispanics. Methods: Cook County hospital is the 3rd largest public hospital in the US. All patients with an order for REG were identified from our pharmacy database. Charts were retrospectively reviewed for cancer stage, age, ethnicity, previous treatments, PFS and OS. Patients with non-colorectal cancer, incomplete data, no evidence of REG usage were excluded. Statistical analysis was done by t-test on subgroups. Results: A total of 42 patients were screened and 30 were included in the study. A comparison of outcomes with CORRECT and CONCUR trials is presented in Table 1. Our study patients, despite being less heavily pre-treated, had a worse OS compared to the clinical trials, with similar PFS. There was a trend towards better PFS and OS in women in our study of 4.3 and 4.8 months compared to men with 1.9 and 3.3 months respectively (p = NS). Six (20%) patients discontinued REG due to intolerance within a median of 1.2 months. The intolerant patients had a significantly higher median BMI of 31 compared to 24.9 for patients who continued the medication to progression (p = 0.019). Conclusions: Compared to CORRECT and CONCUR trials, population of predominantly AA and Hispanics showed a trend towards worse OS despite being less heavily pre-treated indicating worse outcomes in minorities treated with REG. Women showed better PFS and OS compared to men in our study. Patients unable to tolerate REG had significantly higher BMI, indicating a need to study dosing in this subgroup. [Table: see text]

Comparing Topical Treatments for Basal Cell Carcinoma

Superficial basal cell carcinoma is a type of keratinocyte carcinoma that has increasing incidence and substantial morbidity. Jansen etal. report on a randomized trial with 5 years of follow-up that found imiquimod to be more effective than 5-fluorouracil or methyl aminolevulinate photodynamic therapy in preventing superficial basal cell carcinoma recurrence. However, the toxicity and cost of topical treatments, as well as patient preferences, need to be evaluated when making treatment decisions in clinical practice.

Effects of Neoadjuvant 5-Fluorouracil and Cisplatin Therapy in Patients with Clinical Stage II/III Esophageal Squamous Cell Carcinoma.

Neoadjuvant chemotherapy (NAC) with 5-fluorouracil and cisplatin (FP) has been administered to patients with clinical stage II or III esophageal squamous cell carcinoma (ESCC). We aimed to confirm the clinical efficacy and outcomes of NAC with FP. The clinicopathological features and survival of 152 patients with clinical stage II/III ESCC who received NAC with FP followed by radical esophagectomy were analyzed. The R1/2 resection rate was higher (p=0.06) and the high histological response rate was significantly lower (p=0.05) in those with clinical stage III disease. Invasion depth significantly improved in those with less than cT3 (17/30. 57%), but did not in more invasive cases (35/122, 29%) (p=0.004). T Factor was frequently improved in those with clinical stage II (p=0.08). Five-year survival rates in clinical stage II and III were 73% and 41%, respectively. A multivariate analysis identified clinical stage (p=0.01) and residual tumor (p<0.01) as independent prognostic factors. NAC with FP is effective for patients with clinical stage II ESCC, while its potency may be lower for those with clinical stage III or cT3 disease.

Daylight Photodynamic Therapy Versus 5-Fluorouracil for the Treatment of Actinic Keratosis: A Case Series.

IntroductionThe incidence of actinic keratosis (AK) continues to increase worldwide. Currently available options for the treatment of AK include topical 5-fluorouracil (5-FU) and daylight-mediated photodynamic therapy (DL-PDT). This split-face pilot study compared DL-PDT using 16% methyl aminolevulinate (MAL) cream versus 5-FU cream in patients with AK on the face/scalp.MethodsFive male subjects (mean age 70 years) with grade I–III AK on the face/scalp were enrolled. Subjects received a single session of DL-PDT with 16% MAL on one side and topical 5% 5-FU for 21 days on the other side. Evaluations of efficacy, safety, and subject satisfaction were conducted 48 h, 7 days, 14 days, 1 month, and 3 months after treatment.ResultsAt 3 months, the lesion complete response rate was 80% and 93% for DL-PDT and 5-FU, respectively. Lesion partial response was 20% and 7%, respectively. Fewer treatment-related adverse events (AEs) were reported with DL-PDT than with 5-FU, and they resolved spontaneously in 5–7 and 27–30 days, respectively. Subjects preferred DL-PDT because of the lower incidence of AEs and rapid recovery compared with 5-FU.ConclusionDL-PDT is a convenient alternative to 5-FU with good efficacy and a favorable safety profile, allowing patients to effectively treat their AK without compromising their social life.FundingGalderma.

5-FU 投与患者に生じたペラグラの1例

5-FU 投与患者に生じたペラグラの1例

Adjuvant Chemoradiotherapy After Curative Resection for Gastric Cancer

Standard adjuvant therapy for gastric cancer is either postoperative 5-fluorouracil (5-FU) and radiation therapy, or pre- and postoperative

Abstract IA4: The role of inflammation and DNA mismatch repair in colorectal cancer

Abstract Anti-inflammatory drugs, such as aspirin, have been identified as agents that can serve a primary preventative approach towards lessening the burden of colorectal cancer (CRC), as well as be effective secondary prevention for CRC recurrence. Genetic and epigenetic events that drive the pathogenesis of CRC influences a relationship with the immune system that modifies cancer behavior and patient prognosis, as well as the effectiveness of anti-inflammatory drugs and other agents for chemoprevention. Approximately 15% of sporadic CRCs manifest defective DNA mismatch repair (MMR) function due to epigenetic inactivation of the MMR gene MLH1, allowing cancer cells to accumulate hundreds of somatic frameshift mutations in genes that contain microsatellite sequences. Most of the coding microsatellite frameshift mutations are translated into novel truncated proteins, which act as neo-antigens to the patient's immune system, with the patient self-immunizing against the tumor. This defective MMR-driven inflammatory response slows the ability of the CRC to advance and metastasize, and patients present at an earlier stage and survive longer compared to CRC patients with competent MMR tumors. MMR-defective CRCs acquire PD-1 expression, making the tumor more susceptible to immune checkpoint blockade. However, these patients show muted response to adjuvant 5-fluorouracil (5-FU) therapy. There is evidence that aspirin is chemopreventive in Lynch syndrome, a familial form of MMR deficiency, but needs to be studied further. Additionally, approximately 50% of all CRCs manifest dysfunction of the MMR protein MSH3 as a consequence of inflammation and release of the pro-inflammatory cytokine IL-6 from intimately-located immune cells. The isolated MSH3 dysfunction allows cancer cells to accumulate non-mononucleotide microsatellite frameshift mutations that are likely not very immunogenic, as well as DNA double strand breaks as a consequence of loss of MSH3s contribution to homologous recombination repair. These CRC patients are more apt to be advanced stage and possess metastases, demonstrate poor survival, and more common among African American patients. Isolated loss of MSH3 function does not hinder a patient's response to 5-FU, and the effectiveness of immune checkpoint blockade and anti-inflammatory agents has not been tested to date. Specific chromosome breakage points such as at chromosome 9p24.2 are enriched in liver metastases from CRCs with MSH3 dysfunction and modify patient outcome by increasing survival over patients with MSH3 dysfunction alone. Overall, the MMR status of the CRC can inform approach to patient care, and the outcome difference depends on if the MMR defect drives an immune response, or if acquired inflammation causes disruption of MMR via MSH3 cellular mis-localization. Citation Format: John M. Carethers. The role of inflammation and DNA mismatch repair in colorectal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA4.

Lateral retropharyngeal lymph node metastasis from squamous cell carcinoma of the upper gingiva: A case report.

Lateral retropharyngeal lymph node (LRPLN) is located between the internal carotid artery and the prevertebral muscles. Metastasis to the LRPLN is frequent in nasopharyngeal cancer, but is rare in oral cancer. The prognosis of patients with oral cancer with LRPLN metastasis is usually poor. The present study reported a patient with LRPLN metastasis from squamous cell carcinoma of the upper gingiva, who survived for >7 years. Docetaxel, cisplatin and fluorouracil (TPF) therapy was performed as induction chemotherapy and it was planned to subsequently conduct chemoradiotherapy or surgery. As the tumor only exhibited a transient response to TPF, surgery was selected. Postoperatively, only radiotherapy was performed and a favorable outcome was achieved.

Treatment of Actinic Keratoses: A Randomized Split-Site Approach Comparison of Sequential 5-Fluorouracil and 5-Aminolevulinic Acid Photodynamic Therapy to 5-Aminolevulinic Acid Photodynamic Monotherapy.

Actinic keratoses (AKs) are skin lesions resulting from sun exposure and carry a risk of developing into squamous cell carcinoma. Current therapies for AK eradication include topical 5-fluorouracil (5-FU) and photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA). However, sequential therapy with 5-FU-ALA-PDT may offer improved outcome compared to ALA-PDT alone. The purpose of this study is to compare the long-term efficacy of AK clearance by sequential therapy with 5-FU-ALA-PDT versus ALA-PDT alone. This is a single center, randomized split-site approach study on equivalent anatomical and clinical sites. Seventeen patients were enrolled with one half of the site randomized to receive sequential 5-FU-ALA-PDT and the other side with ALA-PDT monotherapy. Total AKs were counted at baseline, 6 and 12 months. Median percentage reduction in AK number at 6 months for 5-FU-ALA-PDT versus ALA-PDT was 100% for 5-FU-ALA-PDT (N = 21) and 66.7% for ALA-PDT (N = 21), p = .001. Median percentage reduction in AK number at 12 months for 5-FU-ALA-PDT versus ALA-PDT was 100% for 5-FU-ALA-PDT (N = 22) and 82.6% for ALA-PDT (N = 22), p = .0002. Sequential therapy with 5-FU-ALA-PDT is more effective at AK clearance at 6 and 12 months compared to ALA-PDT monotherapy.

GTSE1 promotes cell migration and invasion by regulating EMT in hepatocellular carcinoma and is associated with poor prognosis

G2 and S phase-expressed-1 (GTSE1) regulates G1/S cell cycle transition. It was recently reported to be overexpressed in certain human cancers, but its significance and mechanism(s) in hepatocellular carcinoma (HCC) remain unknown. Here, we showed preferential GTSE1 upregulation in human HCC tissues and cell lines that positively correlated with Ki67. GTSE1 knockdown by short hairpin RNA resulted in deficient colony-forming ability and depleted capabilities of HCC cells to migrate and invade. Conversely, exogenous GTSE1 overexpression enhanced colony formation and stimulated HCC cell migration and invasion. Furthermore, GTSE1 silencing was associated with the downregulation of N-cadherin, β-catenin, and Snail, whereas GTSE1 overexpression caused the opposite effects. GTSE1 upregulated Snail via both transcription and protein degradation pathways. Additionally, GTSE1 modulated the sensitivity of HCC to 5-fluorouracil therapy. High GTSE1 correlates with chemo-resistance, while low GTSE1 increases drug sensitivity. Kaplan-Meier survival analysis indicated that high GTSE1 levels were significantly associated with poor overall survival. In conclusion, high expression of GTSE1 is commonly noted in HCC and is closely correlated with migration and invasion by epithelial-to-mesenchymal transition (EMT) modulation. Activated GTSE1 significantly interferes with chemotherapy efficacy and influences the probability of survival of patients with HCC. GTSE1 may thus represent a promising molecular target.

Safe administration of S-1 after 5-fluorouracil-induced cardiotoxicity in a patient with colorectal cancer

Cardiotoxicity is a rare but challenging complication of 5-fluorouracil (5-FU) therapy. Compared with 5-FU, after application of S-1 lower plasma levels of the cardiotoxic metabolite alpha-fluoro-beta-alanine have been reported. Evidence...

ADXS11-001 Lm-LLO Immunotherapy, Mitomycin, 5-fluorouracil (5-FU) and Intensity-modulated radiation therapy (IMRT) for Anal Cancer.

e15072 Background: Human papillomavirus (HPV) DNA is present in the majority of anal cancer. ADXS11-001 Lm-LLO immunotherapy is a live attenuated Listeria monocytogenes ( Lm) bioengineered to secrete a HPV-16-E7 fusion protein targeting HPV transformed cells. The Lmvector is phagocytosed by antigen presenting cells where it cross presents, stimulating MHC class 1 and 2 pathways resulting in specific T-cell immunity. The objective of this study was to determine the safety of ADXS11-001 with mitomycin, 5-FU and IMRT (chemoradiation therapy, CRT) and obtain preliminary data on progression free survival (PFS) in locally advanced anal cancer. Methods: Eligibility included patients (pts) with anal squamous cell cancer and stages T1N2-N3; T2( &lt; 4 cm)N1-N3; T2(≥4cm)N0-N3, T3N0-3, T4N0-3; without evidence of metastases. Pts received standard 54 Gy IMRT with 2 cycles of mitomycin and 5-FU. ADXS11-001, 1x109colony forming units IV, was given x 1 dose before CRT then x 3 additional monthly doses after CRT. Results: The study enrolled the first pt in April 2013. Ten patients were treated (median age 62.5, range 37-71) including 5 with pelvic adenopathy. Two patients had grade 3 toxicities related to the vaccine including chills/rigors (n = 2), back pain (n = 1), hyponatremia (n = 1). All toxicities were within 24 hours of the vaccine and resolved successfully with standard care. There was no exacerbation of CRT toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment which was judged to be unlikely related to ADXS11-001and possibly related to CRT. Eight patients treated on the study had a complete response at six-month sigmoidoscopy. One additional patient who did not undergo six-month sigmoidoscopy had complete response on sigmoidoscopy performed at approximately one year. Eight of 9 patients (89%) are disease-free at a median follow-up of 34 months. Conclusions: ADXS11-001 can be safely administered with CRT for anal cancer. Promising PFS was observed in patients with locally advanced disease. Clinical trial information: NCT01671488.

Preoperative radiation dose escalation for rectal cancer using a concomitant boost strategy improves tumor downstaging without increasing toxicity: A matched-pair analysis

PurposePathologic complete response to neoadjuvant chemoradiation therapy (CRT) is associated with improved outcomes for patients with locally advanced rectal cancer (LARC). Increased response rates have been reported with higher radiation doses, but these studies often lack long-term outcome and/or toxicity data. We conducted a case-control analysis of patients with LARC who underwent definitive CRT to determine the efficacy and safety of intensified treatment with a concomitant boost (CB) approach. Methods and materialsFrom 1995 to 2003, a phase 2 protocol examined CRT with 5-fluorouracil and CB radiation therapy (52.5 Gy in 5 weeks) for patients with LARC. Seventy-six protocol patients were matched (case-control approach) for surgery type, tumor (T) stage, and clinical nodal (N) stage with patients who received standard dose (SD) CRT (5-fluorouracil, 45 Gy). A chart review was performed. McNemar's test and Kaplan-Meier analyses were used for statistical analysis. ResultsThe SD and CB groups did not differ in tumor circumferential involvement and length, but the tumors of CB patients were closer to the anal verge (4.7 vs 5.7 cm; P = .02). Although tumor downstaging was higher in the CB cohort (76% vs 51%; P < .01), pathologic complete response rates did not differ (CB, 17.1% vs SD, 15.8%, P = 1.00). The incidence of grade ≥3 radiation-related toxicities was low and similar in both groups (CB, 10% vs SD, 3%, P = .22). Postoperative (anastomotic leak, wound complications/abscess, bleeding) and late (small bowel obstruction, stricture) complication rates did not differ between the groups (P > .05). The median follow-up was 11.9 years. The 5-year local control rates were higher for CB (100.0%) compared with SD (90.0%) patients (P = .01). CB patients had higher rates of 10-year progression-free survival (71.9% vs 57.6%, P < .01) and overall survival (71.6% vs 62.4%, P = .01) compared with SD patients. ConclusionsCRT dose escalation for patients with LARC is safe and effective. The improved T-downstaging and local control observed in CB patients should encourage further dose escalation studies.

Co-administration of proton pump inhibitors ameliorates nephrotoxicity in patients receiving chemotherapy with cisplatin and fluorouracil: a retrospective cohort study.

The nephrotoxicity of cisplatin (CDDP) is its dose-limiting side effect, and is caused by renal accumulation of CDDP mainly via organic cation transporter 2 (OCT2). Because proton pump inhibitors (PPIs) are known to inhibit OCT2 activity, PPI might ameliorate CDDP-induced nephrotoxicity. In the present study, we retrospectively investigated the effect of co-administration of PPI on CDDP-induced nephrotoxicity. We analyzed the impact of PPI on the development of nephrotoxicity in 133 patients who received CDDP and fluorouracil (5-FU) therapy for the treatment of esophageal cancer or head and neck cancer. Nephrotoxicity that developed within 14 days following CDDP administration was evaluated in accordance with Common Terminology Criteria for Adverse Events ver. 4.0 for acute kidney injury. The rate of nephrotoxicity in patients with PPI (12%, n = 33) was significantly lower than that in patients without PPI (30%, n = 100). Severe nephrotoxicity greater than Grade 2 was not observed in patients with PPI, whereas the rate of hematological toxicity was comparable between patients with and without PPI. Kaplan-Meier analysis showed that the time to nephrotoxicity following CDDP administration was significantly prolonged in patients with PPI. Multivariate analysis revealed that co-administration of PPI with CDDP and 5-FU was an independent factor significantly contributing to the amelioration of nephrotoxicity (odds ratio 0.239, p = 0.033). These findings indicate that co-administration of clinical doses of PPI could ameliorate nephrotoxicity without exacerbation of hematological toxicity in patients receiving CDDP and 5-FU therapy.

When to Assess Treatment Response in Anal Cancer

Standard therapy for anal squamous cancer combines chemotherapy with infusional 5-fluorouracil, mitomycin, and radiation therapy without surgery. The recommended time to assess response is 6 to 12 weeks after initiation of chemoradiotherapy. Patients with incomplete response are referred for salvage abdominal perineal resection. To evaluate the optimal timing of assessment of clinical response to chemoradiotherapy in anal squamous cancer, investigators in the U.K. have conducted a retrospective analysis of the …