Few data are available regarding the treatment of metastatic colorectal cancer elderly patients with anti-EGFR agents in combination with chemotherapy. FOLFOX plus panitumumab is a standard ...first-line option for RAS wild-type metastatic colorectal cancer. Slight adjustments in chemo-dosage are commonly applied in clinical practice to elderly patients, but those modified schedules have never been prospectively tested. Clinical definition of elderly (≥70 years old) patients that may deserve a more or less intensive combination therapy is still debated. Several geriatric screening tools have been developed to predict survival and risk of toxicity from treatment. Among those, the G8 screening tool has been tested in cancer patients showing the strongest prognostic value for overall survival, while the CRASH score can stratify patients according to an estimated risk of treatment-related toxicities.
The PANDA study is a prospective, open-label, multicenter, randomized phase II trial of first-line therapy with panitumumab in combination with dose-adjusted FOLFOX or with 5-fluorouracil monotherapy, in previously untreated elderly patients (≥70 years) with RAS and BRAF wild-type unresectable metastatic colorectal cancer. RAS and BRAF analyses are centralized. Geriatric assessment by means of G8 and CRASH score is planned at baseline and G8 will be re-evaluated at disease progression. The primary endpoint is duration of progression-free survival in both arms. Secondary endpoints include prospective evaluation of the prognostic role of G8 score and the correlation of CRASH risk categories with toxicity.
The PANDA study aims at exploring safety and efficacy of panitumumab in combination with FOLFOX or with 5FU/LV in elderly patients affected by RAS and BRAF wild-type metastatic colorectal cancer, to identify the most promising treatment strategy in this setting. Additionally, this is the first trial in which the prognostic role of the G8 score will be prospectively evaluated. Results of this study will drive further experimental developments for one or both combinations.
PANDA is registered at Clinicaltrials.gov : NCT02904031 , July 11, 2016. PANDA is registered at EudraCT-No.: 2015-003888-10, September 3, 2015.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
e24015
Background: Colorectal cancer (CRC) is the second most frequent malignancy in patients (pts) aged 70. Elderly patients are often excluded by clinical trials; however, improvements in quality ...of life and comorbidities management led to expand the access to anticancer treatments irrespectively of age per se. Finding new tools to stratify vulnerability in elderly pts is crucial to guide clinicians in therapeutic decisions. G8 and timed up and go test (TUG) have been related to prognosis and functional decline in patients affected by several solid tumors. However, no studies focused on TUG and G8 prognostic value in CRC pts are available. In this study, we assessed the prognostic value of G8 and TUG in a cohort of real-life elderly pts with metastatic CRC (mCRC). Methods: GOLD was a multicentre, observational, prospective study in which pts aged 70 with mCRC and eligible to 1
st
line therapy were enrolled. G8 and TUG were performed at screening and at the first documented disease progression (PD). G8 cutoff was 14, as reported in literature; TUG8,5 sec (cutoff set with ROC curve using MedCalc software v 20.027). PFS and OS were described with Kaplan-Meyer curve. All analyzed variables were then compared with multivariate models. Primary endpoint of the study was to assess prognostic value of G8 in OS and PFS. Secondary endpoints were to assess prognostic value of TUG in OS and PFS. Results: Since Oct 2017 to Apr 2019, 109 pts were evaluated in 4 different Oncology Units in Veneto (IT); 4 were not eligible to anticancer treatments and where thus excluded. 105 pts were finally enrolled. Clinical, histological and molecular characteristics were well balanced between pts with G814 vs > 14, with the exception of RASmut, more represented in the G8 > 14 group (p = 0,0195). 39 (37%) pts were aged80; 46 (44%) had ECOG PS1; 55 (53%) had RASmut; 15 (15%) had BRAFmut. 81 (77%) had G814; 78 (75%) had TUG8,5. At a median follow up time of 41,2 months, median OS was 19,41 months (95%CI 15,46-23,19) and median PFS 8,78 months (95% CI 7,53-10,07). OS was longer in patients with G814 (HR 0,61; 95%CI 0,39-0,97; p= 0,0584) and TUG8,5 (HR 0,55; 95%CI 0,35- 0,86; p= 0,0201). PFS was not influenced by G8 (HR 0,86; 95%CI 0,55-1,34; p= 0,5125) nor by TUG (HR 0,71; 95%CI 0,47-1,08). G814 and TUG8,5 conferred better OS also in the subgroup of RASmut (respectively p= 0,0133 and p= 0,0088). Worse OS was observed in presence of > 1 metastatic site (HR = 1,71; 95%CI 1,11 to 2,64; p= 0,0161). At the multivariate analysis, G814 ( p= 0,0202) and single metastatic site ( p= 0,0200) were related to better OS; none of the analysed variables had effect on PFS. Conclusions: In our study G814 and TUG8,5 had prognostic value in OS, but not in PFS, in a real-life population of elderly pts affected by mCRC. G8 and single metastatic site involvement were related to better OS, irrespectively of other clinical, histological and molecular variables.
The aims of the study are to evaluate the clinical outcomes of first-line treatment with platinum-based chemotherapy and cetuximab in patients with relapsing/metastatic head and neck cancer (RM ...HNC) and to identify predictors of treatment response.
This is a retrospective, observational, longitudinal, real-world study involving 6 oncology centres in Italy. All consecutive patients with RM HNC treated between January 2007 and December 2016 with a first-line therapy consisting of a platinum-based chemotherapy regimen plus cetuximab were included. The primary objective of the study was to assess overall survival (OS) and progression-free survival (PFS). Secondary objectives included the identification of predictors of treatment response.
Overall, 297 patients were identified. Median OS was 10.8 months (95% confidence interval CI 9.3–12.2), whereas median PFS was 4.8 months (95% CI 4.3–5.5). On multivariable analysis, independent unfavourable prognostic factors for OS were performance status (PS) Eastern Cooperative Oncology Group (ECOG) >0, presence of residual tumour at primary site, platinum resistance and lack of objective response. Unfavourable predictors for PFS included cancer primary site (paranasal sinuses, hypopharynx), PS ECOG >0, presence of residual tumour at primary site, platinum resistance and lack of objective response. Independent unfavourable predictors of objective response were tumour site (oral cavity, larynx-hypopharynx), residual tumour at primary site and prior chemotherapy.
The availability of new treatment modalities and epidemiological changes make the periodic reassessment of prognostic factors of great relevance to guide clinical practice and the design of future randomised clinical trials.
•Changes in epidemiology and treatment of relapsing/metastatic head and neck cancer (RM HNC) require a reassessment of prognostic factors.•Platinum resistance emerged as an important predictor of shorter progression-free survival and overall survival.•Poor performance status, residual tumour at primary site and no objective response play a prognostic role.•After the adoption of the EXTREME regimen for RM HNC, prognostic factors profile has changed.
BACKGROUNDUpfront anti-EGFR therapy represents the standard of care for patients with left-sided, MSS/pMMR, RAS and BRAF wild-type mCRC. Molecular 'hyperselection' may optimize EGFR inhibition by ...detecting additional resistance alterations.MATERIALS AND METHODSWe used comprehensive genomic profiling on archival samples of elderly patients enrolled in the PANDA trial to detect: HER2 amplification/mutations; MET amplification; NTRK/ROS1/ALK/RET rearrangements; PIK3CA exon 20 mutations; PTEN alterations; AKT1 mutations; MAP2K1 mutations. We defined 'Gene Altered' (GA) patients whose tumour harboured at least one alteration, and 'Hyperselected' (HS) those without. Survival and tumour response outcomes were correlated to hyperselection status alone or combined with primary tumour sidedness or treatment arm.RESULTSGenomic alterations were detected in 41/147 patients (27.9%). PFS, OS and ORR were inferior in GA versus HS (median PFS: 7.6 versus 12.8 months, HR = 2.08, 95% CI: 1.43-3.03, p < 0.001; median OS: 20.0 versus 29.5 months, HR = 1.82, 95% CI:1.23-2.69, p = 0.002; ORR: 51% versus 71%; OR = 0.43, 95% CI: 0.21-0.91, p = 0.02). In the multivariable models, the impact of hyperselection on PFS and OS was confirmed. Lower ORR was observed with 5-FU/LV/panitumumab in GA (40% versus 62%), but not in HS (70% versus 72%). GA was associated with worse survival and response regardless of primary tumour sidedness, whereas in the HS subgroup, right-and left sided tumours had similar outcomes.CONCLUSIONSMolecular hyperselection and comprehensive genomic profiling have a potential usefulness in elderly patients with RAS/BRAF wild-type, pMMR/MSS mCRC, eligible for upfront EGFR inhibition.
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Background: Data on first-line treatment efficacy in elderly patients are limited. Many analyses adopt a questionable cut-off of 65 years and specific evidence with anti-EGFRs is ...low. FOLFOX-panitumumab (pan) is an option for RAS wild-type (wt) untreated mCRC patients. Guidelines recommend considering fluoropyrimidine monotherapy as an option for elderly patients, but no randomized studies have ever explored the role of the combination with an anti-EGFR. Methods: This is a prospective, open-label, multicenter phase II randomized trial. Unresectable and previously untreated RAS- BRAF wt mCRC patients aged ≥70 were randomized to receive FOLFOX-pan (arm A), or 5FU/LV-pan (arm B) for up to 12 cycles followed by pan maintenance until PD. The primary EP was PFS in both arms. Stratification criteria were age (≤75 vs > 75 years), ECOG PS (0–1 vs 2) and geriatric assessment with G8 Score (≤14 vs > 14). In each treatment arm, the null hypothesis for median PFS was set at ≤6 months. Assuming an expected median PFS time ≥9.5 months with both experimental regimens, a sample size of 90 patients in each arm granted to the study a power of 90%, with a type I error rate equal to 5% (1-sided Brookmeyer-Crowley test) for rejecting the null hypothesis. No formal comparison between the two arms was planned. Results: From Jul 2016 to Apr 2019 a total of 394 patients were screened, 211 were deemed eligible for inclusion and 185 were randomized (92 arm A and 93 arm B). Main pts’ characteristics were (arm A/B): males 66%/61%; median age 77/77y; PS≥1 49%/55%; right colon 23%/21%; G8 > 14 31%/30%. At a median follow up of 20.5 mos, 135 (arm A/B: 64/71) PD events were collected. Median PFS was 9.6 (95% CI 8.8-10.9) in arm A with FOLFOX-pan and 9.1 (95% CI 7.7-9.9) in arm B with 5FU/LV-pan. Response rates were (arm A/B): 65%/57%. Grade 3-4 toxicities were (arm A/B): neutropenia 9.8%/1.1%; diarrhea 16.3%/1.1%; stomatitis 9.8%/4.4%; neurotoxicity 3.3%/0%; fatigue 6.5%/4.4%; skin rash 25%/24.2%, hypomagnesemia 3.3%/7.7%. Conclusions: Large prospective randomized studies in molecularly selected elderly mCRC are feasible with multicenter collaborative efforts. Primary EP was met in both treatment arms. 5FU/LV plus panitumumab for up to 12 cycles followed by panitumumab maintenance until PD might be a reasonable option in elderly mCRC patients with RAS/BRAF wt tumors deserving further investigations in phase III trials. Clinical trial information: NCT02904031 .
We report the case of a 64-year-old male patient diagnosed as having inoperable poorly differentiated liver carcinoma that could be completely resected after systemic chemotherapy with cisplatin and ...5-fluorouracil.
Recommendations for managing patients with nasopharyngeal carcinoma (NPC) in non-endemic areas are largely derived from studies conducted in endemic areas. We analysed the impact of treatment ...approaches on survival in non-endemic areas.
In an international, multicentre, retrospective study, we analyse consecutive patients with NPC diagnosed between 2004 and 2017 in 36 hospitals from 11 countries. Treatment was categorised as non-intensive (NIT), including radiotherapy alone or concomitant chemoradiotherapy (cCRT), and intensive (IT) including cCRT preceded by and/or followed by chemotherapy (CT). The impact of IT on overall survival (OS) and disease-free survival (DFS) was adjusted for all the available potential confounders.
Overall, 1021 and 1113 patients were eligible for overall survival (OS) and disease-free survival (DFS) analyses, respectively; 501 and 554 with Epstein Barr-encoded RNA (EBER) status available. In the whole group, 5-year OS was 84% and DFS 65%. The use of NIT was associated with a risk of death or recurrence 1.37 times higher than patients receiving IT. Patients submitted to NIT and induction CT + concurrent concomitant chemo and three-dimensional Conformal Radiation Therapy (3DCRT) had a risk of death or recurrence 1.5 and 1.7 times higher than patients treated with induction CT + cCRT with intensity-modulated radiotherapy (IMRT), respectively. The IT had no impact on OS in neither patients with EBER+ nor in patients with EBER-; IT showed better DFS in EBER+ but not in patients with EBER-.
In low-incidence areas, patients with NPC treated with induction CT followed by concurrent IMRT cCRT achieved the highest DFS rate. The benefit of IT on DFS was restricted to patients with EBER+, suggesting that additional therapy offers no advantages in EBER- cases.
•Nasopharyngeal cancer 5-years OS and DFS rates, in non-endemic area, are 84% and 65%.•Intensive treatment approaches improve DFS in patients with locally advanced cancers.•The benefit of intense treatment on DFS was restricted to patients with EBER+.
Patients included in clinical trials are "selected", and they usually differ from those commonly treated.
From 1999 to 2004, in the Medical Oncology Department of Padua (Italy), 70 metastatic ...colorectal cancers were treated with FOLFOX4.
Our results, compared with those of the registration trial (response rate, duration of response and progression-free survival) appeared lower; overall survival was improved.
The number of therapeutic regimens more than their type influenced the results.
Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study ...was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients.
Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used.
KRAS-mutated cohort included 58 patients, and overall 73 treatments (N = 39 chemotherapy and N = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0-61.8). KRAS mutation at T2 was associated with increased probability of experiencing progressive disease as best radiological response (adjusted odds ratio: 7.3; 95% CI: 2.1-25.0, p = 0.0016). Increased MAFA (T1-T2) predicted shorter progression-free survival (adjusted hazard ratio (HR): 2.1; 95% CI: 1.2-3.8, p = 0.0142) and overall survival (adjusted HR: 3.2; 95% CI: 1.2-8.4, p = 0.0168).
Longitudinal analysis of plasma KRAS mutations correlated with outcome: its early assessment during treatment has great potentialities for monitoring treatment outcome in NSCLC patients.
Molecular profiling of advanced
mutated NSCLC has recently demonstrated the co-existence of multiple genetic alterations. Specifically, co-existing
-mutations in
NSCLCs have been described, despite ...their prevalence at progression and their role in the response to
tyrosine kinase inhibitors (TKIs) remain marginally explored. Aim of our study was to investigate the prevalence of co-existing
mutations at the time of progressive disease and explore their impact on clinical outcome.
We retrospectively analyzed by digital droplet PCR prevalence of
co-mutations in 106 plasma samples of
mutated NSCLC patients, in progressive disease after
TKI treatment as first-line therapy.
co-mutations (codon 12 and 13) were identified in 3 patients (2.8% of analyzed samples), with low allelic frequency (<0.2%), and had a negative impact on clinical outcome to first-line
TKI.
Detection of
mutations in cell-free DNA of
mutant NSCLC patients at progression after first or second generation
TKI is a rare event. Due to their low abundance, the negative impact of
mutations on the response to
TKI remains to be confirmed in larger studies.
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