Individual Patient-level Meta-analysis Research Articles

C-67 | Ticagrelor monotherapy in ST-elevation myocardial infarction: An individual patient-level meta-analysis from TICO and T-PASS trials

C-67 | Ticagrelor monotherapy in ST-elevation myocardial infarction: An individual patient-level meta-analysis from TICO and T-PASS trials

Association between long-term use of calcium channel blockers (CCB) and the risk of breast cancer: a retrospective longitudinal observational study protocol

IntroductionCalcium channel blockers (CCB), a commonly prescribed antihypertensive (AHT) medicine, may be associated with increased risk of breast cancer. The proposed study aims to examine whether long-term CCB use is...

Defining Minimum Treatment Parameters of Ablative Radiation Therapy in Patients With Hepatocellular Carcinoma: An Expert Consensus

External beam radiation therapy (EBRT) is a highly effective treatment in select patients with hepatocellular carcinoma (HCC). However, the Barcelona Clinic Liver Cancer system does not recommend the use of EBRT in HCC due to a lack of sufficient evidence and intends to perform an individual patient level meta-analysis of ablative EBRT in this population. However, there are many types of EBRT described in the literature with no formal definition of what constitutes "ablative." Thus, we convened a group of international experts to provide consensus on the parameters that define ablative EBRT in HCC. Fundamental parameters related to dose, fractionation, radiobiology, target identification, and delivery technique were identified by a steering committee to generate 7 Key Criteria (KC) that would define ablative EBRT for HCC. Using a modified Delphi (mDelphi) method, experts in the use of EBRT in the treatment of HCC were surveyed. Respondents were given 30 days to respond in round 1 of the mDelphi and 14 days to respond in round 2. A threshold of ≥70% was used to define consensus for answers to each KC. Of 40 invitations extended, 35 (88%) returned responses. In the first round, 3 of 7 KC reached consensus. In the second round, 100% returned responses and consensus was reached in 3 of the remaining 4 KC. The distribution of answers for one KC, which queried the a/b ratio of HCC, was such that consensus was not achieved. Based on this analysis, ablative EBRT for HCC was defined as a BED10 ≥80 Gy with daily imaging and multiphasic contrast used for target delineation. Treatment breaks (eg, for adaptive EBRT) are allowed, but the total treatment time should be ≤6 weeks. Equivalent dose when treating with protons should use a conversion factor of 1.1, but there is no single conversion factor for carbon ions. Using a mDelphi method assessing expert opinion, we provide the first consensus definition of ablative EBRT for HCC. Empirical data are required to define the a/b of HCC.

A critical appraisal of the four systematic reviews and meta-analysis on stereotactic body radiation therapy versus external beam radiotherapy for painful bone metastases and where we go from here.

Radiotherapy is an important treatment modality for pain control in patients with bone metastases. Stereotactic body radiation therapy (SBRT), which allows delivering a much higher dose per fraction while sparing critical structures compared to conventional external beam radiotherapy (cEBRT), has become more widely used, especially in the oligometastatic setting. Randomized controlled trials (RCTs) comparing the pain response rate of SBRT and cEBRT for bone metastases have shown conflicting results, as have four recent systematic reviews with meta-analyses of these trials. Possible reasons for the different outcomes between these reviews include differences in methodology, which trials were included, and the endpoints examined and how they were defined. We suggest ways to improve analysis of these RCTs, particularly performing an individual patient-level meta-analysis since the trials included heterogeneous populations. The results of such studies will help guide future investigations needed to validate patient selection criteria, optimize SBRT dose schedules, include additional endpoints (such as the time to onset of pain response, durability of pain response, quality of life (QOL), and side effects of SBRT), and better assess the cost-effectiveness and trade-offs of SBRT compared to cEBRT. An international Delphi consensus to guide selection of optimal candidates for SBRT is warranted before more prospective data is available.

Discriminative performance of pancreatic stone protein in predicting ICU mortality and infection severity in adult patients with infection: a systematic review and individual patient level meta-analysis

BackgroundSeveral studies suggested pancreatic stone protein (PSP) as a promising biomarker to predict mortality among patients with severe infection. The objective of the study was to evaluate the performance of PSP in predicting intensive care unit (ICU) mortality and infection severity among critically ill adults admitted to the hospital for infection.MethodsA systematic search across Cochrane Central Register of Controlled Trials and MEDLINE databases (1966 to February 2022) for studies on PSP published in English using ‘pancreatic stone protein’, ‘PSP’, ‘regenerative protein’, ‘lithostatin’ combined with ‘infection’ and ‘sepsis’ found 46 records. The search was restricted to the five trials that measured PSP using the enzyme-linked immunosorbent assay technique (ELISA). We used Bayesian hierarchical regression models for pooled estimates and to predict mortality or disease severity using PSP, C-Reactive Protein (CRP) and procalcitonin (PCT) as main predictor. We used statistical discriminative measures, such as the area under the receiver operating characteristic curve (AUC) and classification plots.ResultsAmong the 678 patients included, the pooled ICU mortality was 17.8% (95% prediction interval 4.1% to 54.6%) with a between-study heterogeneity (I-squared 87%). PSP was strongly associated with ICU mortality (OR = 2.7, 95% credible interval (CrI) [1.3–6.0] per one standard deviation increase; age, gender and sepsis severity adjusted OR = 1.5, 95% CrI [0.98–2.8]). The AUC was 0.69 for PSP 95% confidence interval (CI) [0.64–0.74], 0.61 [0.56–0.66] for PCT and 0.52 [0.47–0.57] for CRP. The sensitivity was 0.96, 0.52, 0.30 for risk thresholds 0.1, 0.2 and 0.3; respective false positive rate values were 0.84, 0.25, 0.10.ConclusionsWe found that PSP showed a very good discriminative ability for both investigated study endpoints ICU mortality and infection severity; better in comparison to CRP, similar to PCT. Combinations of biomarkers did not improve their predictive ability.

Secondary cytoreduction in platinum sensitive relapsed ovarian cancer: an individual patient level meta-analysis

ObjectiveTo synthesize the role of secondary cytoreduction in recurrent ovarian cancer from the results of randomized studies.MethodsWe conducted a meta-analysis of randomized controlled trials which compared secondary cytoreductive surgery versus...

Multi-center analysis of point-of-care ultrasound for small bowel obstruction: A systematic review and individual patient-level meta-analysis

ObjectiveThe study aimed to assess the diagnostic accuracy of point-of-care ultrasound (POCUS) in identifying small bowel obstruction (SBO) and to investigate the impact of clinician experience level and body mass index (BMI) on POCUS performance for diagnosing SBO in the Emergency Department. MethodsWe systematically searched PubMed and Cochrane databases from January 2011–2022. We performed a meta-analysis using individual patient-level data from prospective diagnostic accuracy studies from which we obtained data from the corresponding authors. Overall test characteristics and subgroup analysis across clinician experience levels and a range of BMI were calculated. The primary outcome was SBO as the final diagnosis during hospitalization. ResultsWe included Individual patient data from 433 patients from 5 prospective studies. Overall, 33% of patients had a final diagnosis of SBO. POCUS had 83.0% (95%CI 71.7%–90.4%) sensitivity and 93.0% (95%CI 55.3%–99.3%) specificity; LR+ was 11.9 (95%CI 1.2–114.9) and LR- was 0.2 (95%CI 0.1–0.3). Residents had exhibited a sensitivity of 73.0% (95%CI 56.6%–84.9%) and specificity of 88.2% (95%CI 58.8%–97.5%), whereas attendings had demonstrated a sensitivity of 87.7% (95%CI 71.1%–95.4%) and specificity of 91.4% (95%CI 57.4%–98.8%). Among those patients with BMI<30 kg/m2, POCUS showed a sensitivity of 88.6% (95%CI 79.5%–94.7%) and a specificity of 84.0% (95%CI 75.3%–90.6%), while patients with BMI ≥ 30 kg/m2 exhibited a sensitivity of 72.0% (95%CI 50.6%–87.9%) and specificity of 89.5% (95%CI 75.2%–97.1%). ConclusionsPOCUS correctly identified those patients with SBO with high sensitivity and specificity. Diagnostic accuracy was slightly reduced when performed by resident physicians and among patients with a BMI ≥ 30 kg/m2.Registration: PROSPERO registration number: CRD42022303598.

An individual patient-level meta-analysis of non–small-cell lung cancer leptomeningeal metastases treated with epidermal growth factor receptor inhibitors.

e21118 Background: Leptomeningeal metastasis (LM) is a debilitating condition associated with advanced non-small cell lung cancer (NSCLC). When driver mutations in the epidermal growth factor receptor (EGFR) are identified, targeted therapies (TT) represent an appealing therapeutic strategy. However, the efficacy of TT for LM is unknown as LM patients are routinely omitted from clinical trials. Methods: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of EGFR TT in EGFR-mutant NSCLC LM in accordance with PRISMA guidelines. EGFR-TTs evaluated were erlotinib, gefitinib, icotinib, afatinib, dacomitinib, osimertinib, zorifertinib, and furmonertinib. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS). To assess differences between groups, shared frailty Cox regression models were used to estimate the hazard ratio (HR), 95% confidence interval (CI) and p-value. Results: 7780 abstracts were screened, identifying 126 publications with 232 patients, corresponding to 272 lines of EGFR-TT for NSCLC LM which met inclusion criteria. The overall median PFS (mPFS) in patients receiving any EGFR-TT was 9.15 months and the median overall survival was 14.5 months. In univariable analyses, osimertinib was associated prolonged PFS compared to other EGFR-TT, (mPFS of 11 versus 8 months, HR = 0.64; 95% CI: 0.44-0.93; P = 0.02). Osimertinib was numerically associated with prolonged OS compared to other EGFR-TT (mOS 16.8 months versus 13.6 months, HR = 0.72; 95% CI 0.44-1.17, P = 0.188). In multivariable analyses, ECOG performance status &gt; 2 was independently associated with shortened PFS (mPFS 10 versus 8 months, HR = 1.54, 95% CI: 1.26-3.04; P &lt; 0.05) and OS (mOS 16.5 versus 10 months, HR = 3.33, 95% CI: 1.80-6.18; P &lt; 0.05). Conclusions: In the largest cohort of NSCLC LM treated with EGFR TT compiled to date, osimertinib is associated with marginally improved outcomes compared to other EGFR TTs. ECOG performance status is an independent predictor of prognosis in these patients. These results highlight the need for prospective studies for this difficult to treat patient population.

Diagnostic accuracy of optical flow ratio: an individual patient-data meta-analysis.

Optical flow ratio (OFR) is a novel method for the fast computation of fractional flow reserve (FFR) from optical coherence tomography. We aimed to evaluate the diagnostic accuracy of OFR in assessing intermediate coronary stenosis using wire-based FFR as the reference. We performed an individual patient-level meta-analysis of all available studies with paired OFR and FFR assessments. The primary outcome was vessel-level diagnostic concordance of the OFR and FFR, using a cut-off of ≤0.80 to define ischaemia and ≤0.90 to define suboptimal post-percutaneous coronary intervention (PCI) physiology. This meta-analysis was registered in PROSPERO (CRD42021287726). Five studies were finally included, providing 574 patients and 626 vessels (404 pre-PCI and 222 post-PCI) with paired OFR and FFR from 9 international centres. Vessel-level diagnostic concordance of the OFR and FFR was 91% (95% confidence interval [CI]: 88%-94%), 87% (95% CI: 82%-91%), and 90% (95% CI: 87%-92%) in pre-PCI, post-PCI, and overall, respectively. The overall sensitivity, specificity, and positive and negative predictive values were 84% (95% CI: 79%-88%), 94% (95% CI: 92%-96%), 90% (95% CI: 86%-93%), and 89% (95% CI: 86%-92%), respectively. Multivariate logistic regression indicated that a low pullback speed (odds ratio [OR] 7.02, 95% CI: 1.68-29.43; p=0.008) was associated with a higher risk of obtaining OFR values at least 0.10 higher than FFR. Increasing the minimal lumen area was associated with a lower risk of obtaining an OFR at least 0.10 lower than FFR (OR 0.39, 95% CI: 0.18-0.82; p=0.013). This individual patient data meta-analysis demonstrated a high diagnostic accuracy of OFR. OFR has the potential to provide an improved integration of intracoronary imaging and physiological assessment for the accurate evaluation of coronary artery disease.

Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials

Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens. We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts to identify trials assessing anthracycline and taxane chemotherapy. Adjuvant or neoadjuvant trials were eligible if they began before Jan 1, 2012. Primary outcomes were breast cancer recurrence and cause-specific mortality. Log-rank analyses yielded first-event rate ratios (RRs) and CIs. 28 trials of taxane regimens with or without anthracycline were identified, of which 23 were deemed eligible, and 15 provided data on 18 103 women. Across all 15 trials that provided individual data, recurrence rates were 14% lower on average (RR 0·86, 95% CI 0·79-0·93; p=0·0004) with taxane regimens including anthracycline than those without. Non-breast cancer deaths were not increased but there was one additional acute myeloid leukaemia case per 700 women treated. The clearest reductions in recurrence were found when anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (10-year recurrence risk 12·3% vs 21·0%; risk difference 8·7%, 95% CI 4·5-12·9; RR 0·58, 0·47-0·73; p<0·0001). 10-year breast cancer mortality in this group was reduced by 4·2% (0·4-8·1; p=0·0034). No significant reduction in recurrence risk was found for sequential schedules of taxane plus anthracycline when compared with docetaxel plus cyclophosphamide (RR 0·94, 0·83-1·06; p=0·30). For the analysis of anthracycline regimens with versus without taxane, 35 trials (n=52 976) provided individual patient data. Larger recurrence reductions were seen from adding taxane to anthracycline regimens when the cumulative dose of anthracycline was the same in each group (RR 0·87, 0·82-0·93; p<0·0001; n=11 167) than in trials with two-fold higher cumulative doses of non-taxane (mostly anthracycline) in the control group than in the taxane group (RR 0·96, 0·90-1·03; p=0·27; n=14 620). Direct comparisons between anthracycline and taxane regimens showed that a higher cumulative dose and more dose-intense schedules were more efficacious. The proportional reductions in recurrence for taxane plus anthracycline were similar in oestrogen receptor-positive and oestrogen receptor-negative disease, and did not differ by age, nodal status, or tumour size or grade. Anthracycline plus taxane regimens are most efficacious at reducing breast cancer recurrence and death. Regimens with higher cumulative doses of anthracycline plus taxane provide the greatest benefits, challenging the current trend in clinical practice and guidelines towards non-anthracycline chemotherapy, particularly shorter regimens, such as four cycles of docetaxel-cyclophosphamide. By bringing together data from almost all relevant trials, this meta-analysis provides a reliable evidence base to inform individual treatment decisions, clinical guidelines, and the design of future clinical trials. Cancer Research UK, UK Medical Research Council.

Abstract P1-01-04: Comparing the Effects of TC and Anthracycline-based Chemotherapy in Women with Breast Cancer HER2 Negative Treated in the Adjuvant Setting – An individual Patient Meta-Analysis

Abstract Background: Among women, breast cancer is the most common diagnosis of non-skin cancer and the fifth cause of oncological-related death worldwide. Adjuvant chemotherapy has been shown to extend overall survival (OS) and disease-free survival (DFS). Anthracyclines are cytotoxic regimens largely used in breast cancer, mainly in patients with risk factors or high burden of disease. The docetaxel and cyclophosphamide (TC) regimen is a Taxane-based treatment, and is an alternative option when anthracyclines are not indicated. However, anthracyclines have a myriad of adverse effects including alopecia, cardiac-related side effects and myelotoxicity. The question that remains is in which breast cancer population anthracycline chemotherapy should be omitted. Methods: A literature search was performed in Embase, Medline, and the Cochrane Libraries up to February 28 2022. We conducted an individual patient-level meta-analysis of 11,902 participants of 7 randomised controlled trials. The target population was adult women, with a histologically confirmed HER2 negative, stage I-III breast cancer who were treated with TC versus anthracycline-based chemotherapy in adjuvant setting under randomised-controlled trials. To analyse OS and DFS, we utilized the generic inverse variance method for time-to-event outcomes using hazard ratio (HR). A sensitivity analysis of risk of bias (ROB) was undertaken to examine the effects of high/moderate risk studies on each study endpoint. The assessment of certainty of evidence was conducted based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Results: With a median follow up of 60 months, the pooled analysis from 7 studies with available data on OS, and from 6 studies on DFS. From a total of 11,778 there was a total of 288 and 281 events of death in the TC and in the anthracycline-based chemotherapy groups, respectively. The analysis of OS revealed HR 1.01, 95% CI (0.86 – 1.19), p = 0.88; high certainty of evidence. From a total of 11,902 participants, there were 639 and 595 recurrence events in the TC and in the anthracycline-based chemotherapy groups, respectively. The analysis of DFS revealed HR 1.07, 95% CI 0.95-1.22, p=0.26; moderate certainty of evidence. No relevant absolute risk of death or recurrence events were found between the two treatments. In the quality of evidence assessment, the heterogeneity across all the studies is likely not more than what is due to chance (i2&amp;lt; 14%). The risk of bias was not a serious concern, and the publication bias was undetected for the endpoints OS and DFS. Conclusion: In this study population, TC chemotherapy likely results little to no difference in OS or DFS compared to anthracyclines-based chemotherapies. Despite the large number of participants and minimum heterogeneity across all the studies, there was no evidence of significant benefit or harm between the treatments. Overall, there is a high to moderate quality of evidence that adjuvant TC chemotherapy does not increase OS or DFS when compared to anthracycline-based chemotherapy in patients with breast cancer HER2-negative. Albeit the choice between the two chemotherapies would need to be balanced considering the specific side-effects that each treatment is likely to cause. Citation Format: Danilo Giffoni M. M. Mata, Mary Smowton. Comparing the Effects of TC and Anthracycline-based Chemotherapy in Women with Breast Cancer HER2 Negative Treated in the Adjuvant Setting – An individual Patient Meta-Analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-01-04.

Biochemical recurrence (BCR) surrogacy for clinical outcomes after radiotherapy for adenocarcinoma of the prostate (BCRSCRAP): A meta-analysis from MARCAP Consortium.

391 Background: Event-free survival, a PSA-driven endpoint, was shown to not be surrogate endpoint for overall survival (OS) in the ICECAP two-stage meta-analytic approach. However, time to biochemical recurrence (TTBCR) in NRG/RTOG 9202 met Prentice criteria for surrogacy. We performed an individual patient data (IPD) meta-analysis of 11 randomized controlled trials evaluating RT dose escalation, ADT use, and adjuvant ADT prolongation to evaluate the surrogacy of time to BCR (TTBCR), censoring for non-prostate cancer deaths, using both approaches to evaluate surrogacy. Methods: This individual patient level meta-analysis was performed using data from the MARCAP consortium, and 11 radiotherapy trials were included. TTBCR was defined as time to developing a BCR or experiencing prostate cancer-specific mortality (PCSM), with censoring at time of other-cause death or loss to follow-up. Landmark analyses were used to test the Prentice criteria for surrogacy. For patient level correlation between TTBCR and OS, we applied a bivariate Copula model to estimate the Kendall’s τ. For trial level correlation of the treatment effect on TTBCR and true endpoints, a weighted linear regression model was applied between the effects of treatment (natural log of hazard ratio [log-HR]) on OS versus TTBCR using a weightage that was inverse variance of BCR log-HR estimate. Results: Based on Prentice criteria, BCR at the landmark time point of 48 months was associated with increased risk of mortality in trials that compared treatment intensification with adjuvant ADT prolongation (HR 2.18 [95% CI 1.95-2.42]), the addition of ADT (HR 1.38 [1.25-1.54]), and RT dose escalation (HR 2.12 [1.83-2.46]) on uni- and multi-variable analyses. At the patient level, there was a low to moderate level correlation between BCR and OS with Kendall’s τ of 0.34 and a R2 of 0.55 for correlation of treatment effect on TTBCR and OS. At the trial level, there was a poor correlation between treatment effect on TTBCR and OS (R2=0.16). Conclusions: This IPD meta-analysis demonstrates that while BCR is prognostic, it is not a surrogate endpoint for OS in localized prostate cancer for patients treated with a diverse array of radiotherapeutic strategies. This highlights the importance of other cause mortality in prostate cancer. Our results highlight the differences in interpretability of Prentice criteria and the two-stage meta-analytic approach and suitability of endpoints for clinical trial design.

181MO Secondary cytoreduction in platinum-sensitive relapsed ovarian cancer: An individual patient level meta-analysis

The role of secondary cytoreduction in recurrent ovarian cancer has not been clearly defined. We aim to synthesize the efficacy of secondary cytoreduction in platinum-sensitive relapsed ovarian cancer patients.

Tumor Control Probability Modeling and Systematic Review of Oligometastatic Prostate Cancer Treated with Stereotactic Ablative Radiotherapy

<h3>Purpose/Objective(s)</h3> Oligometastatic prostate adenocarcinoma is increasingly treated with stereotactic ablative body radiotherapy (SABR), and treatment efficacy requires achieving adequate local control (LC). Reported dose and fractionation schemes vary and evidence supporting a consensus treatment schema is lacking. We sought to define a dose-response curve based on meta-analysis of reported SABR regimens for prostate cancer oligometastases. <h3>Materials/Methods</h3> A systematic literature review was performed through PubMed using MESH terms "neoplasm metastasis," "radiotherapy," and "prostatic neoplasms." Inclusion criteria included radiologically- or biopsy- identified prostate cancer metastases, histologically confirmed prostate cancer diagnosis, metastasis-directed treatment with SABR, follow-up with radiologic assessment of treated metastases, and reporting of SABR dose and fractionation. Review articles were excluded. Doses were converted to equivalent doses of 2 Gy per fraction (EQD₂) with alpha/beta ratio of 1.5. 90% and 95% tumor control probability (TCP) at 6 months, 1 year, and 2 years was calculated using the Poisson model, with TCP = (1/2)<i>^e</i>^{[2γ50 (1-D/D50)/ln2]} and fit determined by least squares analysis in Proc NLIN of a data management and decision management software. The basic parameters of each model are D₅₀, which is the equivalent dose for a LC rate of 50%; and γ, which is the maximum normalized slope (gradient) of the dose response curve. <h3>Results</h3> We screened 733 studies and 16 studies met inclusion criteria. 1,214 metastatic prostate lesions were treated with SABR. The median EQD₂ was 230 Gy (IQR 202.9-286.7) with a median prescription dose of 30 Gy (IQR 24-33.8) in 3 fractions (range 1-10). There was poor model fit at 6 months and 1 year (p>0.05). At 2 years, the median LC was 95.7% (IQR 93.3%-100%). Chi-square test for our model fit was <0.0001, with estimated D₅₀ of 56.35 (95% CI 12.18-100.50) and γ of 0.30 (95% CI -0.05-0.65). TCP of 90% may be achieved with EQD₂ of 179.0 Gy, and TCP of 95% with EQD₂ of 225.8 Gy. This corresponds to a prescription of 41.1 Gy in 3 fractions or 52.3 Gy in 5 fractions for 90% TCP and 46.5 Gy in 3 fractions or 59.2 Gy in 5 fractions for 95% TCP at 2 years. <h3>Conclusion</h3> Although significant dose and fractionation variation is present, excellent TCP for oligometastatic prostate cancer treated with SABR was reported. Our study was limited by availability of prescription doses, rather than dosimetric data, and an individual patient-level meta-analysis to expand on this work is planned. There are many areas of need for continued research as SABR is increasingly utilized for oligometastatic prostate cancer, including durability of LC with longer follow-up, integration of novel imaging techniques into disease assessment, and the impact of systemic therapy on LC assessment.

TACE versus TARE for patients with hepatocellular carcinoma: Overall and individual patient level meta analysis.

Transarterial radioembolization (TARE) is increasingly used as an alternative to transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC). We aimed to perform an overall and individual patient data (IPD) meta-analysis of studies comparing TACE and TARE. We performed a systematic literature search using pre-specified keywords with the aid of an informationist for articles from inception to 3/2020. The primary endpoint was overall survival (OS), and the secondary endpoint was time to progression (TTP). Seventeen studies met inclusion criteria with 2465 unique patients, with one randomized trial, 4 prospective studies and 12 retrospective studies. Barcelona Clinic Liver Cancer (BCLC) stage B (42.8%) was the most common stage followed by BCLC A (30.3%) and BCLC C (29.0%). There was no difference in OS between the two modalities (-0.55 months, 95% CI -1.95 to 3.05). In three studies with available TTP data, TARE resulted in a longer TTP than TACE (mean TTP 17.5 vs. 9.8 months; mean TTP difference 4.8months, 95% CI 1.3-8.3months). IPD-level meta-analysis of 311 patients from three studies showed no difference in overall OS between the two modalities including among subgroups stratified by tumor stage and liver function. Limitations of the current literature include inconsistent length of follow-up, inconsistency in response criteria, and safety reporting. Current data suggest TARE provides significantly longer TTP than TACE, although the two treatments do not significantly differ in terms of OS. Given limitations of the current data, there is rationale for prospective studies comparing these modalities.

Local failure, distant metastasis, and survival after definitive radiotherapy for intermediate- and high-risk prostate cancer: An individual patient-level meta-analysis of 18 randomized trials.

277 Background: The prognostic importance of local failure (LF) after definitive radiotherapy (RT) in patients with NCCN intermediate- (IRPCa) and high-risk prostate cancer (HRPCa) remains unclear, particularly given the likelihood that occult distant metastases (DMs) at presentation may be the true driver of natural history. Here, we leverage individual patient data (IPD) from 18 randomized control trials (RCTs) to evaluate the prognostic impact of LF and the kinetics of DM after RT. Methods: IPD for 18 RCTs were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium, comprising a total of 12533 patients (6288 HRPCa &amp; 6245 IRPCa). Multivariable Cox proportional hazards (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), DM-free survival (DMFS) &amp; LF as a time-dependent covariate, adjusted for clinicodemographic parameters. Markov PH models, defined via transitions between 4 states, were developed to evaluate the aforementioned relationship. Proportional hazards assumption was imposed and examined for both models. Time is from randomization. Results: Median follow-up was 9.1 years. There were 795 (13%) LF &amp; 1288 (21%) DM events for patients with HRPCa; these numbers were 449 (7%) &amp; 451 (7%) for IRPCa. For HRPCa &amp; IRPCa, 81% and 81% of DMs developed from a clinically relapse-free state (cRFS), with a median time of 46 and 60 months, respectively (p &lt; 0.0001). 39% &amp; 13% of DM events occurred within 2 years after RT for HRPCa &amp; IRPCa, respectively. At later time points, DM events were more likely to emerge after an LF event for both HRPCa (9% vs. 34% between 0-2 vs. 8-10 years post-RT, p = 0.001) and IRPCa (10% vs. 34% between 0-2 vs. 8-10 years post-RT, p = 0.008). LF was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75-2.33) &amp; DMFS (HR 1.94, 95% CI 1.75–2.15) (p &lt; 0.01 for all) in patients with HRPCa. LF was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not OS in patients with IRPCa. Patients who had not transitioned to the LF state had a significantly lower HR of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.32, 95% CI 0.21–0.50, p &lt; 0.001). Conclusions: LF is an independent prognosticator of OS, PCSS &amp; DMFS in HRPCa and of DMFS in IRPCa. The predominant mode of DM development is from the cRFS state, underscoring the importance of accurate upfront staging &amp; systemic therapy. However, particularly at late time points, an increasing proportion of DM events originated after diagnosis of a LF, constituting a “second wave” of DM events. This suggests that optimizing local control is also important, though the majority of DM events appear prior to a clinically-detected LF.

Abstract GS2-06: Taxane with anthracycline versus taxane without anthracycline: An individual patient-level meta-analysis of 16,500 women with early-stage breast cancer in 13 randomised trials

Abstract Background: Anthracycline and taxane-containing chemotherapy regimens reduce the rate of breast cancer recurrence by about one third compared to no chemotherapy. However, concerns about the increased risks of cardiac toxicity and leukaemia with anthracyclines have resulted in wider use of taxane chemotherapy schedules without anthracycline, in particular docetaxel-cyclophosphamide (DC). The benefits and risks of this approach have been assessed in several randomised trials but with conflicting results. Methods: We did an individual patient-level meta-analysis of data on 16,500 participants from 13 randomised controlled trials starting before 2010. Four compared 6 courses of DC with and without concurrent anthracycline (Anth), six compared sequential Anth then taxane (3 or 4 courses of Anth then 3 or 4 D, or vice versa) versus 6 courses of DC (resulting in a higher cumulative dose of taxane in the DC group), and 3 compared sequential Anth + D versus other taxane schedules. Primary outcomes were time to invasive breast cancer recurrence (distant, loco-regional, or new contralateral breast primary) and breast cancer mortality (by log-rank subtraction). Log-rank analyses were used to assess the first-event-rate ratio (RR) and confidence intervals. Pre-specified subgroup investigations included site of recurrence, age, ER/PR status, nodal status, tumor diameter, grade and HER2 status. Results: Overall, patients treated with an anthracycline and taxane combination averaged 18% lower rates of breast cancer recurrence (RR 0.82, 95%CI 0.75-0.90; p&amp;lt;0.0001) than those receiving a taxane schedule without anthracycline, equating to an absolute reduction of 3.1% (95%CI 1.4-4.8) in 10-year recurrence. The 10-year risk of death from breast cancer was reduced by 1.8% (RR 0.85, 95%CI 0.75-0.95; p=0.006) with no increase in deaths without recurrence. The proportional reduction in recurrence was greatest in trials of concurrent Anth + DC versus DC (RR 0.66, 95%CI 0.55-0.79; p&amp;lt;0.0001), where the only difference between arms was the addition of anthracycline (cumulative dose of doxorubicin≈300mg/m2). By contrast, in trials of sequential Anth + D versus the higher cumulative taxane dose DC regimen there was no significant benefit from Anth (cumulative dose of epirubicin≈300mg/m2): RR 0.93, 95%CI 0.80-1.07; p&amp;gt;0.1. In sub-group analyses of all trials, the benefit of anthracycline and taxane chemotherapy persisted throughout years 0-1, 2-4 and 5-9 with little data beyond year 10. There was a similar and highly significant proportional reduction in recurrence in ER-positive and in ER-negative disease and the RRs for recurrence did not differ significantly by any other pre-specified group including age, nodal status, tumor diameter, grade and HER2 status. There were no significant increases in deaths from cardiovascular disease or leukaemia, though longer follow-up is needed to fully assess risks. Conclusion: The addition of anthracycline to taxane chemotherapy, compared to taxane alone reduced the risk of breast cancer recurrence by 18% with larger proportional reductions in trials of DC ± concurrent Anth, in which the taxane dose was the same in both groups and the cumulative anthracycline dose was higher. Citation Format: Jeremy Braybrooke, Rosie Bradley, Richard Gray, Robert Hills, Zulian Liu, Hongchao Pan, Richard Peto, Joanne Blum, Xiaosong Chen, Bent Ejlertsen, Wolfgang Janni, Ulrike Nitz, Dennis Slamon, Masakazu Toi, Toru Watanabe, Sandra Swain, Jonas Bergh, on behalf of the Early Breast Cancer Trialists Collaborative Group. Taxane with anthracycline versus taxane without anthracycline: An individual patient-level meta-analysis of 16,500 women with early-stage breast cancer in 13 randomised trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-06.

EFFICACY OF BIOLOGIC DRUGS IN SHORT-DURATION VERSUS LONG-DURATION INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW AND INDVIDUAL-PATIENT-DATA METANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Abstract BACKGROUND Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may associate with higher efficacy, especially in Crohn’s disease (CD). METHODS A systematic review and individual-patient-data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (Oct 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction-of-remission in patients with short-duration (≤18months) versus long-duration disease (&amp;gt;18months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients’ characteristics on the primary outcome. Study PROSPERO registration: CRD42018041961. RESULTS We obtained data from five biologics drug manufacturers and included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab or vedolizumab (6,168 CD, 3,227 UC patients). In CD, induction-of-remission rates were higher in pooled placebo and active arms’ patients with short-disease duration≤18 months (41.4%, 244/589) compared with disease-duration&amp;gt;18months (29.8%, 852/2857, meta-analytically estimated OR=1.33, 95%CI:1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction-of-remission, was not different in short-duration disease ≤18 months (n= 589, OR 1.47, 95%CI:1.01-2.15) compared with longer disease-duration (n=2857, OR 1.43, 95%CI:1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cut-offs and when modelled for individual-patients’ co-variates, including prior anti-TNFs exposure. In exploratory post-hoc analysis comparing patients with colonic-CD (L2) versus small-bowel L1 CD (and excluding ileo-colonic L3 disease) the OR for induction-of-remission in long-duration disease&amp;gt;18months compared with short-duration disease was 0.62 for small-bowel CD (95%CI: 0.42; 0.91) but was not significant in pooled colonic CD population (OR=0.94, 95%CI: 0.66; 1.34) CONCLUSION This Individual patient level meta-analysis of multiple biologics’ clinical trials found there a higher rate of induction-of-remission in early CD for both biologics and placebo, resulting in a treatment-to-placebo effect ratio which is similar across different disease durations. No such relationships between disease-duration and outcomes is found in UC. Rate of remission induction by duration of disease at initiation of treatment. The dots denote proportion of an outcome averaged per the respective year.

DOP62 Efficacy of biologic drugs in short-duration versus long-duration Inflammatory Bowel Disease: A systematic review and an individual-patient data meta-analysis of randomized controlled trials

Abstract Background Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may associate with higher efficacy, especially in Crohn’s disease (CD). Methods A systematic review and individual-patient-data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (Oct 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction-of-remission in patients with short-duration (≤18months) versus long-duration disease (&amp;gt;18months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients’ characteristics on the primary outcome. Study PROSPERO registration: CRD42018041961. Results We obtained data from five biologics drug manufacturers and included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab or vedolizumab (6,168 CD, 3,227 UC patients). In CD, induction-of-remission rates were higher in pooled placebo and active arms’ patients with short-disease duration≤18 months (41.4%, 244/589) compared with disease-duration&amp;gt;18months (29.8%, 852/2857, meta-analytically estimated OR=1.33, 95%CI:1.09–1.64). The primary outcome, proportional biologic/placebo treatment effect on induction-of-remission, was not different in short-duration disease ≤18 months (n= 589, OR 1.47, 95%CI:1.01–2.15) compared with longer disease-duration (n=2857, OR 1.43, 95%CI:1.19–1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cut-offs and when modelled for individual-patients’ co-variates, including prior anti-TNFs exposure. In exploratory post-hoc analysis comparing patients with colonic-CD (L2) versus small-bowel L1 CD (and excluding ileo-colonic L3 disease) the OR for induction-of-remission in long-duration disease&amp;gt;18months compared with short-duration disease was 0.62 for small-bowel CD (95%CI: 0.42; 0.91) but was not significant in pooled colonic CD population (OR=0.94, 95%CI: 0.66; 1.34) Conclusion This Individual patient level meta-analysis of clinical trials of multiple biologics found there are higher rates of induction-of-remission in early CD for both biologics and placebo, resulting in a treatment-to-placebo effect ratio which is similar across different disease durations. No such relationships between disease-duration and outcomes is found in UC

Individual Patient Level Meta-Analysis of Prospective Trials Studying Metastasis-Directed Therapy for Metachronous Oligometastatic Prostate Cancer

Emerging data suggest that metastasis is a spectrum of disease burden rather than part of a binary state. Metastasis-directed therapy (MDT) such as radiation might improve outcomes in individuals with oligometastatic disease. Prospective data of MDT for metachronous oligometastatic or oligorecurrent prostate cancer (PCa) have been limited to single arm or small phase 2 randomized studies. We report an individual patient data meta-analysis to characterize the safety and clinical benefit of MDT in oligorecurrent PCa.Individual patient data was submitted from trials published or in conference proceedings by January 2020. Included were single- or multi-arm prospective trials including only patients with recurrent prostate cancer and ≤5 sites of extracranial disease undergoing MDT (surgery or radiotherapy). We hypothesized that MDT improves ADT-free survival. ADT-free survival was analyzed as the primary outcome and biochemical relapse-free survival as secondary outcome. If hazard ratios (HR) were not constant across the different trials, we calculated standardized survival curves, analyzing the trials separately and pooling the adjusted log HR weighted by sample size. The following covariates were examined with the interaction test: PSA doubling time and localization of disease (nodal vs extra-nodal).We identified 4 trials with published results, 2 single arm and 2 randomized trials, representing in total 174 patients (MDT: 72%, active surveillance (AS): 28%). Patient characteristics differed with respect to imaging at inclusion (conventional vs molecular imaging), PSA doubling time and localization of disease (nodal vs extra-nodal). Non-proportional hazards were detected for ADT-free survival but not for biochemical relapse-free survival. ADT-free survival is improved with MDT over AS (HR: 0.56, 95% CI 0.34 - 0.94, P = 0.03) across all covariates, as well as biochemical relapse-free survival (HR: 0.44, 95% CI 0.29 - 0.67, P < 0.01). Grade 2 and 3 toxicity were observed in 3% and 2%, respectively, of patients treated with MDT.MDT improves both biochemical relapse-free and ADT-free survival as compared to active surveillance with low rates of grade 2 or higher toxicity.