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Cabozantinib is a second-third line agent for sorafenib-experienced HCC patients. Therefore, it can be prescribed as part of a lenvatinib-sorafenib-cabozantinib or atezo/bev-sorafenib-cabozantinib sequence. Tolerability and safety are key concerns, especially for patients reaching a third-line treatment. However, dose reductions to manage adverse events (AEs) may induce fears of reduced efficacy. Analysis of the MULTICABO cohort (96 patients from 15 Italian centers). We evaluated the relative dose-intensity of cabozantinib during the first 8 weeks (8W-DI; expressed a ratio between the cumulative dose actually received and the maximum theoretical dose). The 8W-DI was correlated with disease control at the first imaging, progression-free survival (PFS), and overall survival (OS). To assess the effects of dose reductions after the first 8 weeks on the OS, multivariable time-dependent Cox regressions were carried out. Disease control rate was 63%. The median PFS and OS were and 5.2 and 11.3 months, respectively. The majority of patients (n=45) received the full 60mg daily dose during the first 8 weeks (median 8W-DI 100%, IQR 70-100%). A 90% 8W-DI (equating to a mean 54 mg/daily dose) was chosen for further analysis. A high 8W-DI did not correlate with worse radiological response (OR 1.72, 95% CI 0.72-4.15), PFS (HR 1.39, 95% CI 0.87-2.22), or OS (HR 1.06, 95% CI 0.61-1.83). Sixty-one (63.5%) and 19 (19.8%) patients permanently reduced cabozantinib to 40 and 20 mg/day to manage AEs. In the time-dependent analyses, reduction to 40 mg and 20 mg were associated with increased OS (HR 0.47, 95% CI 0.29-0.76; HR 0.41 95% CI 0.21-0.80, respectively]. Our results underline the importance of tailored dosing of cabozantinib. Dose adjustements to manage AEs should not automatically induce fears of reduced efficacy, as higher 8W-DI were not related to better outcomes while dose reductions to manage AEs were associated with increased OS. [ABSTRACT FROM AUTHOR]

CONTEXT: Existing studies on breakthrough pain (BP) have reported different prevalence rates because of different settings, populations, and assessment methods. These studies have used cross-sectional designs, and the relationship of BP with analgesic treatment has not been evaluated. OBJECTIVES: The aim of this study was to longitudinally assess BP in cancer patients admitted to oncology units. METHODS: A consecutive sample of patients admitted to oncology centers was selected. At admission (T0), three months after admission (T3), and six months after admission (T6), data on background pain and BP were recorded. BP was assessed in terms of its intensity, duration, number of episodes, onset with movement, spontaneous relief after stopping activity, limitation of physical activity, and effectiveness of analgesics. RESULTS: Three hundred two patients completed the study. At T0, T3, and T6, 39%, 38%, and 33% patients, respectively, had continuous pain (P=0.294). Pain intensity significantly decreased (P=0.004 and 0.027 at T3 and T6, respectively). Most patients had BP at T0 (87.1%), T3 (80.9%), and T6 (73.2%), and there was a significant decrease in the prevalence of BP over time (P=0.016). Of 149 patients with BP, pain on movement was recorded in 43.6%, 43.4%, and 32.4% at T0, T3, and T6, respectively (P=0.228). Pain spontaneously decreased or ceased when stopping physical activity in 66%, 56%, and 62% at T0, T3, and T6, respectively (P=0.537). Pain on movement strongly limited physical activity in most patients. CONCLUSION: These data expand current information about BP and underline the need for a longitudinal assessment of a phenomenon that is invariably dependent on stage of disease, patient, and therapeutic factors. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults and frequently relapses. The aim of this study was to assess the efficacy and safety of metronomic temozolomide (TMZ) in the recurrent GBM population. All patients treated at our centre between September 2013 and March 2021 were retrospectively reviewed. The main inclusion criteria were first-line therapy with the Stupp protocol, relapse after the first or subsequent line of therapy, treatment with a metronomic TMZ schedule (50 mg/m2 continuously) and histological diagnosis of isocitrate dehydrogenase wild-type GBM according to World Health Organization 2016 classification. In total, 120 patients were enrolled. The median follow-up was 15.6 months, the median age was 59 years, Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0–2 in 107 patients (89%). O6-methylguanine-DNA-methyltransferase (MGMT) was methylated in 66 of 105 (62%) evaluable patients. The median number of prior lines of treatment was 2 (range 1–7). Three (2%) patients showed a partial response; 48 (40%) had stable disease; 69 (57%) had progressive disease. The median overall survival from the start of metronomic TMZ was 5.4 months (95% confidence interval 4.3–6.4), whereas the median progression-free survival (PFS) was 2.6 months (95% confidence interval 2.3–2.8). At univariate analysis, MGMT methylated and unmethylated patients had a median PFS of 2.9 and 2.1 months (P = 0.001) and a median overall survival of 5.6 and 4.4 months (P = 0.03), respectively. At multivariate analysis, the absence of MGMT methylation (hazard ratio = 2.3, 95% confidence interval 1.3–3.9, P = 0.004) and ECOG-PS ≤ 2 (hazard ratio = 0.5, 95% confidence interval 0.3–0.9, P = 0.017) remained significantly associated with PFS, whereas ECOG-PS ≤ 2 (hazard ratio = 0.4, 95% confidence interval 0.3–07, P = 0.001) was the only factor associated with overall survival. The most common grade 3–4 toxicities were haematological (lymphopenia 10%, thrombocytopenia 3%). Rechallenge with metronomic TMZ is a well-tolerated option for recurrent GBM, even in pretreated patients. Patients with methylated MGMT disease and good ECOG-PS seem to benefit the most from this treatment. • Glioblastoma is the most common primary brain tumour in adults. • There is no general consensus about the best therapy at relapse. • Temozolomide at 50 mg/m2 continuously can be a viable therapeutic option for recurrent glioblastoma patients. • Heavily pretreated patients could benefit from metronomic temozolomide with a satisfying safety profile. [ABSTRACT FROM AUTHOR]

Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was <1%. The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov , registration number: NCT0064660. • TOSCA trial compared 3 or 6 months of adjuvant chemotherapy. • We here provided the updated results of OS at 7 years of median follow up. • The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). • At the last follow-up analysis, the absolute OS difference between arms was <1%. • The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. [ABSTRACT FROM AUTHOR]

Abstract Purpose Because the role of the primary tumour location in the adjuvant setting has not been clearly established in colon cancer, we analysed the clinical outcome according to the primary tumour location from three Italian trials assessing adjuvant therapy in colon cancer. Patients and methods Overall survival (OS) and disease-free survival (DFS) were assessed globally and in each trial, according to right-sided, transverse and left-sided primary colon cancer. Analysis was planned to provide overall and stage-specific results. Results Individual data of 5239 patients were included in this analysis. The right-sided tumours were 1540 (29%), tumours originating in the transverse were 815 (16%) and left-sided tumours were 2884 (55%). At the multivariate analysis, DFS findings from the comparison of the right-sided versus left-sided tumours (hazard ratio [HR] = 1.00; 95% confidence interval [CI] = 0.89–1.14) were not statistically associated with clinical outcomes in the overall population. On the contrary, OS findings, from the comparison of the right-sided versus left-sided tumours, were significantly associated with outcomes (HR = 1.20; 95% CI = 1.04–1.39). In stage II patients, there was no difference in terms of DFS and OS among the three different tumour locations, whereas in stage III patients, the left-sided tumours showed an improved prognosis in terms of OS (HR: 1.36 95% CI = 1.14–1.62, p < 0.001). Conclusion This is the largest analysis demonstrating a prognostic effect of the tumour location on patients with colon cancer receiving adjuvant chemotherapy. Nevertheless, the effect is limited to OS in stage III colon cancer. In stage II tumours, the primary location has a lesser impact. The transverse tumours should be prognostically considered in between the right-sided and left-sided tumours. Highlights • The primary tumour location has a prognostic effect even on patients with colon cancer receiving an adjuvant chemotherapy. • The effect is limited to overall survival in stage III colon cancer. • The transversum tumours should be prognostically considered between right-sided and left-sided tumours. [ABSTRACT FROM AUTHOR]

Background: Six months of oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. A shorter duration of therapy, if equally efficacious, would be advantageous for patients and Health-Care Systems. Patients and methods: TOSCA ['Randomized trial investigating the role of FOLFOX-4 or XELOX (3 versus 6 months) regimen duration and bevacizumab as adjuvant therapy for patients with stage II/III colon cancer] is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months (arm 3 m) versus 6 months (arm 6 m) of FOLFOX4/XELOX. Primary end-point was relapse-free survival. We present here safety and compliance data. Results: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Treatment completion rate without any modification was 35% versus 12% and with delays or dose reduction 52% versus 44% in arm 3 and 6 m. Treatment was permanently discontinued in 8% (arm 3 m) and 33% (arm 6 m). In arm 6 m, 50% of patients discontinuing treatment did so after completing 80% of planned program. Grade 3+ toxicities were higher in arm 6 m than that in 3 m. Grade 2+ neuropathy was 31.2% versus 8.8% (P < 0.0001) while grade 3+ was 8.4 versus 1.3 (P < 0.0001), in arm 3 and 6 m. Seven deaths within 30 days from last treatment administration in arm 6 m and three deaths in arm 3 m were observed (0.3% versus 0.1%, P = 0.34). [ABSTRACT FROM AUTHOR]

Abstract: Background: BRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC), leading to a median Progression Free Survival (PFS) of 4–6months with first-line conventional treatments. Our group recently reported in a retrospective exploratory analysis of a phase II trial that FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab might allow to achieve remarkable results in terms of PFS and Overall Survival (OS) also in this poor-prognosis subgroup. The aim of this work was to prospectively validate our retrospective finding. Patients and methods: This phase II trial was designed to detect an increase in 6month-Progression Free Rate (6m-PFR) from 45% to 80% in a population of BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab. Secondary end-points were PFS, OS, response rate (RR) and the analysis of outcome parameters in the pooled population consisting of both retrospectively and prospectively included patients. This trial is registered with ClinicalTrials.gov, number NCT01437618. Results: Two-hundred-fourteen potentially eligible mCRC patients were screened for BRAF mutational status. Fifteen BRAF mutant patients (7%) were included in the validation cohort. At a median follow up of 25.7months, 6m-PFR was 73%. Median PFS and OS were 9.2 and 24.1months, respectively. In the pooled population, at a median follow up of 40.4months, 6m-PFR was 84%. Median PFS and OS were 11.8 and 24.1months, respectively. Overall RR and disease control rate were 72% and 88%, respectively. Conclusion: Lacking randomised trials in this specific molecular subgroup, FOLFOXIRI plus bevacizumab might be a reasonable option for the first-line treatment of BRAF mutant mCRC patients. [Copyright &y& Elsevier]

Background The FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12–13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies. Patients and methods We conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, and folinate 200 mg/m2 on day 1, followed by fluorouracil 3000 mg/m2 as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12–13–61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m2 after two of the first three patients reported grade 3–4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab ± fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR). Results Eighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7–12.9 months). After amendment, most common grade 3–4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered. Conclusions Adding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras–BRAF wild-type patients are promising. [ABSTRACT FROM PUBLISHER]

Background Actual tolerability of sunitinib is still poorly documented in elderly patients with metastatic renal cell carcinoma (mRCC). Patients and methods Charts of elderly patients treated with sunitinib for mRCC were reviewed in six Italian centers to assess safety (primary objective), efficacy and correlation of toxicity with comprehensive geriatric assessment (CGA) (secondary objectives). Results Sixty-eight patients were eligible, and the median age was 74 years. CGA was carried out in 34 patients (41% fit, 41% vulnerable and 18.5% frail). The dose reduction to 37.5 mg was made upfront or soon after the first cycle in 69.1%. More frequent toxic effects were fatigue (80.9%), mucositis (61.8%) and hypertension (58.8%). Cardiac events occurred in nine patients. In 10 patients, therapy was interrupted early due to rapidly progressive disease (10.3%) or severe toxicity (4.4%: 1 cardiac failure, 1 fatigue, 1 febrile neutropenia). At a median follow-up of 27.1 months, the median OS was 18.3 months and the median PFS was 13.6 months. Correlation was not found between frailty at CGA with severe toxicity nor with response. Conclusions Treatment with sunitinib is effective in elderly patients; yet early interruptions were frequent. Starting treatment at reduced dose and escalating in the absence of severe toxicity could be suggested. [ABSTRACT FROM PUBLISHER]

OBJECTIVES: To document the preliminary validity of a new informed consent form (ICF) model in terms of face/content validity and feasibility, to collect patients' and oncologists' opinions on it, and to explore physicians' and patients' 'knowledge', 'opinions' about 'the information exchanged'. METHODS: The working group for informed consent promoted by the Italian Association of Medical Oncology developed a new ICF model which was tested in ten Italian cancer centers. Patients and physicians received questionnaires on the new ICF model. Twenty-six independent oncologists were interviewed to collect their opinions. RESULTS: Seventy eight cancer patients were enrolled: about 90% reported having received information about diagnosis and therapy and 80% about prognosis. About 63% of oncologists had no difficulty in administering the ICF. Oncologists used 'correct terms' about diagnosis in 92% of patients with localized disease and in 90% with metastasis and about therapy in respectively 75.7% and 80%. About prognosis, oncologists used 'vague' and 'no information-no pertinent terms' in 79% of patients with localized disease and 92.5% of patients with metastasis. CONCLUSIONS: The ICF seemed to have sufficient validity and feasibility. PRACTICE IMPLICATION: This ICF model could mean that patients require oncologists to spend more time explaining the diagnosis, prognosis and treatment, increasing patient's opportunities to participate actively in the care process. [ABSTRACT FROM AUTHOR]

Pem, an immune checkpoint inhibitor, has been demonstrated to be active in various neoplasms with MMRd. No data exist about its efficacy in MMRd glioma patients. MMRd HGG patients relapsed after receiving RT and CT were treated with Pem. MMR status was analyzed by immunohistochemistry, including the MLH1, MSH2, MSH6, and PMS2 markers. MMR deficiency was defined as presence of a weak (wMMRd) or absent (aMMRd) signal on immunohistochemistry for at least one MMR protein. Other inclusion criteria were: ECOG PS 0-2, histologically confirmed gliomas, dexamethasone ≤4 mg. Pem was administered at 200 mg every 3 weeks until disease progression or unacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeks according to the RANO criteria. OS and PFS were evaluated by Kaplan-Meier curves. CTCAE v4.0 was used for toxicity assessment. Among 167 glioma patients, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, all PTS had microsatellite stability. Tumor histologies included 5 anaplastic astrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2 deficiency was found in 6 cases, MSH6 deficiency in 9 cases, PMS2 and MLH1 deficiency in 2 cases. Median number of prior lines of chemotherapy was 1 (range 1-5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showed progressive disease (PD). PTS with anaplastic gliomas showed a statistically significant association with SD (p = 0.03, OR = 3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6 (deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1-13.8), PFS 2.4 ms (95% CI 1.8-2.9). OS was 2.8 ms and 5.6 ms (p = 0.9), PFS was 1.8 ms and 3.1 ms (p = 0.5) in PTS with wMMRd and aMMRd. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6-10.2) and 1.8 ms (95% CI 0.2-3.4), p = 0.002; OS was "not reached" and 2.8 ms in PTS having SD vs PD (p = 0.04). Grade ≥3 adverse events were reported in 8% of PTS. A subgroup of recurrent MMRd HGG patients might benefit from Pem, especially those with anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. Analyses for identifying additional molecular predictive factors is ongoing. The authors. Has not received any funding. All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Treatment for GBM elderly patients (pts) is a challenge in neuro-oncology. The CGA is currently used for assessing elderly pts and its score correlates with outcome in many types of tumors. We have reported some general outcomes of CGA in GBM pts. Here we performed a large retrospective analysis for identifying specific CGA category correlations with PFS and OS Pts aged ≥65 years, with histological diagnosis of GBM and availability of CGA result were enrolled. The CGA was administered before starting radio/chemotherapy (RT/CH) or palliative care we enrolled 113 pts; median age was 71.7 years. Radical surgery was performed in 33% of cases; 80% of pts were treated with RT/CH combination; median number of maintenance temozolomide (TMZ) cycles was 3.9. Most pts had a high Karnofsky Perfrmance Score (80%). According to CGA score, 35% of pts were categorized as "fit", 30% as "vulnerable" and 35% were "frail", and median overall survival was 16.5 vs 12.1 vs 10.3 months (p = 0.1). On multivariate analysis, CGA score proved an independent predictor of survival: vulnerable and frail pts reported an HR of 1.5 and 2.2, respectively, compared to fit pts (p = 0.04). Moreover, we demonstrated a statistical association between CGA and type of treatment, fit pts being more frequently treated with RT/CT (98% vs 90% and 52% of vulnerable and frail pts, respectively, p < 0.001); yet, frail pts received fewer cycles of maintenance TMZ than vulnerable and fit (2.8 vs 5 and 5.2, respectively; p < 0.001). No association between CGA and PFS was demonstrated. CGA score was shown to be a significant predictor of mortality in elderly GBM pts. The score can classify pts into three categories statistically correlating with survival. It could be a useful treatment decision tool suggesting the more appropriate treatment. However, a prospective study is warranted. Veneto Institute of Oncology IOV IRCCS. Has not received any funding. All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in patients (pts) with relapsed GBM with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point. HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P = 0.01 (2-sided). Of 119 randomized pts, 117 participated in the HRQoL evaluation, and 114 had a baseline assessment (n = 56 REG; n = 58 LOM). No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD = 28.6) vs 7.6 (SD = 16.0); p = 0.0081). The rate of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively; p = 0.02). In the REGOMA trial, HRQoL did not change during regorafenib treatment. Pts treated with regorafenib and lomustine reported no significant difference in HRQoL. Giuseppe Lombardi. Has not received any funding. All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]