Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial.

BACKGROUND: FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined. PATIENTS AND METHODS: In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method. RESULTS: CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n = 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS (P < 0.001), and OS (P < 0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy. CONCLUSIONS: CMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making.The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927.

Quality of life assessment in patients with metastatic colorectal cancer receiving maintenance therapy after first-line induction treatment: a preplanned analysis of the phase III AIO KRK 0207 trial.

BACKGROUND: 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. PATIENT AND METHODS: 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. RESULTS: 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). CONCLUSION: 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. CLINICAL TRIALS NUMBER: NCT00973609 (ClinicalTrials.gov).

Development of treatment strategies in locally advanced non-small cell lung cancer (take home messages).

In the last decade combined modality treatment approaches contributed to the progress of therapy in locally advanced non-small cell lung cancer. With this management strategies younger patients (<70 years) with locally advanced disease and a good performance status (ECOG 0,1) have survival benefits compared to sole locoregional treatment. Further development of these treatment concepts is warranted. To adopt optimal tailored therapy to prognostic consistent patient groups exact staging of disease is mandatory. Moreover, refinements of the staging system would be helpful to identify in defined anatomical stages, patient subgroups who will benefit from systemic treatment options different from chemotherapy (i.e. tyrosine kinase-inhibition of the epidermal growth factor receptor family, anti-angiogenic treatment). The current status of developing treatment strategies in locally advanced non-small cell lung cancer is discussed.

Rhinocerebral zygomycosis in a patient with acute lymphoblastic leukemia.

We report a case of a 28-year-old man with acute lymphoblastic leukemia who developed rhinocerebral zygomycosis during induction chemotherapy. This life-threatening fungal infection is an infrequent cause of neutropenic fever, and is occasionally found in patients with leukemia and lymphoma, or patients with severely compromised defence mechanisms due to other diseases. It is caused by moulds belonging to the Mucoraceae family, and is characterized by local destruction of the affected organ. In our patient, the infection spread from the paranasal sinuses to the right orbit, destroyed intraorbital structures and resulted in blindness within days. Biopsy from the right maxillary sinus was performed and mucormycosis was suspected through microscopic examination. Culture of the resected specimen identified Rhizopus arrhizus as the causing agent. Treatment of zygomycosis should consist of radical surgical debridement of the infected tissue, together with intensive broad-spectrum antimycotic therapy with amphotericin B. What could be learned from this case is, that aggressive approaches to identify the cause of infection is necessary, and that aggressive treatment strategies are inevitable to overcome the infection. Furthermore, treatment of the underlying disease should be continued as soon as possible.

Contact hypersensitivity to disodium hexachloroplatinate in mice.

Complex platinum (Pt) compounds are known as occupational respiratory sensitizers whereas their role in skin exposure is unclear. In this study, both skin irritation and induction of contact hypersensitivity by halide Pt salts were characterized in mice. Repeated application of Na2[PtCl6] (5% in acetone) to both ears of naive BALB/c mice induced activation of the draining auricular lymph nodes. Flow cytometric analysis revealed a striking increase in the number of lymph node cells expressing proliferating cell nuclear antigen. In separate experiments, Na2[PtCl6] or acetone were applied only to the right ear of mice on 4-8 consecutive days and the animals were challenged on the left ear 6 days later. Ear thickness was determined before and 0.5, 24, 48, and 72 h after challenge with 0.5 or 2% Na2[PtCl6] or acetone. Maximal swelling of the left ear was recorded at 48 h in Pt-sensitized mice challenged with 2% Na2[PtCl6]. Furthermore, the concentration of Na2[PtCl6] required for sensitization caused an irritant reaction as demonstrated by significant swelling of the right ear. These data support the concept that both irritant and allergic contact dermatitis to halide Pt salts may occur in humans. Concerning skin exposure to halide Pt salts, Pt-induced irritant reactions resulting from an intrinsic adjuvant's activity of the compound could be a prerequisite for sensitization.