Melanie Kripp

Cetuximab-Based Treatment of Metastatic Anal Cancer: Correlation of Response with KRAS Mutational Status

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 ≥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.

Treatment of epidermal growth factor receptor antagonist-induced skin rash: results of a survey among German oncologists.

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.

Does the Addition of Cetuximab to Radiochemotherapy Improve Outcome of Patients with Locally Advanced Rectal Cancer? Long-Term Results from Phase II Trials

Purpose. The addition of cetuximab to radiochemotherapy (RCT) failed to improve complete response rates in locally advanced rectal cancer (LARC). We report the long-term results in patients treated within two sequential clinical trials. Methods. Patients receiving neoadjuvant RCT using capecitabine and irinotecan (CapIri) within a phase I/II trial or CapIri + cetuximab within a phase II trial were evaluated for analysis of disease-free survival (DFS) and overall survival (OS). KRAS exon 2 mutational status had been analyzed in patients receiving cetuximab. Results. 37 patients from the CapIri trial and 49 patients from the CapIri-cetuximab treatment group were evaluable. Median follow-up time was 75.2 months. The 5-year DFS rate was 82% (CapIri) and 79% (CapIri-cetuximab) (P = 0.62). The median OS was 127.4 months. 5-year OS was 73% for both groups (CapIri and CapIri-cetuximab) (P = 0.61). No significant difference in DFS (P = 0.86) or OS (P = 0.39) was noticed between patients receiving CapIri and those receiving CapIri-cetuximab with KRAS wild-type tumors. Conclusions. As the addition of cetuximab did not improve neither DFS nor OS it should not play a role in the perioperative treatment of patients with LARC, not even of patients with (K)RAS WT tumors.

Treatment of lymphomatous and leukemic meningitis with liposomal encapsulated cytarabine

Liposomal encapsulated cytarabine (DepoCyte®, Mundipharma GmbH, Limburg/Lahn, Germany) is a slow-release formulation of conventional cytarabine. It is licensed for intrathecal use in patients with lymphomatous and leukemic meningitis. DepoCyte® obtained superior response rates, improved patient quality of life and improved the time to neurological progression in a randomized albeit small clinical trial. In this review we briefly summarize the clinical data and discuss them in light of clinical problems and possible treatment scenarios.

Integrating patient reported measures as predictive parameters into decisionmaking about palliative chemotherapy: a pilot study

BackgroundSystemic treatment has proven to improve physical symptoms in patients with advanced cancer. Relationship between quality of life (QoL) or symptom burden (SYB) and treatment efficacy (tumour response and survival) is poorly described. Therefore, we evaluated the predictive value of pretreatment QoL and SYB on treatment outcomes.MethodsEligible patients had metastatic gastrointestinal cancers and were about to receive 1st/2nd line palliative chemotherapy. 47 patients were consecutively enrolled. QoL and SYB were assessed by EORTC QLQ-C30 and MSKCC MSAS questionnaires before treatment and after first response evaluation after 8–12 weeks. Logistic regression analysis of QoL and SYB for prediction of objective treatment efficacy was performed. Patients were categorized according to response rate (RR) based on RECIST1.1 and progression free survival (PFS). PFS was categorized by a ratio (individual PFS/expected PFS) in above median (ratio ≥ 1) or below median PFS (ratio < 1). QoL and SYB were analysed for RR groups (partial response, stable or progressive disease) and PFS ratio (PFSR).ResultsObjective response to chemotherapy and increase in PFS were associated with better pretreatment QoL and less SYB. Patients with future objective treatment efficacy (PFSR ≥ 1) evidenced clinically relevant better role/emotional/cognitive/social functioning and less fatigue and appetite loss at baseline in comparison to PFSR < 1 (>10 points difference). Lowest scores in all functioning scales at treatment start were seen in patients with future PFSR < 1. Global health status (EORTC), PSYCH subscale and global distress index (MSAS) predicted PFSR, even if adjusted for gender, age, cancer type, ECOG and line of treatment (p < 0.05). Interestingly, improved QoL and SYB (subjective benefit) were noted even in patients with worse pretreatment status and no objective tumour response.ConclusionFuture non-responders seem to show distinct QoL patterns before chemotherapy. This may facilitate early detection of patients deriving less or even no benefit from treatment regarding prolongation of survival. Even in patients with primarily progressive disease QoL and SYB may improve during treatment. Integration of QoL and SYB assessment into decision-making about palliative chemotherapy seem to be an important approach to improve patient outcome and should be further evaluated.

Alpha-fetoprotein expressing metastastic adenocarcinoma of the esophago-gastric junction responding favorably to capecitabine and oxaliplatin.

Alpha-fetoprotein-producing metastatic adenocarcinoma of the stomach or the esophago-gastric junction usually exhibits either no or only short-term remission while receiving palliative chemotherapy. We report on a 76-year-old male patient suffering from an unresectable alpha-fetoprotein-producing adenocarcinoma of the esophago-gastric junction with several liver metastases. He was treated with capecitabine and oxaliplatin-based combination therapy. A long-lasting major remission was observed resulting in a survival of 18.5 months.

Prognostic Impact of mRNA Expression Levels of HER1–4 (ERBB1–4) in Patients with Locally Advanced Rectal Cancer

Background. No predictive or prognostic biomarker is available for patients with locally advanced rectal cancer (LARC) undergoing perioperative chemoradiotherapy (CRT). Members of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases EGFR (HER1, ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4) are therapeutic targets in several cancers. The analysis was performed to assess expression levels and study the potential prognostic impact for disease-free and overall survival in patients with LARC. Patients and Methods. ERBB1–4 mRNA expression and tumor proliferation using Ki-67 (MKI67) mRNA were evaluated using RT-quantitative PCR in paraffin-embedded tumor samples from 86 patients (median age: 63) treated with capecitabine or 5-fluorouracil-based CRT within a phase 3 clinical trial. Results. A positive correlation of HER4 and HER2, HER3 and HER2, and HER4 and HER3 with each other was observed. Patients with high mRNA expression of ERBB1 (EGFR, HER1) had significantly increased risk for recurrence and death. Patients with high mRNA expression of MKI67 had reduced risk for relapse. Conclusion. This analysis suggests a prognostic impact of both ERBB1 and MKi67 mRNA expression in LARC patients treated with capecitabine or fluorouracil-based chemoradiotherapy.

Baseline and On-Treatment Markers Determining Prognosis of First-Line Chemotherapy in Combination with Bevacizumab in Patients with Metastatic Colorectal Cancer.

Background: In metastatic colorectal cancer, no upfront or on-treatment markers are available to determine the prognosis or efficacy for chemotherapy in combination with bevacizumab. Patients and Methods: The current analysis was performed to evaluate the prognostic value of disease and patient characteristics (age, number of metastatic sites, stage of primary tumor, performance status, carcinoembryonic antigen (CEA)) and on-treatment changes of CEA (response after 8-12 weeks of treatment and specific patterns of CEA kinetics) in patients from an observational cohort study of chemotherapy with bevacizumab. Results: Baseline factors were available from 1,438 patients. Patients with baseline CEA levels > 20 ng/ml, more than 1 metastatic site, and age > 75 years showed significantly lower progression-free (PFS) and overall survival in multivariate analysis. A CEA response of > 30% during treatment was associated with increased PFS. In addition, the pattern of CEA kinetics predicts survival and response to treatment. Conclusion: In summary, baseline CEA, number of metastatic sites, and age are strong independent prognostic factors for survival. By monitoring CEA, clear patterns with distinct prognostic value can be determined. CEA kinetics and/or response after 8-12 weeks might be a useful and simple tool to stratify the post-induction treatment approach based on individual prognosis in the future.

Outcome of Colorectal Cancer Patients Treated with Combination Bevacizumab Therapy: A Pooled Retrospective Analysis of Three European Cohorts from the Angiopredict Initiative

Background/Aims: This study is aimed at analyzing the survival rates and prognostic factors of stage IV colorectal cancer patients from 3 European cohorts undergoing combination chemotherapy with bevacizumab. Methods: Progression free-survival (PFS) and overall survival (OS) were analyzed in 172 patients using the Kaplan-Meier method and uni- and multivariable Cox proportional hazards regression models. Results: The median PFS was 9.7 and the median OS 27.4 months. Patients treated at centers in Germany (n = 97), Ireland (n = 32), and The Netherlands (n = 43) showed a median PFS of 9.9, 9.2, and 9.7 months, OS of 34.0, 20.5, and 25.1 months, respectively. Patients >65 years had a significantly shorter PFS (9.5 vs. 9.8 months) but not OS (27.4 vs. 27.5 months) than younger patients. High tumor grade (G3/4) was associated with a shorter PFS, T4 classification with both shorter PFS and OS. Fluoropyrimidine (FP) chemotherapy backbones (doublets and single) had comparable outcomes, while patients not receiving FP backbones had a shorter PFS. In multivariable analysis, age and non-FP backbone were associated with inferior PFS, T4 classification and therapy line >2nd were significantly associated with poor PFS and OS. Conclusion: The observed survival rates confirm previous studies and demonstrate reproducible benefits of combination bevacizumab regimens. Classification T4, non-FP chemotherapy backbone, and age >65 were associated with inferior outcome.

Konsensusempfehlungen deutscher Experten - Management der Therapie mit Idelalisib

Idelalisib, die erste Substanz in der Wirkklasse der Phosphatidylinositol 3-Kinase delta (PI3Kδ)-Inhibitoren, ist in Deutschland für die Therapie von Patienten mit chronischer lymphatischer Leukämie (CLL) und follikulärem Lymphom (FL) zugelassen. Im Rahmen eines Expertenmeetings wurden Empfehlungen für das Therapiemanagement erarbeitet, um das Nutzen-Risiko-Profil von Idelalisib weiter zu diskutieren. In klinischen Studien [2] hat Idelalisib in den zugelassenen Indikationen eine hohe Wirksamkeit gezeigt. Doch wie jede effektive Behandlung kann auch die Idelalisib-Therapie mit Nebenwirkungen assoziiert sein, deren Management im klinischen Alltag beherrscht werden muss. Als wichtige potenzielle Nebenwirkungen wurden in diesem Zusammenhang insbesondere Kolitiden, Infektionen unter anderem mit dem Cytomegalievirus (CMV) und Pneumocystis jirovecii-Pneumonien (PJP) sowie nichtinfektiöse Pneumonitiden definiert.