Early clinical trial unit tumor board: a real-world experience in a national cancer network.

PURPOSE: Early clinical trials are the first step into clinical therapies for new drugs. Within the six Bavarian university-based hospitals (Augsburg, Erlangen, Regensburg, Munich (LMU and TU), Würzburg) we have enrolled a virtual network platform for patient discussion. METHODS: The virtual Early Clinical Trial Unit Tumor Board (ECTU Tumor Board) is a secured web-based meeting to evaluate early clinical trial options for patients, where representatives from local ECTUs participate. We retrospectively analyzed patient cases discussed between November 2021 and November 2022. RESULTS: From November 2021 to November 2022, a total of 43 patients were discussed in the ECTU Tumor Board. Median age at diagnosis was 44.6 years (range 10-76 years). The median number of previous lines of therapies was 3.7 (range 1-9 therapies) including systemic treatment, surgery, and radiation therapy. A total of 27 different tumor entities were presented and 83.7% (36/43) patients received at least one trial recommendation. In total, 21 different active or shortly recruiting clinical trials were recommended: ten antibody trials, four BiTE (bispecific T cell engager) trials, six CAR (chimeric antigen receptor) T-cell trials, and one chemotherapy trial. Only six trials (28.6%) were recommended on the basis of the previously performed comprehensive genetic profiling (CGP). CONCLUSION: The ECTU Tumor Board is a feasible and successful network, highlighting the force of virtual patient discussions for improving patient care as well as trial recruitment in advanced diseases. It can provide further treatment options after local MTB presentation, aiming to close the gap to access clinical trials.

[Paraneoplasms of the skin]. / Paraneoplasien der Haut.

The cutaneous manifestations of malignancies include nonmalignant skin disorders that occur in association with malignancies (facultative paraneoplastic dermatoses) and skin disorders that are always associated with hematologic diseases or solid tumors (obligate paraneoplastic dermatoses). Paraneoplastic increase of growth factors or immunological reactions lead to a variety of inflammatory, hyperkeratotic or proliferative skin reactions. When paraneoplastic dermatoses develop before cancer is diagnosed, recognition of these skin diseases can accelerate both the diagnosis and treatment. The presence of unexplained cutaneous findings should lead to a multidisciplinary evaluation of the patient. This manuscript summarizes the cutaneous manifestations associated with hematologic disorders and solid tumors, their localization and treatment options.

Tumor markers CEA and CA 19-9 correlate with radiological imaging in metastatic colorectal cancer patients receiving first-line chemotherapy.

In patients with metastatic colorectal cancer (mCRC), radiological imaging represents the current standard to evaluate the efficacy of chemotherapy. However, with growing knowledge about tumor biology, other diagnostic tools become of interest which can supplement radiology. The aim of the present study was to examine the correlation of tumor and serum markers with radiological imaging in patients with mCRC receiving first-line therapy. Patients were included if tumor (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9)) and serum marker (lactatdehydrogenase (LDH), γ-glutamyltransferase (γGT), alkaline phosphatase (AP), C-reactive protein (CRP), leucocyte count (WBC), hemoglobin (Hb)) levels were available at baseline and at least two times during treatment. The decline and increase of tumor and serum markers over time were approximated for each patient by estimating slopes depending on the radiological assessment. A linear mixed effects multiple regression model for each subject was used to evaluate the intra-class correlation of these slopes modeling tumor and serum marker changes with radiological imaging. Data of 124 patients (41 female, 83 male; median age 62.9 years, range 27-85) who received first-line chemotherapy for mCRC from 11/2007 to 04/2010 were analyzed retrospectively. CEA level slopes (n = 49; slopes = 102) differed between radiologically determined progressive disease (PD) and partial response (PR) (p = 0.005) and between PD and stable disease (SD) (p = 0.042). CA 19-9 level slopes (n = 57; slopes = 127) also showed a significant difference between PD and PR (p = 0.002) and PD and SD (p = 0.058). Furthermore, CRP slopes (n = 62; slopes = 134) differed significantly between PD and PR (p = 0.009). For LDH, ALP, γGT, Hb, and WBC, no correlations were observed. The results indicate the correlation of the tumor markers CEA, CA 19-9, and the serum marker CRP with radiological imaging in patients with mCRC receiving first-line chemotherapy. Further data analyses would be helpful to develop a predictive model for tumor response based on an early tumor marker increase or decrease.

Left-sided primary tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer treated with cetuximab plus chemotherapy: an analysis of the AIO KRK-0104 trial.

PURPOSE: AIO KRK-0104 investigated first-line therapy of metastatic colorectal cancer (mCRC) with cetuximab, capecitabine and irinotecan versus cetuximab, capecitabine and oxaliplatin. This analysis investigated the impact of primary tumor location on outcome of patients. PATIENTS AND METHODS: Left-sided primary tumors were defined as tumors from rectum to left flexure, while tumors in the remaining colon were regarded right sided. Overall survival (OS), progression-free survival (PFS) and response rate were correlated with primary tumor location. A Cox regression model was used to evaluate interaction between primary tumor location and KRAS mutation. RESULTS: Of 146 patients of the AIO KRK-0104 trial, 100 patients presented left-sided (of those 68 KRAS codon 12/13 wild-type) and 46 patients right-sided primary tumors (of those 27 KRAS codon 12/13 wild-type). Left-sided tumors were associated with significantly longer OS (p = 0.016, HR = 0.63) and PFS (p = 0.02, HR = 0.67) as compared to right-sided tumors. These effects were present in the KRAS codon 12/13 wild-type population (HR OS: 0.42; HR PFS: 0.54), while no impact of primary tumor location was evident in patients with KRAS codon 12/13 mutant tumors (HR OS: 1.3; HR PFS: 1.01). A significant interaction of KRAS status and primary tumor location concerning OS and PFS was observed. CONCLUSION: Our findings suggest that primary tumor location and KRAS codon 12/13 mutational status interact on the outcome of patients with mCRC receiving cetuximab-based first-line therapy. Left-sided primary tumor location might be a predictor of cetuximab efficacy.

Resection of pulmonary metastases from colon and rectal cancer: factors to predict survival differ regarding to the origin of the primary tumor.

BACKGROUND: The purpose of the present study was to determine differences in prognostic factors for survival of patients with pulmonary metastases resected in curative intent from colon or rectum cancer. METHODS: Between 1980 and 2006, prognostic factors after resection of pulmonary metastases in 171 patients with primary rectum or colon tumor were evaluated. Survival of patients after surgical metastasectomy was compared with that of patients receiving standard chemotherapy by matched-pair analysis. RESULTS: Median survival after pulmonary resection was 35.2 months (confidence interval 27.3-43.2). One-, 3-, and 5-year survival for patients following R0 resection was 88.8, 52.1, and 32.9 % respectively. Complete metastasectomy (R0), UICC stage of the primary tumor, pleural infiltration, and hilar or mediastinal lymph node metastases are independent prognostic factors for survival. Matched-pair analysis confirmed that pulmonary metastasectomy significantly improved survival. Although no difference in survival for patients with pulmonary metastases from lower rectal compared to upper rectal or colon cancer was observed, factors to predict survival are different for patients with lower and middle rectal cancer (R0, mediastinal and/or hilar lymph nodes, gender, UICC stage) compared with patients with upper rectal or colon cancer (R0, number of metastases). CONCLUSIONS: Our results indicate that distinct prognostic factors exist for patients with pulmonary metastases from lower rectal compared with upper rectal or colon cancer. This supports the notion that colorectal cancer should not be considered as a single-tumor entity. Metastasectomy, especially after complete resection resulted in a dramatic improvement of survival compared with patients treated with chemotherapy alone.

Prognostic factors for 60-day mortality in first-line treatment of metastatic colorectal cancer (mCRC): individual patient analysis of four randomised, controlled trials by the AIO colorectal cancer study group.

BACKGROUND: The 60 day mortality is an established parameter for chemotherapy-related safety in randomised trials for metastatic colorectal cancer (mCRC). Prognostic factors associated with 60-day mortality would be helpful to identify high-risk patients in advance. PATIENTS AND METHODS: Individual baseline patient data from four randomised, controlled trials from the Arbeitsgemeinschaft Internistische Onkologie (AIO) study group were retrospectively analysed. Chemotherapy consisted of fluoropyrimidine (5-FU/capecitabine), irinotecan, oxaliplatin with or without bevacizumab or cetuximab. Prognostic factors were identified by univariate and multivariate logistic regression models in two cohorts: one limited to ECOG PS 0 and 1 and one including ECOG PS 2 patients. RESULTS: A total of 1377 patients were evaluated. The analysis of ECOG PS 0, 1 and 2 patients consisted of 898 patients where a total of 33 deaths within the first 60 days of treatment (3.7%) occurred. In multivariate analysis, 60-day mortality was significantly associated with ECOG PS 2 and high leucocyte count (white blood cell, WBC). Odds ratio was 6.28 for WBC and 12.92 for ECOG PS 2. Exclusion of ECOG PS 2 patients but inclusion of one trial limited to ECOG PS 0 and 1 patients resulted in 1302 assessable patients and 44 early deaths (3.4%). In both cohorts, around 50% of deaths were disease related. WBC was confirmed as a significant risk factor for early death (OR 7.60). A combined score using ECOG PS 2 and WBC ≥8.000/µl is able to identify high-risk patients with a sensitivity of 18% and specificity of 98%. CONCLUSIONS: In this large retrospective analysis of individual patient data, around 50% of early deaths were disease related. Elevated WBC was found strongly associated with increased 60-day mortality in first-line treatment of mCRC. The proposed AIO-60-Day-Mortality score serves as an additional trial exclusion criterion.

Evaluation of prognostic factors in liver-limited metastatic colorectal cancer: a preplanned analysis of the FIRE-1 trial.

BACKGROUND: Liver-limited disease (LLD) denotes a specific subgroup of metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: A total of 479 patients with unresectable mCRC from an irinotecan-based randomised phase III trial were evaluated. Patients with LLD and non-LLD and hepatic resection were differentiated. Based on baseline patient characteristic, prognostic factors for hepatic resection were evaluated. Furthermore, prognostic factors for median overall survival (OS) were estimated via Cox regression in LLD patients. RESULTS: Secondary liver resection was performed in 38 out of 479 patients (resection rate: 7.9%). Prognostic factors for hepatic resection were LLD, lactate dehydrogenase (LDH), node-negative primary, alkaline phosphatase (AP) and Karnofsky performance status (PS). Median OS was significantly increased after hepatic resection (48 months), whereas OS in LLD (17 months) and non-LLD (19 months) was comparable in non-resected patients. With the inapplicability of Koehne's risk classification in LLD patients, a new score based on only the independent prognostic factors LDH and white blood cell (WBC) provided markedly improved information on the outcome. CONCLUSION: Patients undergoing hepatic resection showed favourable long-term survival, whereas non-resected LLD patients and non-LLD patients did not differ with regard to progression-free survival and OS. The LDH levels and WBC count were confirmed as prognostic factors and provide a useful and simple score for OS-related risk stratification also in LLD.

FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306.

BACKGROUND: The AIO KRK-0306 trial compares the efficacy of infusional 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC). In October 2008, an amendment terminated the inclusion of patients with KRAS-mutated tumours. This subgroup of patients is evaluated in the present analysis, while the study is ongoing for patients with KRAS wild-type tumours. METHODS: Patients were randomly assigned to FOLFIRI (Tournigand regimen) every 2 weeks plus cetuximab (400 mg/m2 day 1, followed by 250 mg/m2 weekly=arm A) or bevacizumab (5 mg/kg every 2 weeks=arm B). Among 336 randomised patients, KRAS mutation was demonstrated in 100 assessable patients. The primary study end point was objective response rate (ORR). RESULTS: ORR was 44% [95% confidence interval (CI) 29% to 59%] in arm A versus 48% (95% CI, 33% to 62%) in arm B. Progression-free survival was 7.5 versus 8.9 months (hazard ratio: 1.0) and overall survival was 22.7 versus 18.7 months (hazard ratio: 0.86) in arms A versus B, respectively. CONCLUSIONS: This is the first head to head comparison of cetuximab versus bevacizumab in first-line treatment of mCRC. In the present evaluation of patients with KRAS-mutated tumours, neither strategy demonstrated a clearly superior outcome.

The influence of KRAS and BRAF mutations on the efficacy of cetuximab-based first-line therapy of metastatic colorectal cancer: an analysis of the AIO KRK-0104-trial.

Our study investigated the impact of specific KRAS mutations and BRAF mutation on progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated within the AIO KRK-0104-trial as first-line therapy. In total, 146 (of 185) patients were included in this analysis. Seventy-nine patients presented with KRAS/BRAF wild-type (wt), 41 patients with a KRAS codon 12 and nine patients with a KRAS codon 13 mutation. Seventeen patients presented a BRAF-mutated tumor. The patients of our study were treated with CAPIRI/CAPOX plus cetuximab. Major differences regarding PFS and OS were observed depending on the mutation of the tumor. PFS was 8 months in patients with wt-tumors, 5.8 months with codon 12-mutated, 9.9 months with codon 13-mutated and 4.2 months with BRAF-mutated tumors. OS was 23.5 months in patients with wt-tumors, 18.9 months with codon 12-mutated, 26.2 months with codon 13-mutated and 13.0 months with BRAF-mutated tumors. Although the conventional separation of patients with KRAS wild-type versus KRAS mutant tumors did not have a significant impact on outcome parameters in the AIO KRK 0104-trial, this analysis demonstrates that markedly differing results are obtained when subtypes of KRAS and BRAF mutation are taken into account.

Correlation of capecitabine-induced skin toxicity with treatment efficacy in patients with metastatic colorectal cancer: results from the German AIO KRK-0104 trial.

BACKGROUND: The AIO KRK-0104 randomised phase II trial investigated the efficacy and safety of two capecitabine-based regimens: combination of capecitabine and irinotecan (CAPIRI) plus cetuximab (CAPIRI-C) and combination of capecitabine with oxaliplatin (CAPOX) plus cetuximab (CAPOX-C) in the first-line treatment of metastatic colorectal cancer (mCRC). Treatment-related skin toxicity (ST) was evaluated separately for capecitabine and cetuximab. The present analysis investigates the correlation of capecitabine-attributed ST (Cape-ST) and parameters of treatment efficacy. METHODS: Patients with mCRC were randomised to cetuximab (400 mg m(-2), day 1, followed by 250 mg m(-2) weekly) plus CAPIRI (irinotecan 200 mg m(-2), day 1; capecitabine 800 mg m(-2), twice daily, days 1-14, every 3 weeks), or cetuximab plus CAPOX (oxaliplatin 130 mg m(-2), day 1; capecitabine 1000 mg m(-2), twice daily, days 1-14, every 3 weeks). RESULTS: Of 185 recruited patients, 149 (CAPIRI-C, n=78; CAPOX-C, n=71) received study treatment beyond the first tumour assessment and were evaluable for efficacy. Capecitabine-attributed ST, predominantly hand-foot syndrome, was observed in 32.2% of patients. Capecitabine-attributed ST grade 1-3 was associated with a significantly higher disease control rate (DCR) (97.9 vs 86.1%, P=0.038) compared with grade 0 toxicity. Moreover, Cape-ST grade 1-3 related to a markedly longer progression-free survival (PFS) (9.9 vs 5.6 months, P<0.001) and overall survival (OS) (32.8 vs 22.4 months, P=0.008). Separate analyses of treatment arms indicated that the effect of Cape-ST on PFS remained significant for both arms, whereas the effect on OS remained apparent as a strong trend. CONCLUSION: This analysis supports the hypothesis that for the evaluated regimens, a correlation exists between Cape-ST and treatment efficacy regarding DCR, PFS, and OS.