To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy.
A total of 1239 patients ...from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan–Meier method, log-rank tests and Cox models.
In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) and overall survival (OS) multivariate hazard ratio (HR) for PFS: 1.20 (1.02–1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17–1.70), P < 0.001. BRAF mutation was also associated with inferior PFS multivariate HR: 2.19 (1.59–3.02), P < 0.001 and OS multivariate HR: 2.99 (2.10–4.25), P < 0.001. Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared with unmutated tumors multivariate HR 2.26 (1.25–4.1), P = 0.001. A similar trend for OS was seen in the KRAS G13D-variant n = 71, multivariate HR 1.46 (0.96–2.22), P = 0.10. More frequent KRAS exon 2 variants like G12D n = 152, multivariate HR 1.17 (0.86–1.6), P = 0.81 and G12V n = 92, multivariate HR 1.27 (0.87–1.86), P = 0.57 did not have significant impact on OS.
Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D (trend) being associated with rather poor survival.
Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We ...examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial.
Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1–4) were used to assess individual-level surrogacy of NAR for DFS.
After a median follow-up of 50months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS 75.9% (95% confidence interval CI 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P=0.034; PC 1) and resulted in a shift toward lower NAR groups (P=0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P<0.001; PC 3). NAR score remained an independent prognostic factor for DFS low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106–7.020; P<0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303–2.98; P=0.001 in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4.
Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.
Zusammenfassung
Hintergrund
Der nationale und globale Anstieg von Krebserkrankungen führt zu einer Vertiefung der praktischen Präventionsmaßnahmen. Es muss aber auch eine Bewusstseinsänderung in den ...verschiedenen Bevölkerungsschichten erfolgen, um diese Maßnahme erfolgreich umsetzen zu können. Auf Bundesebene werden nationale Strategien zur Stützung der Forschung eingeleitet und umgesetzt. Zudem fördert das Präventionsgesetz die Umsetzung der praktischen Maßnahmen in den Lebenswelten der verschiedenen Zielgruppen. Die strategische Ausrichtung der Maßnahmen stützt die individuelle Entscheidung zur Krebsprävention. Als reduzierende Interaktionen werden Lebensstilfaktoren, Vorsorge- und Früherkennungsmaßnahmen gestärkt.
Material und Methoden
Diese Arbeit basiert auf einer selektiven Literaturrecherche in der Datenbank PubMed zum Thema Prävention, Früherkennung und Verhaltensänderung.
Schlussfolgerung
Die Ausrichtung der Projekte der Krebsprävention haben sich in theoretischem Ansatz und in Bezug auf die Ansprache an die Zielgruppen verändert. Um Maßnahmen passgenau verhaltens- und verhältnispräventiv auszurichten, bedarf es einer spezifischen alltagsorientierten Ansprache und damit einhergehender Stärkung von Gesundheitskompetenz und -verhalten der Bevölkerung. Die strukturellen Interventionen auf Bundesebene werden durch die Nationale Dekade gegen Krebs gebündelt.
The German rectal cancer trial CAO/ARO/AIO-04 has shown a significant benefit in 3-year disease-free survival (DFS) of adding oxaliplatin to a standard preoperative 5-fluorouracil (5-FU)-based ...chemoradiotherapy (CRT) and adjuvant chemotherapy in patients with locally advanced rectal cancer. The use of oxaliplatin as adjuvant treatment in elderly patients with colon cancer is controversial. We therefore investigated the impact of age on clinical outcome in the CAO/ARO/AIO-04 phase III trial.
We carried out a post hoc analysis of the CAO/ARO/AIO-04 phase III trial evaluating primary and secondary end points according to age. Patient and tumor characteristics, NCI CTC adverse events grades 3–4 (version 3.0), dose intensities as well as survival and recurrence data were analyzed in three specified age groups (<60, 60–70, and ≥70years). The influence of age as a continuous variable on DFS was modeled using a subpopulation treatment effect pattern plot (STEPP) analysis.
A total of 1232 patients were assessable. With the exception of Eastern Cooperative Oncology Group status (P<0.001), no differences in patient and tumor characteristics were noticed between age groups. Likewise, toxicity pattern, dose intensities of CRT and surgical results were similar in all age groups. After a median follow-up of 50months, in patients aged <60years a significant benefit of adding oxaliplatin to 5-FU-based CRT and adjuvant chemotherapy was observed for local (P=0.013) and systemic recurrences (P=0.023), DFS (P=0.011), and even overall survival (OS; P=0.044). The STEPP analysis revealed improved hazard ratios for DFS in patients aged 40–70years compared with elderly patients treated with oxaliplatin.
The addition of oxaliplatin significantly improved DFS and OS in younger patients aged <60years with advanced rectal cancer. Patients aged ≥70years had no benefit.
NCT00349076
This randomized phase II trial investigated the efficacy and safety of capecitabine/oxaliplatin (CapOx) plus bevacizumab and dose-modified capecitabine/irinotecan (mCapIri) plus bevacizumab as ...first-line therapy in patients with metastatic colorectal cancer (mCRC).
Patients received bevacizumab 7.5 mg/kg with oxaliplatin 130 mg/m2/day 1 plus capecitabine 1000 mg/m2 bid/days 1–14 or with irinotecan 200 mg/m2/day 1 plus capecitabine 800 mg/m2 bid/days 1–14 both every 21 days. The primary end point was 6 months progression-free survival (PFS).
A total of 255 patients were enrolled. The intent-to-treat population comprised 247 patients (CapOx–bevacizumab: n = 127; mCapIri–bevacizumab: n = 120). The six-month PFS rates were 76% (95% CI, 69%–84%) and 84% (95% CI, 77%–90%). Median PFS and OS were 10.4 months (95% CI, 9.0–12.0) and 24.4 months (95% CI, 19.3–30.7) with CapOx–bevacizumab, and 12.1 months (95% CI, 10.8–13.2) and 25.5 months (95% CI, 21.0–31.0) with mCapIri–bevacizumab. Grade 3/4 diarrhea as predominant toxic effect occurred in 22% of patients with CapOx–bevacizumab and in 16% with mCapIri–bevacizumab.
Both, CapOx–bevacizumab and mCapIri–bevacizumab, show promising activity and an excellent toxic effect profile. Efficacy is in the range of other bevacizumab-containing combination regimen although lower doses of irinotecan and capecitabine were selected for mCapIri.
The unique analysis, the first preplanned HRQOL analysis of the phase III AIO KRK 0207 trial, demonstrates that continuation of active maintenance treatment (FP/Bev or Bev alone) after induction ...treatment is not associated with a remarkable detrimental effect on HRQOL compared with treatment discontinuation. Median EORTC QLQ-C30 scores and deterioration rates did not differ between maintenance arms.
First-line maintenance strategies are a current matter of debate in the management of mCRC. Their impact on patient's health-related quality of life (HRQOL) has not yet been evaluated. The objective of this study was to assess whether differences in HRQOL during any active maintenance treatment compared with no maintenance treatment exist.
Eight hundred and thirty-seven patients were enrolled in the AIO KRK 0207 trial. Four hundred and seventy-two underwent randomization (after 24 weeks of induction treatment) into one of the maintenance arms: FP plus Bev (arm A), Bev alone (arm B), or no active treatment (arm C). HRQOL were assessed every 6 weeks during induction and maintenance treatment independent from treatment stop, delay, or modification, and also continued after progression, using the EORTC QLQ-C30, QLQ-CR29. The mean value of the global quality of life dimension (GHS/QoL) of the EORTC QLQ-C30, calculated as the average of all available time points after randomization was considered as pre-specified main endpoint. Additionally, EORTC QLQ-C30 response scores were analyzed.
For HRQOL analysis, 413 patients were eligible (arm A: 136; arm B: 142, arm C: 135). Compliance rate with the HRQOL questionnaires was 95% at time of randomization and remained high during maintenance (98%, 99%, 97% and 97% at week 6, 12, 18 and 24). No significant differences between treatment arms in the mean GHS/QoL scores were observed at any time point. Also, rates of GHS/QoL score deterioration were similar (20.5%; 17.2% and 20.7% of patients), whereas a score improvement occurred in 36.1%; 43.8% and 42.1% (arms A, B and C).
Continuation of an active maintenance treatment with FP/Bev after induction treatment was neither associated with a detrimental effect on GHS/QoL scores when compared with both, less active treatment with Bev alone or no active treatment.
NCT00973609 (ClinicalTrials.gov).
Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy ...improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem's macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n=34) or CHOP (n=30). R-CHOP resulted in significantly higher overall response (OR) rate (94 vs 67%, P=0.0085) in the LPL patients and in the WM subgroup (91 vs 60%, P=0.0188). With a median observation time of 42 months, R-CHOP induced a significantly longer time to treatment failure (TTF) with a median of 63 months for R-CHOP vs 22 months in the CHOP arm in the LPL patients (P=0.0033) and in the WM subgroup (P=0.0241). There was no major difference of treatment-associated toxicity between both treatment groups. These data indicate that the addition of rituximab to front-line chemotherapy improves treatment outcome in patients with LPL or WM.
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