Standard versus fractionated high-dose cisplatin plus radiation for locally advanced head and neck cancer: Results of the CisFRad (GORTEC 2015-02) randomized phase II trial.

BACKGROUND: Chemoradiotherapy with high-dose cisplatin (HD-Cis: 100 mg/m2 q3w for three cycles) is the standard of care (SOC) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Cumulative delivered dose of cisplatin is prognostic of survival, even beyond 200 mg/m2 but high toxicity compromises its delivery. AIM: Cisplatin fractionation may allow, by decreasing the peak serum concentration, to decrease toxicity. To date, no direct comparison was done of HD-Cis versus fractionated high dose cisplatin (FHD-Cis). METHODS: This is a multi-institutional randomized phase II trial, stratified on postoperative or definitive chemoradiotherapy, comparing HD-Cis to FHD-Cis (25 mg/m2/d d1-4 q3w for 3 cycles) in patients with LA-HNSCC. The primary endpoint was the cumulative delivered cisplatin dose. RESULTS: Between December 2015 and April 2018, 124 patients were randomized. Median cisplatin cumulative delivered dose was 291 mg/m2 (IQR: 251;298) in the FHD-Cis arm and 274 mg/m2 (IQR: 198;295) in the HD-Cis arm (P = 0.054). The proportion of patients receiving a third cycle of cisplatin was higher, with a lower proportion of grade 3-4 acute AEs in the FHD-Cis arm compared to the HD-Cis arm: 81 % vs. 64 % (P = 0.04) and 10 % vs. 17 % (P = 0.002), respectively. With a median follow-up of 48 months (IQR: 41;55), locoregional failure rate, PFS and OS were similar between the two arms. CONCLUSION: Although the primary endpoint was not met, FHD-Cis allowed more cycles of cisplatin to be delivered with lower toxicity, when compared to SOC. FHD-Cis concurrently with RT is a treatment option which deserves further consideration.

Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. METHODS: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). RESULTS: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. CONCLUSIONS: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.

Season of radiotherapy and outcomes of head & neck cancer patients in the MACH-NC & MARCH meta-analyses.

BACKGROUND: A single institution retrospective study suggested that head and neck squamous cell cancer (HNSCC) patients receiving radiotherapy (RT) during "dark" season (fall/winter) may have better outcomes than those treated during "light" season (spring/summer), possibly secondary to seasonal variations in cell cycle progression. We investigated the impact of season of RT in two large, multi-institutional, prospective datasets of randomized trials. METHODS: Individual patient data from the MACH-NC and MARCH meta-analyses were analyzed. Dark season was defined as mid-radiotherapy date during fall or winter and light the reverse, using equinoxes to separate the two periods. Primary endpoint was progression-free survival (PFS) and secondary endpoint was locoregional failure (LRF). The effect of season was estimated with a Cox model stratified by trial and adjusted on sex, tumor site, stage, and treatment. Planned sensitivity analyses were performed on patients treated around solstices, who received "complete radiotherapy", patients treated with concomitant radio-chemotherapy and on trials performed in Northern countries. RESULTS: 11320 patients from 33 trials of MARCH and 6276 patients from 29 trials of MACH-NC were included. RT during dark season had no benefit on PFS in the MARCH (hazard ratio[HR]: 1.01 [95%CI 0.97;1.05],p=0.72) or MACH-NC dataset (HR:1.00 [95%CI 0.94;1.06],p=1.0. No difference in LRF was observed in the MARCH (HR:1.00 [95%CI 0.94;1.06,p=0.95) or MACH-NC dataset (HR:0.99 [95%CI 0.91; 1.07],p=0.77). Sensitivity analyses showed similar results. CONCLUSION: Season of RT had no impact on PFS or LRF in two large databases of HNSCC.

Hepatic arterial oxaliplatin plus intravenous 5-fluorouracil and cetuximab for first-line treatment of colorectal liver metastases: A multicenter phase II trial.

BACKGROUND: The efficacy and tolerability of hepatic arterial infusion (HAI) oxaliplatin plus systemic 5-fluorouracil and cetuximab as frontline treatment in patients with colorectal liver metastases (CRLM) are unknown. METHODS: In this multicenter, single-arm phase II study, patients with CRLM not amenable to curative-intent resection or requiring complex/major liver resection, and no prior chemotherapy for metastatic disease, received HAI oxaliplatin and intravenous 5-fluorouracil, leucovorin and cetuximab, every two weeks until disease progression, limiting toxicity or at least 3 months after complete response or curative-intent resection/ablation. The primary endpoint was overall response rate (ORR). RESULTS: 35 patients, mostly with bilateral (89%), multiple CRLM (>4, 86%; >10, 46%) were enrolled in eight centers. The ORR was 88% (95% CI, 71%-96%) among evaluable patients (n = 32), and 95% (95% CI 70-100%) among the 22 wild-type RAS/BRAF evaluable patients. After a median follow-up of 8.8 years (95% CI, 8.7-not reached), median progression-free survival was 17.9 months (95% CI, 15-23) and median overall survival (OS) was 46.3 months (95% CI, 40.0-not reached). 23 of the 35 patients (66%), including 22 (79%) of the 25 patients with wild-type RAS tumor, underwent curative-intent surgical resection and/or ablation of CRLM. HAI catheter remained patent in 86% of patients, allowing for a median of eight oxaliplatin infusions (range, 1-19). Treatment toxicity was manageable, without toxic death. CONCLUSION: HAI oxaliplatin plus systemic 5-fluorouracil and cetuximab appears highly effective in the frontline treatment of patients with unresectable CRLM and should be investigated further.

Individual Participant Data Network Meta-Analysis of Neoadjuvant Chemotherapy or Chemoradiotherapy in Esophageal or Gastroesophageal Junction Carcinoma.

PURPOSE: The optimal neoadjuvant treatment for resectable carcinoma of the thoracic esophagus (TE) or gastroesophageal junction (GEJ) remains a matter of debate. We performed an individual participant data (IPD) network meta-analysis (NMA) of randomized controlled trials (RCTs) to study the effect of chemotherapy or chemoradiotherapy, with a focus on tumor location and histology subgroups. PATIENTS AND METHODS: All, published or unpublished, RCTs closed to accrual before December 31, 2015 and having compared at least two of the following strategies were eligible: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). All analyses were conducted on IPD obtained from investigators. The primary end point was overall survival (OS). The IPD-NMA was analyzed by a one-step mixed-effect Cox model adjusted for age, sex, tumor location, and histology. The NMA was registered in PROSPERO (CRD42018107158). RESULTS: IPD were obtained for 26 of 35 RCTs (4,985 of 5,807 patients) corresponding to 12 comparisons for CS-S, 12 for CRS-S, and four for CRS-CS. CS and CRS led to increased OS when compared with S with hazard ratio (HR) = 0.86 (0.75 to 0.99), P = .03 and HR = 0.77 (0.68 to 0.87), P < .001 respectively. The NMA comparison of CRS versus CS for OS gave a HR of 0.90 (0.74 to 1.09), P = .27 (consistency P = .26, heterogeneity P = .0038). For CS versus S, a larger effect on OS was observed for GEJ versus TE tumors (P = .036). For the CRS versus S and CRS versus CS, a larger effect on OS was observed for women (P = .003, .012, respectively). CONCLUSION: Neoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS and tumor location for CS. A strong OS difference between CS and CRS was not identified.

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

BACKGROUND: The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. METHODS: For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. FINDINGS: The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). INTERPRETATION: The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. FUNDING: Institut National du Cancer and Ligue Nationale Contre le Cancer.

Intra-arterial hepatic bevacizumab and systemic chemotherapy in hepatic metastasis of colorectal cancer: A phase II multicentric trial in second-line treatment.

INTRODUCTION: Intra-arterial hepatic (IAH) treatment has shown promising results in the management of patients with unresectable colorectal liver metastases (CRLM) the prognosis of which is poor. Bevacizumab adjunction to standard chemotherapy has been shown to improve survival of this patient population. This prospective study was conducted to assess the efficacy and safety of IAH bevacizumab combined to systemic chemotherapy after first-line treatment failure in patients with CRLM. METHODS: Included patients had dominant or isolated unresectable CRLM progressing after standard first-line treatment for metastases of colorectal cancer. Three patients had less than 30% liver invasion, three patients between 30 and 50%, two more than 50% and data was missing in two patients. An intra-hepatic catheter was implanted surgically or percutaneously. Bevacizumab 7.5 mg/kg was administered once every 3 weeks in combination with capecitabine 2000 mg/m² per day for 2 weeks and oxaliplatin 130 mg/m² or irinotecan 200 mg/m² once every 3 weeks. The primary end-point was the objective response rate. RESULTS: Between June 2013 and February 2015, 10 patients were included. The trial was prematurely closed because of the lack of financial support and poor accrual. The patients had a median of 6 [1-9] cycles of treatment. Partial response was achieved in 2 patients (20%) and a R0 liver metastases resection in one another. All patients died of disease progression. The median overall and progression-free survival rates were respectively 14.0 (95% IC [4.8 - 25.8] and 5.4 months (95% IC [1.6 - 6.2]). Four patients had severe side effects but no toxic death occurred. CONCLUSION: IAH bevacizumab combined to systemic chemotherapy is feasible and safe in patients with unresectable isolated or dominant CRLM progressing after a first-line systemic treatment. Based on the low number of patients included in our study, our results suggest that this treatment does not increase dramatically the response rate versus an adapted systemic treatment. However, considering the safety data provided in this study, arterial infusion of bevacizumab in adjunction to chemotherapeutic agents could be evaluated in the future.

ANtiangiogenic Second-line Lung cancer Meta-Analysis on individual patient data in non-small cell lung cancer: ANSELMA.

BACKGROUND: Now that immunotherapy plus chemotherapy (CT) is one standard option in first-line treatment of advanced non-small cell lung cancer (NSCLC), there exists a medical need to assess the efficacy of second-line treatments (2LT) with antiangiogenics (AA). We performed an individual patient data meta-analysis to validate the efficacy of these combinations as 2LT. METHODS: Randomised trials of AA plus standard 2LT compared to 2LT alone that ended accrual before 2015 were eligible. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, main end-point), progression-free survival (PFS) and subgroup analyses. RESULTS: Sixteen trials were available (8,629 patients, 64% adenocarcinoma). AA significantly prolonged OS (HR = 0.93 [95% confidence interval {CI}: 0.89; 0.98], p = 0.005) and PFS (0.80 [0.77; 0.84], p < 0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.8% [-0.4; +4.0] and +3.5% [+1.9; +5.1], respectively. The OS benefit of AA was higher in younger patients (HR = 0.87 [95% CI: 0.76; 1.00], 0.89 [0.81; 0.97], 0.94 [0.87; 1.02] and 1,04 [0.93; 1.17] for patients <50, 50-59, 60-69 and ≥ 70 years old, respectively; trend test: p = 0.02) and in patients who started AA within 9 months after starting the first-line therapy (0.88 [0.82; 0.99]) than in patients who started AA later (0.99 [0.91; 1.08]) (interaction: p = 0.03). Results were similar for PFS. AA increased the risk of hypertension (p < 0.0001), but not the risk of pulmonary thromboembolic events (p = 0.21). CONCLUSIONS: In the 2LT of advanced NSCLC, adding AA significantly prolongs OS and PFS, but the benefit is clinically limited, mainly observed in younger patients and after shorter time since the start of first-line therapy.

Meta-analysis of chemotherapy in nasopharynx carcinoma (MAC-NPC): An update on 26 trials and 7080 patients.

PURPOSE: Chemotherapy, when added to radiotherapy, improves survival in locally advanced nasopharyngeal carcinoma (NPC). This article presents the second update of the Meta-Analysis of Chemotherapy in NPC. METHODS: Published or unpublished randomized trials assessing radiotherapy (±a second chemotherapy timing) with/without chemotherapy in non-metastatic NPC patients were identified. Updated data were sought for studies included in the previous rounds of the meta-analysis. The primary endpoint was overall survival. All trials were analyzed following the intent-to-treat principle using a fixed-effects model. Treatments were classified in five subsets according to chemotherapy timing. The statistical analysis plan was pre-specified. RESULTS: Eighteen new trials were identified. Individual patient data were available for seven. In total, the meta-analysis now included 26 trials and 7,080 patients. The addition of chemotherapy reduced the risk of death, with a hazard ratio (HR) of 0.79 (95% confidence interval (CI) [0.73; 0.85]), and an absolute survival increase at 5 and 10 years of 6.1% [+3.9; +8.3] and + 8.4% [+5.7; +11.1], respectively. The largest effect was observed for concomitant + adjuvant, induction (with concomitant in both arms) and concomitant chemotherapy, with respective HR [95%CI] of 0.68 [0.59; 0.79] (absolute survival increase at 5 years: 12.3% (7.0%;17.6%)), 0.73 [0.63; 0.86] (6.0% (2.5%;9.5%)) and 0.81 [0.70; 0.92] (5.2% (0.8%;9.6%)). The benefit of chemotherapy was also demonstrated by improvement in progression-free survival, cancer mortality, locoregional control and distant control. There was a significant interaction between patient age and chemotherapy effect. CONCLUSION: This updated meta-analysis confirms the benefit of concomitant chemotherapy and concomitant + adjuvant chemotherapy, and suggests that addition of induction or adjuvant chemotherapy to concomitant chemotherapy improves tumor control and survival. The benefit of chemotherapy decreases with increasing patient age.

A frequentist one-step model for a simple network meta-analysis of time-to-event data in presence of an effect modifier.

INTRODUCTION: Individual patient data (IPD) present particular advantages in network meta-analysis (NMA) because interactions may lead an aggregated data (AD)-based model to wrong a treatment effect (TE) estimation. However, fewer works have been conducted for IPD with time-to-event contrary to binary outcomes. We aimed to develop a general frequentist one-step model for evaluating TE in the presence of interaction in a three-node NMA for time-to-event data. METHODS: One-step, frequentist, IPD-based Cox and Poisson generalized linear mixed models were proposed. We simulated a three-node network with or without a closed loop with (1) no interaction, (2) covariate-treatment interaction, and (3) covariate distribution heterogeneity and covariate-treatment interaction. These models were applied to the NMA (Meta-analyses of Chemotherapy in Head and Neck Cancer [MACH-NC] and Radiotherapy in Carcinomas of Head and Neck [MARCH]), which compared the addition of chemotherapy or modified radiotherapy (mRT) to loco-regional treatment with two direct comparisons. AD-based (contrast and meta-regression) models were used as reference. RESULTS: In the simulated study, no IPD models failed to converge. IPD-based models performed well in all scenarios and configurations with small bias. There were few variations across different scenarios. In contrast, AD-based models performed well when there were no interactions, but demonstrated some bias when interaction existed and a larger one when the modifier was not distributed evenly. While meta-regression performed better than contrast-based only, it demonstrated a large variability in estimated TE. In the real data example, Cox and Poisson IPD-based models gave similar estimations of the model parameters. Interaction decomposition permitted by IPD explained the ecological bias observed in the meta-regression. CONCLUSION: The proposed general one-step frequentist Cox and Poisson models had small bias in the evaluation of a three-node network with interactions. They performed as well or better than AD-based models and should also be undertaken whenever possible.

Individual patient data meta-analysis of neoadjuvant chemotherapy followed by surgery versus upfront surgery for carcinoma of the oesophagus or the gastro-oesophageal junction.

INTRODUCTION: Which neoadjuvant treatment for locally advanced thoracic oesophagus (TE) or gastro-oesophageal junction carcinoma is best remains an open question. Randomised controlled trials variously accrued patients with adenocarcinoma and squamous cell carcinoma, making strong conclusions hard to obtain. The primary objective of this individual participant data meta-analysis was to investigate the effect of neoadjuvant chemotherapy on overall survival (OS). PATIENTS AND METHODS: Eligible trials should have closed to accrual before 2016 and compared neoadjuvant chemotherapy and surgery (CS) to surgery alone. All relevant published and unpublished trials were identified via searches of electronic databases, conference proceedings and clinical trial registers. The main end-point was OS. Investigators were contacted to obtain the individual patient data, which was recorded, harmonised and checked. A random-effects Cox model, stratified by trial, was used for meta-analysis and subgroup analyses were preplanned. RESULTS: 16 trials were identified as eligible. Individual patient data were obtained from 12 trial and 2478 patients. CS was associated with an improved OS versus surgery, hazard ratio (HR) = 0.83 [0.72-0.96], p < 0.0001, translating to an absolute benefit of 5.7% at 5-years from 16.8% to 22.5%. Treatment effects did not vary substantially between adenocarcinoma (HR = 0.73 [0.62-0.87]) and squamous cell carcinoma (HR = 0.91 [0.76-1.08], interaction p = 0.26). A somewhat more pronounced effect was observed in gastro-oesophageal junction (HR = 0.68 [0.50-0.93]) versus TE (HR = 0.87 [0.75-1.00], interaction p = 0.07). CS was also associated with a greater disease-free survival (HR = 0.74 [0.64-0.85], p < 0.001). CONCLUSIONS: Neoadjuvant chemotherapy conferred a better OS than surgery alone and should be considered in all anatomical location and histological subtypes.

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Individual patient data meta-analysis of prophylactic cranial irradiation in locally advanced non-small cell lung cancer.

BACKGROUND: Prophylactic cranial irradiation (PCI) was compared to observation in several randomized trials (RCTs), and a reduction greater than 50% was shown regarding the incidence of brain metastases (BM). However, none of these studies showed an improvement of overall survival (OS), possibly related to relatively small sample sizes and short follow-up. The aim of this meta-analysis was therefore to assess the impact of PCI on long term OS for stage III non-small cell lung cancer (NSCLC) compared to observation based on the pooled updated individual patient RCT data. METHODS: Seven RCTs were eligible, and data from the four most recent trials (924 patients) could be retrieved. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Inter-trial heterogeneity was studied using the I2 test. In addition, the 5-year absolute survival difference between arms was calculated for all endpoints. The pre-specified toxicities were reported descriptively. RESULTS: The median follow-up was 97 months (74-108). Compared to observation, no statistically significant impact of PCI on OS was observed (HR 0.90 [0.76-1.07] p = 0.23, 5-year absolute difference 1.8% [-5.2-8.8]). PCI significantly prolonged progression-free survival (HR 0.77 [0.66-0.91] p = 0.002) and BM-free survival (HR 0.82 [0.69-0.97] p = 0.02). The number of patients with high-grade (≥3) toxicity was 6.4% (21/330) for PCI. CONCLUSION: No OS benefit by PCI was observed, but PCI prolonged the progression-free survival and BM-free survival at an increased risk of late memory impairment and fatigue.

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group.

BACKGROUND AND PURPOSE: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). CONCLUSION: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.

Tumour-infiltrating lymphocyte density is associated with favourable outcome in patients with advanced non-small cell lung cancer treated with immunotherapy.

BACKGROUND: The established role of morphological evaluation of tumour-infiltrating lymphocytes (TILs) with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. We aimed to determine TIL association with the outcome for ICIs and for chemotherapy in advanced NSCLC. METHODS: This is a multicenter retrospective study of a nivolumab cohort of 221 patients treated between November 2012 and February 2017 and a chemotherapy cohort of 189 patients treated between June 2009 and October 2016. Patients with available tissue for stromal TIL evaluation were analysed. The presence of a high TIL count (high-TIL) was defined as ≥10% density. The primary end-point was overall survival (OS). RESULTS: Among the nivolumab cohort, 64% were male, with median age of 63 years, 82.3% were smokers, 77% had performance status ≤1 and 63% had adenocarcinoma histology. High-TIL was observed in 22% patients and associated with OS (hazard ratio [HR] 0.48; 95% confidence interval [95% CI]: 0.28-0.81) and progression-free survival [PFS] (HR = 0.40; 95% CI: 0.25-0.64). Median PFS was 13.0 months (95% CI: 5.0-not reached) with high-TIL versus 2.2 months (95% CI: 1.7-3.0) with the presence of a low TIL count (low-TIL). Median OS for high-TIL was not reached (95% CI: 12.2-not reached) versus 8.4 months (95% CI: 5.0-11.6) in the low-TIL group. High-TIL was associated with the overall response rate (ORR) and disease control rate (DCR) (both, P < .0001). Among the chemotherapy cohort, 69% were male, 89% were smokers, 86% had performance status ≤1 and 90% had adenocarcinoma histology. High-TIL was seen in 37%. Median PFS and OS were 5.7 months (95% CI: 4.9-6.7) and 11.7 months (95% CI: 9.3-13.0), respectively, with no association with TILs. CONCLUSIONS: High-TIL was associated with favourable outcomes in a real-world immunotherapy cohort of patients with NSCLC, but not with chemotherapy, suggesting that TILs may be useful in selecting patients for immunotherapy.

Predictive classifier for intensive treatment of head and neck cancer.

BACKGROUND: This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer. METHODS: This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH-NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS). RESULTS: Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16-negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84-0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90-1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75-0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78-0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86-1.08; P for interaction = .011). CONCLUSIONS: LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.

Hepatic arterial infusion of oxaliplatin plus systemic chemotherapy and targeted therapy for unresectable colorectal liver metastases.

BACKGROUND: Hepatic arterial infusion (HAI) combined with systemic chemotherapy has shown promising results in patients with unresectable colorectal liver metastases (CRLM), even after failure to systemic therapy. Addition of systemic targeted therapies has been investigated with controversial results regarding tolerance, especially with HAI-floruxidine when combined with systemic bevacizumab. Our study aimed to analyse feasibility, safety and efficacy of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies. METHODS: Between 2005 and 2016, single-centre consecutive patients with unresectable CRLM who received at least one cycle of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies (cetuximab/panitumumab or bevacizumab) were analysed. RESULTS: A total of 89 patients (median age 55 years (range, 26-76 years) who previously received a median number of one systemic chemotherapy regimen (range, 0-5) including oxaliplatin in 78% of cases were included. Median number of HAI-oxaliplatin cycles was 9 (range, 1-28) combined with systemic chemotherapy and targeted therapies (LV5FU2 [63%], FOLFIRI [36%]) plus anti-EGFR (30%), or bevacizumab (70%). Grade 3/4 toxicities included neutropenia (40%), HAI-related abdominal pain (43%) and neurotoxicity (12%). The intent-to-treat objective response rate was 42%, and 45% had stable disease, allowing complete CRLM resection/ablation in 27% of patients. After a median follow-up of 72 months, median overall and progression-free survival was 20 and 9 months, respectively. CONCLUSION: Addition of targeted therapy to systemic chemotherapy combined with HAI-oxaliplatin is feasible, safe and shows promising activity, even after systemic chemotherapy failure.

Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-analysis of Individual Patient Data From Randomized Clinical Trials.

Importance: Both α-emitting and ß-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an α-emitting RI, radium 223 (223Ra), vs standard of care. Yet no head-to-head comparison has been done between α-emitting and ß-emitting RIs. Objective: To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of α-emitting RIs with ß-emitting RIs. Data Sources: PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms included randomized trials, radioisotopes, radiopharmaceuticals, and prostate cancer. Data were collected, checked, and analyzed from February 2017 to October 2018. Study Selection: Selected trials included patients with prostate cancer, recruited more than 50 patients from January 1993 to June 2013, compared RI use with no RI use (placebo, external radiotherapy, or chemotherapy), and were randomized. Patients were diagnosed with histologically proven prostate cancer and disease progression after both surgical or chemical castration and have evidence of bone metastasis. Nine randomized clinical trials were identified as eligible, but 3 were excluded for insufficient data. Data Extraction and Synthesis: Individual patient data were requested for each eligible trial, and all data were checked with a standard procedure. The log-rank test stratified by trial was used to estimate hazard ratios (HRs), and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The between-trial heterogeneity of treatment effects was evaluated by Cochran test and I2 and was accounted by a random-effects (RE) model. Main Outcomes and Measures: Overall survival; secondary outcomes were symptomatic skeletal event (SSE)-free survival and adverse events. Results: Based on 6 randomized clinical trials including 2081 patients, RI use was significantly associated with OS compared with no RI use (HR, 0.86; 95% CI, 0.77-0.95; P = .004) with high heterogeneity (χ25 = 24.46; P < .001; I2 = 80%), but this association disappeared when using an RE model (HR, 0.80; 95% CI, 0.61-1.06; P = .12; τ2 = 0.08). The heterogeneity is explained both by the type of RI and by the inclusion of 2 outlier trials that included 275 patients; the OS benefit was significantly higher with the α-emitting RI 223Ra (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the ß-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10) (P for interaction = .004). Excluding the outlier trials led to an overall HR of 0.82 (95% CI, 0.73-0.92; P < .001) (between-trial heterogeneity: χ23 = 6.51; P = .09; I2 = 54%) using an FE model and an HR of 0.80 (95% CI, 0.65-0.99; P = .04; τ2 = 0.02) using an RE model. The HR for SSE-free survival was 0.81 (95% CI, 0.69-0.93; P = .004) (between-trial heterogeneity: χ23 = 6.71; P = .08; I2 = 55%) when using an FE model and was 0.76 (95% CI, 0.58-1.01; P = .06; τ2 = 0.04) when using an RE model. There were more hematological toxic effects with RI use compared with no RI use (OR, 1.48; 95% CI, 1.17-1.88; P = .001). Conclusions and Relevance: In metastatic CRPC, a significant improvement of OS and SSE-free survival was obtained with bone-targeted α-emitting but not ß-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity.