Prognostic and predictive impact of metastatic organ involvement on maintenance therapy in advanced metastatic colorectal cancer: Subgroup analysis of patients treated within the PanaMa trial (AIO KRK 0212).

Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with 5-fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver-limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver-limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13-1.93; P = .004) and OS (HR 1.37, 95% CI 0.98-1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver-limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30-2.83; P < .001), and OS (HR 2.38, 95% CI 1.51-3.76; P < .001) of maintenance therapy. Pmab-containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39-0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57-1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR-based maintenance therapy is considered.

Desire for biological parenthood and patient counseling on the risk of infertility among adolescents and adults with hemoglobinopathies.

BACKGROUND: Both diagnosis and treatment of hemoglobinopathies have been associated with an increased risk of fertility impairment. German guidelines recommend annual monitoring of fertility parameters to enable early detection of fertility impairment and/or to offer fertility preservation (FP) when indicated. We explored the general desire for parenthood, the frequency of recalling fertility counseling and testing, and the utilization of FP in adolescents and adults with hemoglobinopathies. PROCEDURE: In a cross-sectional study, patients aged 12-50 years, treated in Germany, Austria, or Switzerland, were surveyed on fertility-related aspects. Medical data, including fertility testing results, were collected from patient records. RESULTS: Overall, 116/121 eligible patients, diagnosed with sickle cell disease (70.7%), thalassemia (27.6%), or other hemoglobinopathy (1.7%), participated in our study (57.8% female, median age 17.0 years, range 12-50 years). All participants required treatment of the underlying hemoglobinopathy: 68.1% received hydroxyurea, 25.9% required regular blood transfusions, and 6.0% underwent hematopoietic stem cell transplantation (HSCT). Most patients (82/108, 75.9%) stated a considerable to strong desire for (future) parenthood, independent of sex, education, diagnosis, or subjective health status. Fertility counseling was only recalled by 32/111 patients (28.8%) and least frequently by younger patients (12-16 years) or those treated with regular blood transfusions or hydroxyurea. While fertility testing was documented for 59.5% (69/116) in medical records, only 11.6% (13/112) recalled previous assessments. FP was only used by 5.4% (6/111) of patients. CONCLUSION: Most patients with hemoglobinopathies wish to have biological children, yet only few recalled fertility counseling and testing. Adequate patient counseling should be offered to all patients at risk for infertility.

Health-related quality of life of children born to childhood cancer survivors in Germany.

OBJECTIVE: Rising childhood cancer survival rates have increased the importance of health-related quality of life (HRQL) assessment. While survivors show comparable HRQL to peers, concerns that cancer treatment could impact the health of prospective children were reported. No previous publications address HRQL of childhood cancer survivor offspring. METHODS: We assessed survivor offspring HRQL using the parental KINDL questionnaire. Matched-pair analysis was conducted with data from the general population (KiGGS study) using age, gender and education (1:1, n = 1206 cases). Multivariate analyses were conducted to detect the influence of parental diagnose and treatment on offspring HRQL. RESULTS: Overall, within KINDL dimensions, survivors reported comparable to higher HRQL for their children than the general population. Survivor parents reported significantly (p < 0.001) higher psychological (86.7% vs. 83.0%, Cohen's d = 0.3) and self-esteem (79.1% vs. 73.3%, Cohen's d = 0.5) well-being scores for younger children (3-6-year-olds). As time since diagnosis increased, parents reported higher well-being scores. Accordingly, recently diagnosed survivors reported significantly lower psychological well-being scores (p = 0.28; OR = 0.457; 95% CI = 0.228-0.918) for their children. With increasing age, average HRQL scores decreased in both cohorts; yet, this drop was less pronounced for survivor offspring. The biggest difference between age groups (7-10- vs. 14-17-year-olds) was found for school-specific well-being (6.2-point drop in survivor offspring vs. 18.2-point drop in KiGGS offspring). CONCLUSION: Comparable to higher parentally assessed HRQL was reported for survivor offspring compared to peers. These findings are reassuring and consistent with self-reported HRQL in childhood cancer survivors. Type of parental cancer diagnosis and treatment showed no negative impact on offspring HRQL.

Negative Hyperselection of Resistance Mutations for Panitumumab Maintenance in RAS Wild-Type Metastatic Colorectal Cancer (PanaMa Phase II Trial, AIO KRK 0212).

PURPOSE: We evaluated additional mutations in RAS wild-type (WT) metastatic colorectal cancer (mCRC) as prognostic and predictive biomarkers for the efficacy of added panitumumab to a 5-fluorouracil plus folinic acid (FU/FA) maintenance as pre-specified analysis of the randomized PanaMa trial. PATIENTS AND METHODS: Mutations (MUT) were identified using targeted next-generation sequencing (NGS; Illumina Cancer Hotspot Panel v2) and IHC. RAS/BRAF V600E/PIK3CA/AKT1/ALK1/ERBB2/PTEN MUT and HER2/neu overexpressions were negatively hyperselected and correlated with median progression-free survival (PFS) and overall survival (OS) since start of maintenance treatment, and objective response rates (ORR). Univariate/multivariate Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: 202 of 248 patients (81.5%) of the full analysis set (FAS) had available NGS data: hyperselection WT, 162 (80.2%); MUT, 40 (19.8%). From start of maintenance therapy, hyperselection WT tumors were associated with longer median PFS as compared with hyperselection MUT mCRC (7.5 vs. 5.4 months; HR, 0.75; 95% CI, 0.52-1.07; P = 0.11), OS (28.7 vs. 22.2 months; HR, 0.53; 95% CI, 0.36-0.77; P = 0.001), and higher ORR (35.8% vs. 25.0%, P = 0.26). The addition of panitumumab to maintenance was associated with significant benefit in hyperselection WT tumors for PFS (9.2 vs. 6.0 months; HR, 0.66; 95% CI, 0.47-0.93; P = 0.02) and numerically also for OS (36.9 vs. 24.9 months; HR, 0.91; 95% CI, 0.61-1.36; P = 0.50), but not in hyperselection MUT tumors. Hyperselection status interacted with maintenance treatment arms in terms of PFS (P = 0.06) and OS (P = 0.009). CONCLUSIONS: Extended molecular profiling beyond RAS may have the potential to improve the patient selection for anti-EGFR containing maintenance regimens.

Optimal maintenance strategy following FOLFOX plus anti-EGFR induction therapy in patients with RAS wild type metastatic colorectal cancer: An individual patient data pooled analysis of randomised clinical trials.

BACKGROUND: Anti-EGFR antibodies plus doublet chemotherapy is the standard of care in RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No phase-3 level of evidence is available to guide treatment de-escalation after anti-EGFR-based first-line. Several randomised clinical trials investigated de-intensification strategies with 5-fluorouracil/leucovorin (5-FU/LV) and/or anti-EGFR. METHODS: We performed an individual patient data pooled analysis of Valentino, Panama, MACRO-2, COIN-B trials including RAS wild-type mCRC patients who received first-line therapy with FOLFOX plus panitumumab or cetuximab followed by pre-specified maintenance strategy. Only patients who started maintenance according to the assigned arm were included. Patients were categorised by type of maintenance (i.e. 5-FU/LV, anti-EGFR or 5-FU/LV + anti-EGFR). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of maintenance; toxicity was evaluated for the maintenance treatment period. RESULTS: A total of 518 patients were included in the pooled analysis. Overall, 123, 185 and 210 patients received maintenance with 5-FU/LV, anti-EGFR, 5-FU/LV + anti-EGFR, respectively. Median PFS was 5.6, 6.0 and 9.0 (P = 0.009) and OS was 25.7, 24.0 and 28.0 months (P = 0.134) in 5-FU/LV, anti-EGFR and 5-FU/LV + anti-EGFR arms, respectively. Monotherapy maintenance (either 5-FU/LV or anti-EGFR) was inferior to combination in terms of PFS (hazard ratios [HR] 1.26, P = 0.016) and non-significantly trending also in OS (HR 1.20, P = 0.111). An increase of overall any grade and grade ≥ 3 AEs and selected AEs was reported in combination compared to either 5-FU/LV or anti-EGFR arms. CONCLUSIONS: This pooled analysis including four randomised phase II supports the use of 5-FU/LV plus anti-EGFR as the preferred maintenance regimen. Data provide rational for a more individualised maintenance treatment approach based on tumour and patients features.

Depth of response of induction therapy and consecutive maintenance treatment in patients with RAS wild-type metastatic colorectal cancer: An analysis of the PanaMa trial (AIO KRK 0212).

BACKGROUND: In patients with RAS wild-type metastatic colorectal cancer, depth of response (DpR) has gained importance as a novel end-point in clinical trials. We investigated the overall DpR, as well as the prognostic and predictive impact of DpR to induction therapy (six cycles of 5-fluorouracil, leucovorin [FU/FA], oxaliplatin [FOLFOX] and panitumumab [Pmab]) on consecutive maintenance therapy (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial. METHODS: Central radiological assessment was performed according to RECIST 1.1. DpR was defined as percentage change in tumour diameter within defined time intervals (induction therapy, maintenance therapy, total course of therapy). For prognostic and predictive analyses, median DpR (

Health-related quality of life in patients with RAS wild-type metastatic colorectal cancer treated with fluorouracil and folinic acid with or without panitumumab as maintenance therapy: a prespecified secondary analysis of the PanaMa (AIO KRK 0212) trial.

BACKGROUND: The PanaMa trial demonstrated significant benefit in progression-free survival with the addition of panitumumab (Pmab) to fluorouracil and folinic acid (FU/FA) as maintenance therapy following first-line induction therapy with FOLFOX/Pmab in patients with RAS wild-type metastatic colorectal cancer. Here, we report health-related quality of life (HRQOL) analyses from the PanaMa trial. METHODS: HRQOL outcomes were evaluated using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at every cycle of therapy until disease progression/death. HRQOL outcomes were mean and individual changes in EORTC QLQ-C30 from baselines (before induction therapy and before maintenance therapy) to each cycle of treatment. Comparative analyses were performed by randomisation status and treatment arm for induction- and maintenance-therapy, respectively. The trial is registered with clinicaltrials.gov (NCT01991873). RESULTS: At least one HRQOL questionnaire was completed by a total of 349/377 (93%) patients who received induction therapy, and by 237/248 (96%) patients who were randomised and received maintenance therapy. During induction therapy, most HRQOL dimensions remained stable or showed improvement, while appetite loss and diarrhoea significantly deteriorated. During maintenance therapy, HRQOL dimensions remained stable, while those that deteriorated during induction therapy showed significant improvement, without significant differences between the treatment arms. CONCLUSION: Maintenance therapy improves HRQOL dimensions that initially deteriorated during induction therapy while stabilising HRQOL in other dimensions. The addition of Pmab to FU/FA as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer prolongs progression-free survival without negative impact on HRQOL.

Health outcomes in offspring born to survivors of childhood cancers following assisted reproductive technologies.

PURPOSE: An increasing number of childhood cancer survivors are using assisted reproductive technologies (ART) to overcome treatment-related fertility impairment. We report perinatal and health outcomes of offspring born to survivors following ART. METHODS: The FeCt Multicenter Offspring Study surveyed the health of offspring of childhood cancer survivors. Health outcomes in offspring born to survivors following ART (n = 57, 4.6%) or after spontaneous conception (n = 1182) were assessed in the German cohort (n = 1239) using bivariate analysis. Findings were put into the context of the general German population by health outcome assessment in 1:1 matched-pair analysis (n = 2478). RESULTS: Nearly twice the survivors used ART compared with numbers reported for the German general population (4.6% vs. 2.6%). Successful pregnancies were achieved after a median of two cycles, mainly using non-cryopreserved oocytes/sperm. Multiple sibling births (p < 0.001, 28.1% vs. 3.0%) and low birth weight (p = 0.008; OR = 2.659, 95% CI = 1.258-5.621) occurred significantly more often in offspring born to survivors who utilized ART than spontaneously conceived children, whereas similar percentages were born preterm or too small for their gestational age. ART did not increase the prevalence of childhood cancer or congenital malformations in offspring born to survivors. CONCLUSION: ART use by childhood cancer survivors was successful with both fresh and cryopreserved oocytes/sperm, and did not influence perinatal health or health outcomes when known confounders were taken into account. IMPLICATIONS FOR CANCER SURVIVORS: Oncofertility is an important component of patient care. Our study implicates that the utilization of ART by adult survivors of childhood cancer does not put offspring at additional risk for adverse perinatal or health outcomes.

Health of children born to childhood cancer survivors: Participant characteristics and methods of the Multicenter Offspring Study.

INTRODUCTION: Research on childhood cancer survivor offspring has been limited to genetic disease occurrence, malformations or non-hereditary cancers. However, previous surveys indicated that survivors harbor fears about their (prospective) children's overall health. Our Multicenter Offspring Study examined extensive health aspects in children born to survivors and their siblings providing comprehensive information to be used in patient counseling to elucidate and alleviate existing concerns. METHODS: Using a specifically designed questionnaire, childhood cancer survivors and their siblings were surveyed on their offspring's health (Supplementary material). Recruitment strategies depended on local infrastructures and standards of participating centers, including registry-based and direct approaches. Group differences were tested non-parametrically and effect sizes were calculated. RESULTS: In total, 1126 survivors reported on 1780 offspring and 271 siblings reported on 441 offspring. Response rates ranged from 32.1% (Czech Republic) to 85.0% (Austria). Respondents were more likely to be female (p = .007), older at time of survey (p < .001), diagnosed 1980-1999 (p < .001) and treated with chemotherapy (p < .001). Compared to siblings, survivors were younger at time of survey (35 years vs. 39 years, p < .001) and at first birth (29 years vs. 30 years, p < .001). Survivor and sibling offspring only differed in terms of age at survey (6.3 years vs. 8.9 years, p < .001). CONCLUSION: The Multicenter Offspring Study investigates a wide variety of health aspects in offspring born to survivors and their siblings in five European countries. Our study cohorts form a solid basis for future analyses; yet, certain limitations, due to differences in approach among participating centers, must be considered when interpreting findings.