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Background/purpose: To evaluate the usage of RT in trial protocols for anti-cancer drugs approved by the US Food and Drug Administration (FDA)., Methods: Drugs which had been granted an FDA approval between 2010 and 2017 for the treatment of solid tumors in adults were identified. Use of RT in relation to each drug's approval date was reviewed on ClinicalTrials.gov., Results: Out of 42 drugs, none was initially approved for an indication which mandates RT. One drug (2.4%) has a post-approval label extension for sequential usage after RT. 5846 records were screened, exclusion of non-cancer trials and duplicates resulted in 4254 protocols out of which 2919 were industry-sponsored (68.6%). RT was tested in 350 (8.2%) studies. Out of 75 drug/RT trials which were initiated prior to approval, fourteen had not yet started recruitment, 45 were recruiting, one was completed, one prematurely terminated and fourteen fully-recruited but ongoing at approval time. Out of the fully-recruited or completed studies, results from four studies on three drugs were already published. In 52.4% of drugs, no patient had been treated with a drug/RT combination at the approval date. Drug/RT studies were less likely industry-sponsored (p < 0.001) and more likely initiated post-approval (p < 0.001) compared to drug-only trials. Despite this imbalance, pre-approval drug/RT trials were still mostly industry-sponsored (65.3%)., Conclusion: No drug/RT data were publicly available in over 90% of newly approved anti-cancer drugs. These results indicate that clinicians must rely on postmarketing surveillance to identify drug/RT interactions as data from trials are unavailable at approval., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the association between prostate-specific antigen (PSA) response and progression-free and overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel., Methods: Men with mCRPC receiving cabazitaxel (25 mg/m 2 , every 3 weeks) plus oral prednis(ol)one (10 mg/day) were enrolled in the non-interventional, prospective QoLiTime study. Main outcome measures were progression-free survival and overall survival, in all patients and in those who showed a ≥ 50 or a ≥ 30% decrease in PSA relative to baseline after four cycles of cabazitaxel, as well as quality-of-life parameters., Results: Of the 527 men (median age 72 years), 266 received ≥ 4 cycles of cabazitaxel and had PSA response data. After four cycles, 34.6% of men achieved a PSA decrease ≥ 50% and 49.6% a decrease ≥ 30%. Median progression-free survival was 7.7 (95% CI 6.2, 9.5) months, and overall survival was 19.5 (95% CI 16.0, 30.9) months, corresponding to 1-year event rates of 39.4 and 78.8%, respectively. Median progression-free survival was longer in PSA responders versus non-responders (15.7 vs 5.5 months at 50% cut-off; 15.7 vs 5.3 months for 30% cut-off; both P < 0.0001). Overall survival (50% cut-off) was 23.3 months in responders and 16.0 months in non-responders (P = 0.068); corresponding data at the 30% cut-off are 21.7 and 16.0 months (P = 0.057). Overall, 55.4% of men experienced ≥ 1 adverse event, 59.6% of whom had a serious adverse event., Conclusion: PSA response after four cycles of cabazitaxel is associated with improved progression-free survival in men with mCRPC treated with cabazitaxel plus prednis(ol)one.

Background: Oxaliplatin is a platinum-based antineoplastic agent used for the treatment of colorectal cancer and other gastrointestinal tumors. In combination with 5-fluorouracil for instance it is given in the so-called FOLFOX regimen in patients with colorectal cancer in the adjuvant as well as the palliative treatment setting. Cumulative neuropathy is a common cause of treatment discontinuation. Other toxicities are generally tolerable and managed by dose reductions and/or supportive treatment. While chronic cardiotoxic effects of cytostatics are well described, there are few reports on acute cardiotoxic reactions., Case Report: The present case describes the sudden development of a transient coronary vasospasm in a 56-year-old male patient mimicking an acute ST segment elevation myocardial infarction during systemic treatment with oxaliplatin., Conclusion: Oxaliplatin is one of the most commonly used cytostatics for gastrointestinal cancer. Coronary vasospasm has never been reported for oxaliplatin. Thus it is crucial to keep in mind that acute cardiotoxic side effects may occur, even with chemotherapeutic agents without a prior evidence-based description of such events., (© 2018 S. Karger GmbH, Freiburg.)

Purpose: Studies investigating combinations of anti-epidermal growth factor receptor monoclonal antibodies such as panitumumab or cetuximab with standard chemoradiation therapy protocols in rectal cancer have yielded disappointing results. Because of the supposed negative interaction of epidermal growth factor receptor inhibition and chemoradiation therapy, we conducted a phase 2 study using single-agent panitumumab in combination with radiation therapy in patients with RAS wild-type locally advanced rectal cancer., Methods and Materials: Patients with RAS wild-type locally advanced (clinical stage II or III) rectal cancer localized 0 to 12 cm from the anus were eligible for study participation. The primary objective of the study was to determine pathologic complete response (pCR). Secondary objectives comprised assessing the safety, surgical morbidity, clinical response, tumor downstaging, and tumor regression grading according to Dworak., Results: A total of 54 patients with a median age of 58 years were treated. In 3.7% of patients, pCR was achieved. Downstaging of the primary tumor or lymph nodes was seen in 65% of patients. No grade ≥2 hematologic toxicity was seen. The most common grade ≥3 nonhematologic toxicities were skin toxicity (24%) and diarrhea (10%)., Conclusions: Panitumumab in combination with radiation therapy as neoadjuvant treatment for locally advanced rectal cancer showed a favorable toxicity profile but failed to meet the predefined pCR rate to justify further clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Gastric cancer and cancer of the oesophagogastric junction is diagnosed in the locally advanced or metastatic setting in 55 - 65 % of the cases and is generally treated with perioperative or palliative chemotherapy. For patients with metastatic disease, it is important to reliably determine the HER2 status for potential treatment with trastuzumab. Unfortunately this assessment is not trivial and afflicted with problems of pronounced tumor heterogeneity as well as with an unclear HER2 scoring algorithm. We report an 80 year old male patient diagnosed with an advanced adenocarcinoma of the oesophagogastric junction (uT3 uN + cM0; Siewert II). The initial external HER2 test was negative (HER2 value 1 +) but was repeated in-house. On the basis of more extensive biopsies focal but strong HER2 positivity (HER2 value 3 +, ~10 % of the tumor cells positive) was demonstrated. The patient subsequently received a combination of oxaliplatin, 5-fluorouracil/folinic acid and trastuzumab, resulting in an improvement of symptoms and a tumor regression. The discrepancy of the two HER2 tests performed was caused by heterogeneity of HER2 expression, not detectable during initial sampling due to a low number of tumor containing biopsies. In addition, uncertainties of the HER2 scoring algorithm of oesophagogastric cancer samples could have played a role. This case report illustrates that oesophagogastric carcinoma with an only minor HER2 positive clone may benefit from an anti-HER2 therapy in combination with chemotherapy. It also describes problems and challenges associated with HER2 testing of oesophagogastric carcinoma, especially when only a few tumor-bearing biopsies could be obtained., Competing Interests: Interessenkonflikt: Ralf Hofheinz, Daniela Hirsch und Timo Gaiser haben Referenten- und Beratungs-Honorare, sowie Reisekostenunterstützung der F. Hoffmann-La Roche AG erhalten., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background/aim: The aim of this work was to evaluate the efficacy and safety of second-line treatment with weekly high-dose 5-fluorouracil (5-FU) as a 24-hour infusion (24-h inf.) combined with sodium folinic acid (FA) (AIO-regimen) plus irinotecan (Iri.) after pretreatment with AIO-regimen plus oxaliplatin (L-OHP)., Patients and Methods: Patients with non-resectable distant CRC metastases were enrolled in a prospective phase II study for palliative second-line treatment after previous progression of first-line treatment in accordance with the AIO-regimen plus oxaliplatin. On an outpatient basis, the patients received a treatment regimen comprising of weekly 80 mg/m 2 irinotecan in the form of a 1-hour i.v. infusion and 2,000 mg/m 2 5-FU combined with 500 mg/m 2 sodium folinic acid administered as a 24-h infusion i.v. once weekly., Results: During second-line treatment, a total of 59 patients received 520 chemotherapy applications. As the main higher-grade symptom of toxicity, diarrhea (NCI-CTC-toxicity grade 3) presented in 8 patients (13.6%, 95%CI=5.1-23.7), followed by leukocytopenia (CTC grade 3) in 3 patients (5.1%, 95%CI=0-11.9), followed by thrombocytopenia (CTC grade 3) in 1 patient (1.7%, 95%CI=0-5.1). Fifty-nine patients were evaluable for treatment response. The remission data can be summarized as follows: complete remission (CR); n=0; partial remission (PR); n=6 (10%; 95%CI=3.4-18.6); stable disease (SD); n=31 (53%; 95%CI=39.0-64.4); progressive disease (PD); n=19 (33%; 95%CI=20.3-44.1). The median progression-free survival (PFS) rate (n=59) was 4.2 months (range=3.8-5.8 months). The median survival time counted from the start of second-line treatment (n=59) 14.2 months (range 8.2-17.3 months) and the median survival time counted from the start of first-line therapy (n=59) 25 months (range 19-27 months)., Conclusion: Palliative second-line treatment according to the AIO regimen plus irinotecan offers both a favourable toxicity profile and promising efficacy in second-line and palliative sequential therapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The epidermal growth factor receptor (EGFR) is involved in development and progression of some gastrointestinal cancers, and is targeted by monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) used to treat these conditions. Targeted agents are generally better tolerated than conventional chemotherapy, but have characteristic toxicities that can affect adherence, dosing, and outcomes. Skin conditions are the most common toxicities associated with EGFR inhibitors, particularly papulopustular rash. Other common toxicities include mucosal toxicity, electrolyte imbalances (notably hypomagnesaemia), and diarrhoea, while the chimaeric mAb cetuximab is also associated with increased risk of infusion reactions. With appropriate prophylaxis, the incidence and severity of these events can be reduced, while management strategies tailored to the patient and the degree of toxicity can help to ensure continuation of anti-cancer therapy. Here, we review the main toxicities associated with EGFR-inhibiting mAbs and TKIs in patients with gastrointestinal cancers, and provide recommendations for prophylaxis and treatment., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Adenocarcinoma of the esophagogastric junction (EGJ) and stomach remains one of the most common causes of cancer-related death worldwide. Although there is increasing data on the mutational landscape of esophagogastric cancer, phase III trials often yield negative results, and there is a paucity of approved targeted agents. For the time being, the subset of patients carrying HER2-positive metastatic tumors can receive trastuzumab in addition to chemotherapy. Furthermore, ramucirumab has been found to be active both as a single agent and in combination with paclitaxel. Herein, we give an overview of currently approved targeted treatments for locally advanced/resectable as well as unresectable/metastatic EGJ/gastric adenocarcinoma, summarizing the underlying clinical studies. Moreover, further potential targets still under investigation are presented., (© 2016 S. Karger GmbH, Freiburg.)

Background: BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 "basket" study of vemurafenib in BRAF V600 mutation-positive nonmelanoma cancers., Methods: We enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation-positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival., Results: In the cohort with non-small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim-Chester disease or Langerhans'-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had disease progression during therapy. There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab. Safety was similar to that in prior studies of vemurafenib for melanoma., Conclusions: BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers. Preliminary vemurafenib activity was observed in non-small-cell lung cancer and in Erdheim-Chester disease and Langerhans'-cell histiocytosis. The histologic context is an important determinant of response in BRAF V600-mutated cancers. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT01524978.).

Background: Docetaxel is a widely used cytotoxic agent. This study evaluates the impact of docetaxel toxicities on patient's health-related quality of life (QoL)., Patients and Methods: We conducted a multicenter, prospective, non-interventional trial, in which the QoL was assessed using the EORTC QLQ-C30 questionnaires at baseline and every 4 weeks up to 40 weeks in patients receiving a docetaxel-based chemotherapy for metastatic disease. Treatment-related adverse events were correlated with the corresponding QoL scores. Uni- and multivariate analyses were applied., Results: From January 2008 to June 2011, a total of 2659 patients were included. The majority of patients (48.1%) had prostate cancer, followed by breast (17.1%) and non-small-cell-lung cancer (15.8%). Patients received a median of 5 docetaxel cycles with the median dose of 75 mg/m(2). The presence of grade 3/4 diarrhea showed the strongest effect on global health status/QoL average scores (50.91 versus 33.06), followed by vomiting (50.91 versus 35.17), dyspnea (50.94 versus 35.81), mucositis/stomatitis (50.88 versus 36.41), nausea (50.91 versus 36.68), infection (50.90 versus 37.14), fatigue (50.90 versus 43.82) and anemia (50.91 versus 41.03), P < 0.05 for all comparisons. Grade 3/4 leukopenia/neutropenia, alopecia, constipation, neurotoxicity and nail disorders had no significant impact on the global health status/QoL or other items., Conclusion: In this large non-interventional trial, docetaxel-associated grade 3 or 4 toxicities were shown to have a strong detrimental effect on patient's QoL. Notably, diarrhea and vomiting had the strongest negative impact on QoL measures. This has to be kept in mind while making therapeutic decisions and providing optimized supportive treatment measures., Clinical Trials Number: This study was registered at Deutsches Krebsstudienregister (DKSR, primary registry in the WHO Registry Network) with the ID 527., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Regorafenib is the first tyrosine kinase inhibitor approved for metastatic colorectal cancer. In 2 phase III trials, regorafenib significantly improved progression-free and overall survival in patients who had been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor therapy, and, if (K)RAS wild type, an anti-epidermal growth factor receptor therapy. Its safety profile is in line with other multikinase and/or tyrosine kinase inhibitors approved for different indications. Commonly reported adverse events specifically associated with regorafenib include hand-foot skin reaction and hypertension, whereas others such as fatigue, diarrhea, and liver dysfunction may occur during both targeted and cytotoxic treatments. These adverse events frequently occur within the first cycles of treatment, are transient, and decrease in incidence over time. Patient selection, education, and management, as well as close communication between oncologists or trained nurses and patients, are essential for prevention and mitigation of treatment toxicity as is rapid implementation of dose modifications and temporary discontinuations. Effective management of adverse events enables patients who are responding to stay on treatment for a substantial period of time and thereby receive the full benefit of regorafenib therapy. This review aims to provide guidance around prophylaxis and management of regorafenib-associated adverse events.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. The growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM), which is modified by matrix metalloproteinases (MMPs). The MMP family is still relevant to cancer research, as it promotes malignant transformation, cell proliferation and modulation of angiogenesis even in the early stages of cancer. The proteolytic processing of bioactive molecules by MMP-14 (MT1-MMP) causes severe abnormalities in connective tissue, defective angiogenesis and premature death. MMP-2 (gelatinase A) and MMP-14 also play a role in degradation of basement membrane and cell carcinoma invasion. Imatinib blocks the PTK receptor c-kit and forestalls its PTK activity. The aim of the present study was to investigate the expression pattern of MMP-14 and MMP-2 in human papilloma virus (HPV)-negative and p16-positive SCC and to evaluate the chemosensitivity of the tumour cells to the chemotherapeutic agents, imatinib and 5-fluorouracil (5-FU). We incubated the SCC cell lines with imatinib (18 and 30 µmol/ml) and 5-FU (1 and 5 µmol/ml) and detected MMP-14 and MMP-2 by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) after 48, 72, 120, 192 and 240 h. We detected expression of MMP-2 and MMP-14 in all incubated tumour cell lines. With imatinib in particular, we found a reliable trend towards decreased MMP-2 and MMP-14 expression levels in p16-positive and p16-negative SCC tumour cell lines in addition to an induced apoptotic effect. We found statistically significant imatinib-induced suppression of MMP-2- and MMP-14, dependent on the incubation time and the cell line. We detected a significant suppression of MMP-2 and MMP-14 especially in p16-negative HNSCC14C cells after prolonged treatment time with imatinib. Dose escalation of imatinib and 5-FU had no statistically significant effect on the expression of MMP-2 or MMP-14. The p16-positive SCC cells exhibited higher expression of total protein. We detected a significant suppression of MMP-2 and MMP-14 in all the incubated SCC cell lines, partially after treatment with imatinib. We found higher suppression of MMP-2 in the CERV196 cells after incubation with imatinib. We detected a reliable trend towards increased chemosensitivity of p16-positive tumour cells in vitro after treatment with imatinib. Extended studies and clinical trials are needed to further investigate these findings in HPV-associated HNSCC.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. In several tumour entities, the tyrosine kinase receptor c-KIT is associated with tumour transformation in the epithelial tissue in cases of aberrant expression. Furthermore, tumour development and dissemination are a result of dysregulated cellular pathways such as the WNT/β-catenin pathway. β-Catenin is a multifunctional protein within the canonical WNT signalling pathway and a pivotal factor for the stabilization of cell-cell interactions. In malignant tissues, β-catenin triggers tumour proliferation and progression. The aim of this study is to investigate the expression patterns of c-KIT and β-catenin in human papillomavirus-negative and p16-positive SCC and to evaluate the chemosensitivity of the tumour cells to the chemotherapeutical agents docetaxel and 5-fluorouracil (5-FU)., Materials and Methods: We incubated the tumour cell lines with docetaxel (5 μmol/ml) and 5-FU (1 μmol/ml) and detected β-catenin and c-KIT by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) after 48, 72, 120, 192 and 240 h., Results: We found a reliable trend towards decreased β-catenin expression levels in p16-positive and p16-negative tumour cell lines when incubated with docetaxel, in addition to induced apoptotic effect. At best, 5-FU had a slight influence on the alteration of the expression of β-catenin. Dose escalation of docetaxel and 5-FU had no statistically significant effect on the expression of β-catenin or c-KIT. In HPV-negative HNSCC, a reduced expression level of β-catenin and c-KIT was detected in an incubation period-dependent manner. p16-transformed SCC (CERV196) cells were characterized by a reduced susceptibility to docetaxel induced alteration of β-catenin expression., Conclusion: We were unable to confirm the clinically-substantiated increased chemosensitivity of p16-positive tumour cells in vitro. Extended studies and clinical trials are needed to investigate these findings further in HPV-associated HNSCC.

Resistance to chemotherapy is a major obstacle for curative treatment of human gastric cancer (GC). However, the underlying molecular mechanisms are largely unknown. Wingless-type MMTV integration site family members (WNTs) are secreted glycoproteins involved in embryogenesis and, on inappropriate expression in the adult, in cancer. Here, we show expression of WNT6 in GC patient specimens, human GC cell lines and in a mouse model of GC. In human GC cells, WNT6 expression was enhanced by caveolin-1 (Cav1), a scaffold protein of plasma membrane caveolae. WNT6 knock-down and overexpression experiments demonstrated that WNT6 increased the resistance to apoptotic cell death induced by the anthracycline chemotherapeutics epirubicin (Epi) and doxorubicin (Dox). Epi increased the activity of the human WNT6 promoter through Cav1-dependent binding of β-catenin to the proximal WNT6 promoter. Epi increased both WNT6/Wnt6 and Cav1 expression in human GC cells and within the tumor area of a murine model of GC (CEA424-SV40 TAg). In GC patients, WNT6 expression was positively associated with the tumor stage and the nodal status, and inversely correlated with the response to ECF (Epi, cisplatin, 5-fluorouracil) chemotherapy. These results showed that WNT6 and Cav1 are upregulated by chemotherapeutics and enhance the resistance of GC cells to anthracycline drugs. Understanding the molecular mechanisms driving WNT6/Cav1-induced drug resistance will provide benefits in developing new therapies for GC.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy. It is known to be the most common neoplasm appearing in the upper aerodigestive tract. The poor 5‑year survival rate has remained unchanged in the last decades even though improved techniques in surgery, radiation and chemotherapy have been established. In contrast to the overall decreasing incidence of head and neck cancer in the US, the incidence of HPV-associated oropharyngeal cancer is increasing, indicating the importance of viral etiology. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). Matrix metalloproteinases (MMP) have been shown to play key roles in the remodeling of the ECM. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukaemia. But it also has an inhibitory impact, e.g., on the protein-tyrosine-kinase (PTK) receptor c-kit and on its PTK activity in HNSCC. In this study, we incubated the HNSCC cell lines HNSCC 11A and 14C and the p16-positive SCC line CERV196 with increasing concentrations of imatinib or carboplatin. After an incubation time of up to 10 days, we evaluated MMP-2 and -14 expression by ELISA techniques and immunohistochemistry. MMP-2 and -14 expression was demonstrated in all incubated tumor cell lines. Especially incubation with imatinib resulted in a significant decrease in MMP expression in incubated cell lines. Our results indicate that the expression of MMP-2 and -14 is suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially keeping in mind the moderate toxicity of imatinib.

Background: Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine., Methods: This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m(2) days 1-14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) days 1-38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m(2) days 1-5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m(2) daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m(2) per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m(2) days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m(2) for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993., Findings: Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41-72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67-82] vs 67% [58-74]; p=0·0004; post-hoc test for superiority p=0·05). 3-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fluorouracil group (p=0·07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0·04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group; grade 3-4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3-4 vs three [2%] any grade, no grade 3-4), fatigue (55 [28%] any grade, no grade 3-4 vs 29 [15%], two [1%] grade 3-4), and proctitis (31 [16%] any grade, one [<1%] grade 3-4 vs ten [5%], one [<1%] grade 3-4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4)., Interpretation: Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer., Funding: Roche Pharma AG (Grenzach-Wyhlen, Germany)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The most common neoplasm arising in the upper aerodigestive tract is head and neck squamous cell carcinoma (HNSCC). Tumor growth, invasion and systemic dissemination is a multistep process of dysregulated cellular signaling pathways and an altered cell-cell and cell-matrix interaction. Aberrant Wnt/β-catenin signaling is linked to tumor development and dissemination in several tumor entities. β-catenin is a multifunctional protein within the canonical Wnt pathway, which is an important factor for reducing cell-cell adhesion in malignant tissue and for triggering cell cycle progression and unscheduled proliferation. Another pivotal factor in carcinogenesis is the tyrosine kinase receptor c-kit, which in the case of dysregulated expression is associated with neoplastic transformation in epithelial tissue. This study evaluates the expression pattern of secreted and nuclear β-catenin and c-kit in p16-positive and HPV-negative squamous cell carcinomas (SCC) and the vulnerability of therapy with the tyrosine kinase inhibitor imatinib as a potential targeted treatment modality compared to platinum-based chemotherapeutic drugs. The different squamous tumor cell lines were incubated with increasing concentrations of carboplatin (3 or 7.5 µmol/ml) and imatinib (18 or 30 µmol/ml). ELISA and immunohistochemical methods were carried out after 48, 72, 120, 192 and 240 h. We detected a reliable trend towards significantly decreased cytosolic and nuclear β-catenin and c-kit expression levels in p16-positive SCC and non-HPV HNSCC cells induced by imatinib exposure for an extended incubation period, whereas platinum-based agents had no or, at best, a slight influence. Virus-transformed squamous cell carcinoma (CERV196) cells were characterized by a reduced susceptibility to an imatinib-altered β-catenin expression. Further studies are planned to investigate this observance in HPV-positive HNSCC in vitro. The implementation of a selective molecular therapy in established chemotherapeutic regimes may enhance the efficacy of platinum-based chemotherapy without increased toxicity and could thus improve the clinical outcome in HNSCC, irrespective of the HPV status.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy. The development of new treatment modalities in order to improve long-term survival of patients with HNSCC is imperative. Numerous studies have demonstrated that carcinogenesis and tumor cell dissemination is influenced by the tumor microenvironment. The protein-kinase-receptors (PTKs) are essential elements of the intracellular signal transduction pathway and regulate cell growth, development and apoptosis. Cell proliferation, migration, induction of tumor vascularization and carcinogenesis, invasion is regulated by a variety of angiogenic factors, such as PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor) and their respective tyrosine kinase receptors (PDGF-R and VEGF-R). They present promising targets for anti-cancer therapy through abrogation of impaired signaling pathways. Indeed, imatinib, a small molecule drug targeting these protein kinases, has antiproliferative effects in several cancer types. The purpose of this study was to investigate the potential synergism of imatinib and carboplatin on the expression of PDGF, PDGF-R α/ß and VEGF in different HNSCC cell lines. Several tumor cell lines were subjected to increasing concentrations of carboplatin (3 and 7.5 µmol/l) and imatinib (18 and 30 µmol/l) and ELISA, immunohistochemical methods and RQ-PRC after 48, 72, 120 and 240 h were used to assess their expression levels. While PDGF-Rα/ß expression was unimpaired at lower imatinib concentrations (18 µmol/l), PDGF-Rα/ß expression was suppressed at 30 µmol/l, and suppression was enhanced by the presence of carboplatin. By RQ-PCR, a significant reduction of PDGF-Rα/ß expression was detected (p<0.5). We observed explicit significant reduction in VEGF levels with increasing concentrations of imatinib and with the combination of the two chemotherapeutic drugs (p<0.5). We report for the first time evidence of synergism of imatinib and carboplatin in suppressing VEGF, PDGF and PDGF-Rα/ß expression in HNSCC.

Background: Skin toxicities are frequent in patients receiving epidermal growth factor receptor (EGFR) antagonists. Grading and management of these skin reactions are poorly standardized., Materials and Methods: We conducted a survey among German oncologists using a 7-item questionnaire distributed by e-mail via the working groups Internistische Onkologie (AIO) and Dermatologische Onkologie (ADO). The oncologists were provided with pictures and history of a patient with an acneiform rash and were asked to provide information on grading and treatment strategies., Results: 106 medical oncologists and 43 dermatooncologists responded to the survey. The scoring of the skin rash was indicated as follows (National Cancer Institute common toxicity criteria (NCICTC) grades 1/2/3;%): 10/59/31. 22% of the polled medical oncologists use preemptive treatment of skin rash. In the presented case, 91% chose local treatment with mainly hydrocortisone or antibiotic cream, and 64% chose systemic treatment with an antibiotic or isotretinoin. Only 9% of the medical oncologists would have referred the patient to a dermatologist. Dermatooncologists used more local antibiotics (p = 0.006) and rather less local steroids (p = 0.199). With regard to systemic treatment, dermatooncologists more often used isotretinoin (p = 0.002). In addition, dermatooncologists less often delayed cetuximab treatment because of skin toxicity (p = 0.009)., Conclusions: The results of the present analysis illustrate that grading and treatment of EGFR antagonistinduced skin toxicities are very heterogeneous. Clearly, more randomized trials and a simple and reliable grading system are warranted., (Copyright 2010 S. Karger AG, Basel.)

Background: No standard chemotherapy regimen can be defined for patients with metastatic squamous cell carcinoma of the anus due to the low incidence of this disease and the high cure rate of localized tumors. Anal cancers universally express the epidermal growth factor receptor (EGFR) and KRAS mutations have not been reported in anal cancer thus far., Methods: We report on 7 patients with metastatic anal cancer treated with cetuximab - a chimeric antibody against EGFR - on a compassionate use basis along with the results of KRAS mutational analysis., Results: Marked tumor shrinkage was noted in several patients using cetuximab monotherapy or cetuximab/irinotecan combination as first or subsequent treatment line (usually after failure of cisplatin-based regimens). Two out of seven patients harbored KRAS mutations. Both patients had progressive disease receiving cetuximab, while the remaining 5 patients had either a partial remission (n = 3), a minor remission (n = 1) or no change lasting > or =6 months after previous rapid tumor progression., Conclusion: Cetuximab-based treatment appears to be a valuable treatment option for patients with metastatic KRAS wild-type anal cancer after failure of or as an alternative to cisplatin/5-fluorouracil-based therapy., (Copyright 2009 S. Karger AG, Basel.)

Purpose: Deviant expression of platelet-derived growth factor receptor-beta (PDGFRbeta) and c-kit was shown in patients with colorectal cancer. In the present study, mRNA expression of PDGFRbeta and c-kit in 33 patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy with cetuximab/capecitabine/irinotecan in correlation with the tumor regression rate was investigated., Methods and Materials: Pretherapeutic biopsy cores and tumor material from the resected specimens were collected in parallel with normal rectal mucosa. The expression levels of PDGFRbeta and c-kit were measured by quantitative polymerase chain reaction. Tumors were classified as good responders (tumor regression grade [TRG], 2-3) or poor responders (TRG, 0-1)., Results: The TRG evaluation of the resected specimen was TRG 0-1 in 11 and TRG 2-3 in 22. The median normalized ratios in the pretreatment mucosa vs. tumor biopsy cores was as follows: PDGFRbeta ratio of 15.2 vs. 49.5 (p <0.0001) and c-kit ratio of 0.94 vs. 0.67 (p = 0.014). The same tendency was observed for the median PDGFRbeta ratios after chemoradiotherapy completion: 34.2 vs. 170.0 (p <0.0001). The PDGFRbeta and c-kit mRNA expression values in the pretreatment tumor biopsy cores were lower than the values in the resected specimens: PDGFRbeta ratio 49.5 vs. 170.0 (p = 0.0002) and c-kit ratio 0.67 vs. 1.1 (p = 0.0003). Nevertheless, no correlation was seen between the pretherapeutic PDGFRbeta and c-kit mRNA expression and the pathologic regression rate., Conclusion: Cetuximab-based chemoradiotherapy increased PDGFRbeta levels even further compared with the pretreatment samples and deserves further investigation.

Background: Increasing the rate of pathological complete remissions after neoadjuvant chemoradiation of rectal cancer has become a strategy to further improve the long-term oncological outcome of patients. This report evaluates the influence of preoperative intensified radiochemotherapy on the rate and outcome of surgical complications., Materials and Methods: Patients with primary rectal cancer at stages cT3/4cNx or N+ without metastasis were preoperatively treated either with capecitabine and irinotecan or with capecitabine, irinotecan and ceutximab with a concurrent radiation (50.4 Gy). Surgery was scheduled 4-7 weeks after completion of the chemoradiation. Perioperative complications were prospectively documented during the patient's hospital stay., Results: Fifty-nine patients (median age 60; male/female: 46/13) undergoing surgery at a single center were analysed. The median distance of the tumour from the dentate line was 5 cm. The operations performed were low anterior resection (n=45), Hartmann's procedure (n=4) and abdominoperineal resection (n=10). Total mesorectal excision with R0-resection was accomplished in all but one patients. Histopathological regression was described in four grades (0-3) as defined by the Japanese Society for Cancer of the Colon and Rectum. Tumors were called major responsive when assigned to the regression grades 3 or 2, and minor or nonresponsive at regression grades 1 or 0. In total, 33 patients (55.9%) had a regression grade 2 or 3. Among them, 12 patients showed a pathological complete response without any residual cancer cell (20.3%). Seven out of 45 patients (15.5%) with sphincter-preserving surgery suffered from suture breakdown; they all had previously shown a major response of the resected tumor. Two of them died during the hospital stay., Conclusions: While in general, patients undergoing neoadjuvant intensified treatment suffer from a slight increase in surgical complications, this is markedly enhanced in patients with good treatment responses. Our results underline the oncological benefit of intensified neoadjuvant chemoradiation, but the severity of complications in low rectal anastomosis of patients with good response after neoadjuvant therapy should alert surgeons and oncologists.

BBR 3438, a member of the 9-aza-anthrapyrazole family designed to decrease anthracycline dependent cardiotoxicity and to improve efficacy provided high in vivo activity in gastric carcinoma xenograft models. The present study was carried out to assess the efficacy and safety of BBR 3438 applied at a dose of 50 mg/m(2) four-weekly as an 1-hour infusion to pretreated patients with gastric cancer. Twenty-seven patients received at least one administration of BBR 3438. Lymph nodes and liver were the most common sites of metastases. A total of 94 cycles were administered (median 2, range 1-6). The main toxicity consisted of (worst per patient [%]; NCIC CTC grades 1/2/3/4) neutropenia 7/7/19/52 (one case of febrile neutropenia), stomatitis 15/19/4/-, nausea 22/26/7/-, vomiting 19/7/7/-, alopecia 15/33/-/-. Neutrophil nadir (520/mul) was reached after a median 15 days. The median time to recovery to < or = grade 1 neutropenia was 13.5 days. The median average cumulative dose of BBR 3438 was 166.8 mg, and the median dose intensity was 48.8 mg/m(2). Left ventricular ejection function (LVEF) was monitored with multiple-gated angiography (MUGA). Median LVEF values at baseline and at the end of cycle 2 were 67.5% and 65%, respectively, and no patient showed a relevant decrease of LVEF. In 25 patients evaluable for response no remission was observed. Four patients (16%) had stable disease. Median time to progression was 51 days, median overall survival was 64 days. In all, the feasibility and tolerability of BBR 3438 applied 4-weekly at a dose of 50 mg/m(2) was confirmed and neither relevant LVEF decreases nor hints of cardiac toxicity were observed. In terms of antitumor activity, BBR 3438 was found to be ineffective in the treatment of gastric cancer.

Among several drug delivery systems, liposomal encapsulated anti-cancer agents represent an advanced and versatile technology. Several formulations of liposomal anthracyclines are approved, e.g. for the treatment of metastatic breast cancer (pegylated and non-pegylated liposomal doxorubicin) or AIDS-related Kaposi's sarcoma (pegylated liposomal doxorubicin and liposomal daunorubicin). Meanwhile, virtually all anti-cancer drugs have been encapsulated in liposomes using different technologies. This review will summarize preclinical and clinical data of approved and exemplary emerging liposomal anti-cancer agents.

Background: In a phase III study recruiting patients with stage II colon cancer the effect of adjuvant therapy with edrecolomab, a murine monoclonal antibody to the cell-surface glycoprotein 17-1A, was compared to observation alone., Patients and Methods: From January 1997 until July 2000 a total of 377 patients were postoperatively stratified according to tumor stage (T3 vs. T4) and center, and randomly allocated to either treatment with edrecolomab (cohort A, n = 183) or observation (cohort B, n = 194). Patients in cohort A received a total of 900 mg edrecolomab. The study was terminated prematurely because of discontinuation of drug supply in Germany., Results: 305 patients were eligible for the primary endpoint of overall survival and 282 patients for disease-free survival. After a median follow-up of 42 months overall survival and disease-free survival were not significantly different. Toxicity was mild., Conclusions: In the present study, postoperative adjuvant treatment with edrecolomab in patients with resected stage II colon cancer did not improve overall or disease-free survival.

The aim of this study was to determine the dose-limiting toxicity (DLT) and establish the recommended dose for mitomycin C added every 3 weeks to the standard combination dose of capecitabine. Cohorts of at least three patients with pretreated gastrointestinal carcinoma received capecitabine 1000 mg m(-2) orally twice daily on days 1-14 plus i.v. bolus mitomycin C on day 1 at doses of 4, 6, 8 or 10 mg m(-2) (corresponding to dose levels I-IV). Cycles were repeated every 3 weeks. Two treatment cycles were considered for the evaluation of DLTs. Of the 53 patients enrolled, the majority had colorectal (n=27) or gastric (n=14) cancers. Patients had received a median of two lines of prior chemotherapy (34% with >/=3 lines and 87% with prior 5-FU-based therapy). At the recommended dose level (IV, n=30), grade 3 adverse events during cycles 1 and 2 were: anaemia (10%); leukopenia (3%); thrombocytopenia (3%); stomatitis/mucositis (3%); hand-foot syndrome (3%). Two patients experienced DLTs (mucositis, n=1; neutropenic fever, n=1), but there were no grade 4 events. The median dose intensity for capecitabine and mitomycin C was 100% during cycles 1 and 2 and only four patients required postponement of therapy. Of the 43 patients evaluable for efficacy, seven achieved partial and minor remissions (16%; 95% CI, 5-28%), and 12 patients (28%) had stable disease. The favourable safety profile and promising activity of the capecitabine/mitomycin C combination, even in heavily pretreated patients, warrant further evaluation in patients with advanced colorectal and gastric cancers.

Only two patients with adequately documented oxaliplatin-induced autoimmune haemolytic anaemia have previously been reported. We report here a third patient with an immune-haematological finding favouring a bispecific mechanism (immune-complex and penicillin type) of oxaliplatin-induced haemolysis.