Consolidation Treatment Research Articles

Management of patients with locally advanced rectal cancer in the total neoadjuvant therapy (TNT) era: Experience from Argentina.

85 Background: In the last years a paradigm shift has changed the way we manage non metastatic rectal cancer. The varied options within TNT have gradually been adapted in our country. This study aims to depict the strategies implemented. Methods: A prospective and retrospective observational study was performed from 2020 to 2024 including stage II-III rectal cancer patients treated at three centers in Buenos Aires, Argentina. Data was extracted from medical records. Results: 68 patients were included in the analysis. Median age was 59 years (IQR 48–71). 72% were male. 88% (60) had stage III disease, and 12% (8) stage II. Geriatric assessment was performed in 7 of 19 patients aged over 70 (5 frail). All patients were staged with high resolution MRI and discussed in multidisciplinary tumor board. Mismatch repair was assessed in 72%(49) of patients, only one had MLH1 deficiency. 79%(54) patients received TNT: 22%(12) short course vs 78%(42) long course radiotherapy; 24%(13) induction vs 76%(41) consolidation chemotherapy. Preferred chemotherapy regimen was CAPOX both in induction and consolidation chemotherapy (69.7% and 63.4%, respectively) Despite small numbers non significant differences in risk factors were found between TNT vs non TNT groups (Table). We registered 13 Grade 3-4 toxicity events: 3 in induction chemotherapy, 7 in consolidation and 3 in radiotherapy. Clinical complete response was achieved in 25.9% of TNT (11 consolidation, 3 induction) and 7.1%(1) of non-TNT (p=0.25). Watch and Wait was employed in 9 patients in TNT and 1 in non TNT group. 40 patients underwent surgery in the TNT and 11 in the non-TNT group; complete pathological response was reached in 17.5% (7) and 9% (1), respectively. Overall relapse rate was 19.14% (13): 2.94% (2) local and 16.2% (11) systemic. (TNT: 1.85%(1) local vs 18.5%(10) metastatic; nonTNT: 7.14%(1) both local and metastatic) p=0.4. At a median follow-up of 20 months (IQR 15–32 months), 2-year progression-free survival (PFS) rate was 87% (95% CI: 38–98%) in the non-TNT group and 78% (95% CI: 61–88%) in the TNT group. Conclusions: This study highlights the feasibility of worldwide adoption of TNT. We describe the preferred regimens and results of TNT in three high volume centers in Argentina. Long course radiotherapy and consolidation treatment with CAPOX are the predominant strategies. Non operative management is routinely offered to complete responders. Our efficacy results are comparable with published literature. Comprehensive geriatric assessment is recommended but still partially applied. In line with recent findings MMR testing has been widely adopted as an initial workup parameter. TNT %(n=54) non-TNT %(n=14) p T4 disease 26 (14) 21 (3) 0.99 N2 37 (20) 29 (4) 0.75 EMVI positivity 49 (26) 18 (3) 0.16 Circumferential resection margin <1 mm 29.6 (16) 28.57 (4) 0.23 Low-lying tumors 33 (18) 43 (6) 0.54

Oligometastatic NSCLC: Current Perspectives and Future Challenges

Oligometastatic non-small cell lung cancer (NSCLC) represents a separate entity with a different biology and prognosis compared to stage IV NSCLC. Challenges range from the very definition of oligometastatic disease to the timing and techniques of local treatments, and their benefit in prolonging patient survival. Most of the international consensus and guidelines agree on the need for shared criteria, such as appropriate stadiation and even tissue biopsy if needed, in order to select patients that could really benefit from personalised strategies. Multidisciplinary evaluation is crucial in order to define if every lesion is amenable to radical local treatment, which appears to be the most important criterion across different guidelines. A distinction must be made depending on the time of oligo-disease detection, separating de novo oligometastatic disease from oligorecurrence, oligoprogression and oligoresidual disease. These separate entities imply a different biology and prognosis, and treatment strategies consequently must be tailored. Locoregional approaches are therefore often contemplated in order to ensure the best outcome for the patient. In non-oncogene-addicted disease, the advent of immune checkpoint blockers (ICBs) allows physicians to take into consideration consolidative treatments, but timing, technique and subsequent systemic treatment remain open issues. In oncogene-addicted NSCLC, local treatments are nowadays preferably reserved to cases of oligoprogression, but the advent of new, more potent drugs might challenge that. In this review, we summarised the current knowledge, consensuses and data from retrospective and prospective trials, with the aim of shedding some light on the topic and emphasising the unmet clinical need.

Influence of Organ-Specific Extranodal Involvement on Survival Outcomes in Stage IV Diffuse Large B-Cell Lymphoma.

The prognostic significance of extranodal sites in stage IV diffuse large B-cell lymphoma (DLBCL) remains uncertain, making it challenging to select appropriate treatment strategies for individual patients. In this study, we aimed to evaluate the influence of different extranodal sites on prognosis in young patients with stage IV DLBCL who achieved complete remission (CR) following initial chemo-immunotherapy and to explore the potential of autologous hematopoietic stem cell transplantation (ASCT) as a consolidation treatment for specific patient subgroups. We retrospectively reviewed data from 119 patients with DLBCL aged < 60 years who achieved CR after chemo-immunotherapy between 2008 and 2020. Patient survival rates were analyzed in correlation with different extranodal sites using univariate and multivariate models. Additionally, we assessed the effect of ASCT on 5-year progression-free survival (PFS) and overall survival (OS) in patients with different extranodal sites involved. A retrospective bicenter study. Univariate analysis revealed a significant decrease in survival rates in patients with a Deauville score of 3 and those with extranodal DLBCL affecting the spleen, bone marrow, nasosinus, and liver. In multivariate analysis, only nasosinusal involvement remained a significant predictor of reduced OS. Patients with spleen involvement benefited significantly from ASCT in terms of 5-year PFS and OS, whereas those with nasosinusal involvement did not demonstrate any survival advantage with ASCT. Our findings highlight the influence of specific extranodal sites on the prognosis of patients with stage IV DLBCL. The data indicate a clear need for precise patient stratification based on extranodal involvement for more effective treatment planning. Notably, patients with spleen involvement appear to benefit from ASCT, suggesting that this strategy could be useful in this subgroup. Further prospective studies are needed to confirm and incorporate these findings into clinical practice.

What is the ideal approach-doublet, triplet, or quadruplet(s)?

Significant progress has been made in the treatment of multiple myeloma (MM), with the introduction of several new drugs with different mechanisms of action. The treatment of newly diagnosed MM has evolved dramatically with the development of highly effective combinations that include 1 or more of the new drugs. Despite the continuing improvement in the overall survival of patients with MM, nearly a quarter of the patients have significantly inferior survival, often driven by a combination of factors, including tumor genetics and host frailty. The focus of initial therapy remains rapid control of the disease with reversal of the symptoms and complications related to the disease with minimal toxicity and a reduction in early mortality. The selection of the specific regimen, to some extent, depends on the ability of the patient to tolerate the treatment and the underlying disease risk. It is typically guided by results of randomized clinical trials demonstrating improvements in progression-free and/or overall survival. While increasing risk calls for escalating the intensity of therapy by using quadruplet combinations that can provide the deepest possible response and the use of autologous stem cell transplant, increasing frailty calls for a reduction in the intensity and selective use of triplet or doublet regimens. The choice of subsequent consolidation treatments and maintenance approaches, including duration of treatment, also depends on these factors, particularly the underlying disease risk. The treatment approaches for newly diagnosed myeloma continue to evolve, with ongoing trials exploring bispecific antibodies as part of initial therapy and CAR T cells for consolidation.

Application of Multi-level Network Meta-Regression in the NICE Technology Appraisal of Quizartinib for Induction, Consolidation and Maintenance Treatment of Newly Diagnosed FLT3-ITD-Positive Acute Myeloid Leukaemia: An External Assessment Group Perspective.

Application of Multi-level Network Meta-Regression in the NICE Technology Appraisal of Quizartinib for Induction, Consolidation and Maintenance Treatment of Newly Diagnosed FLT3-ITD-Positive Acute Myeloid Leukaemia: An External Assessment Group Perspective.

Cellulose consolidated with polyethylene glycol: The nanoscale mechanisms revealed by hybrid Monte Carlo/molecular dynamics modeling

Polyethylene glycol (PEG) consolidation treatment is a widely used conservation strategy for wooden culture relics. However, the consolidation mechanism of PEG is still open to interpretation. PEG-cellulose, the representative component of wood cell wall, interactions are governed by various coupled multi-scale mechanisms which require nano-scale investigation. In this study, a hybrid molecular dynamics and grand canonical Monte Carlo (MD/GCMC) simulation combined with rule of mixture (RoM) analyses are employed to reveal the underlying mechanisms of PEG-induced consolidation. We found that PEG200 reduces moisture adsorption and swelling at museological conditions, confirming its consolidation effect. At high PEG content, a crossover behavior is identified at humid conditions (RH>80) where excessive sorption and swelling are observed surpassing the untreated sample. The molecular modeling results are found to be consistent with experimental observations. Furthermore, the structural and mechanical properties of the hydrated samples are assessed by examining the porosity distribution, mechanical properties, and hydrogen bonding network. Results indicate mechanical softening induced by PEG treatment. A modified mixture model is proposed based on molecular modeling results that incorporate sorption and swelling coupling, porosity filling and mechanical softening behaviors. Two key mechanisms are identified explaining the consolidation effect of PEG: first, the PEG fills the porosities of amorphous structure thus diminishing sorption sites; second, the polymer structure prohibits PEG from further swelling thus constraining water sorption. The model and theoretical framework can serve as a guide for the design of novel consolidant materials by identifying the key molecular features of an ideal consolidant.

Outcomes of Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia Given Blinatumomab As Last Consolidation Treatment before Allogeneic Hematopoietic Cell Transplantation

Outcomes of Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia Given Blinatumomab As Last Consolidation Treatment before Allogeneic Hematopoietic Cell Transplantation

Consolidation Enhancement of Weathered Coal Gangue Utilized for Aggregate Filling of Cement Pavement in Mining Area

The large-scale, open-air storage of coal gangue often leads to oxidation and decomposition due to natural weathering, resulting in decreased strength and instability, which limits its wider application in concrete pavement. To address these issues, this paper proposed a composite consolidation treatment for weathered coal gangue (WCG), assessing its effectiveness and enhancement mechanisms through aggregate performance tests, mixture performance tests, and microscopic visualization analyses. Results indicated that the initial and post-20 dry–wet cycle crushing values of WCG were 23.96% and 47.94%, respectively, failing to meet required standards. However, applying a composite consolidation treatment using a lithium curing agent and cement paste significantly improved WCG’s robustness and stability. After 4 days of treatment, the crushing value, impact value, and Vickers hardness of WCG had reached 18.3%, 6.58%, and 113.52 kgf/mm², respectively, fully meeting the standards for aggregate filling in mini concrete pavements. Furthermore, tests demonstrated that the lithium curing agent induced the formation of hydrated calcium silicate and calcium aluminate on both the surface and interior of the WCG, enhancing its structural stability. Approximately 5–12 wt.% of the curing agent penetrates and encapsulates the WCG, strongly bonding and reinforcing its internal weak surfaces. These findings offer potential solutions and technical insights for the large-scale management of weathered coal gangue.

Systemic induction therapy in patients with locally advanced or node-positive urothelial carcinoma: Evaluating treatment outcomes

Background The presence of lymph node metastases in patients with urothelial carcinoma (UC) plays a pivotal role in disease management and prognosis. Patients with locally advanced irresectable or clinically node-positive UC are often considered ineligible for surgery due to the extent of affected lymph nodes. Long term remission or even cure may be achieved in a subset of patients who experience response to systemic induction therapy and consolidative locoregional treatment. Objective To assess the pathological response to preoperative systemic induction therapy followed by radical surgery in patients with locally advanced irresectable or clinically node-positive UC. Methods Searches were performed until September 2023 in 5 databases (EMBASE, MEDLINE, Web-of-Science, Cochrane and Pubmed Publisher). Studies including patients with cT4bNxM0/cTxN1-3M0 UC, treated with induction chemotherapy or non-chemo induction therapy followed by radical surgery, were selected. The primary outcome was the pathological complete response (pCR) rate, i.e., the proportion of patients without residual disease in the surgical resection specimen (ypT0N0). Secondary outcomes included overall and cancer-specific survival (OS, CSS). Results Fourteen studies were included, representing 5715 patients. Two studies reported on non-chemo induction therapy. The reported pCR rate in patients receiving induction chemotherapy varied from 9% to 27% compared to 25% after induction immunotherapy. The 5-year OS and CSS after induction chemotherapy and radical surgery ranged from 25 to 34% and 30 to 49%. Conclusion Systemic induction therapy in patients with locally advanced irresectable or clinically node-positive UC resulted in modest pCR rates. Due to considerable heterogeneity between studies, no direct comparison on the efficacy of induction therapy regimens was possible.

Outcomes of children and young adults with B-cell acute lymphoblastic leukemia given blinatumomab as last consolidation treatment before allogeneic hematopoietic stem cell transplantation.

Blinatumomab has remarkable efficacy in patients with relapsed/refractory (r/r) or measurable residual disease (MRD)-positive B-cell acute lymphoblastic leukemia (B-ALL). In many patients, blinatumomab treatment is followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, the influence of blinatumomab on HSCT outcomes in children and young adults (YA) remains to be fully elucidated. We conducted a single-center, retrospective analysis on patients given blinatumomab as last treatment before HSCT. Seventy-eight pediatric and YA patients were evaluated. With a median follow-up of 23.23 months, the 2-year disease-free (DFS) and overall survival (OS) probability were 72.2% and 89.2%, respectively, with a 2-year cumulative incidence (CI) of non-relapse mortality (NRM) of 2.6%. A trend toward improved 2-year DFS, but not OS, was noted in patients transplanted in first complete remission (CR1) (92.9%) compared to those in second or greater remission (CR2/3) (68.5%, p=0.18) due to a lower CI of relapse (0% vs. 29.9%, p=0.05). Among CR2/3 patients, those receiving the sequential combination of inotuzumab and blinatumomab had a significantly lower CI of relapse as compared to those who did not receive inotuzumab (9.5% vs. 40.4%, p=0.023). Relapse after HSCT occurred in 16 patients, all exhibiting CD19-positive blasts; 10 of them received anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy and 2 inotuzumab as salvage therapy, leading to a 2-year post-relapse OS of 52.7%. Our results indicate that HSCT following blinatumomab in children and YA with B-ALL is highly effective, being associated with low NRM and not affecting the efficacy of subsequent salvage immunotherapies, including CAR-T cells.

The impact of hepatitis B surface antigen seroconversion on the durability of functional cure induced by pegylated interferon alpha treatment

BackgroundHepatitis B surface antigen (HBsAg) loss is regarded as a pivotal criterion for assessing functional cure in patients diagnosed chronic hepatitis B (CHB). We conducted the research to investigate the real-world performance of HBsAg seroconversion in sustaining HBsAg loss.MethodsThis retrospective analysis confirmed 295 patients who attained HBsAg loss through combination therapy involving nucleos(t)ide analogues (NAs) and pegylated interferon alpha (peg-IFNα). Employing Kaplan–Meier estimates method to conduct survival analysis. The forest plot was used to visualize the results of multivariate Cox regression, and selected variables were included in the nomogram.ResultsHBsAg seroreversion was observed in 45 patients during follow-up periods, with a lower recurrence risk in patients with HBsAg seroconversion at the end of peg-IFNα therapy (EOT) (10.3% vs 37.3% at 96-week, P < 0.0001). Moreover, the sustainability of hepatitis B surface antibody (anti-HBs) in participants continuing therapy after HBsAg seroconversion was superior to those discontinued prematurely (72.5% vs 54.5% at 96 weeks, P = 0.012). Additionally, the former group was also relatively less likely to experience HBsAg reversion during long-term observation (8.4% vs 14.3% at 96 weeks, P = 0.280). Hepatitis B envelope antigen (HBeAg) status, anti-HBs status and consolidation treatment screened by multivariable analysis were utilized to construct a predictive model for HBsAg reversion. The concordance index(C-index = 0.77) and calibration plots indicated satisfactory discrimination and consistency of nomogram.ConclusionsHBsAg seroconversion was beneficial for sustaining functional cure in patients treated with peg-IFNα. Continuing consolidation therapy after HBsAg seroconversion also contributed to maintain HBsAg seroconversion and improve the durability of HBsAg loss. The nomogram illustrated its efficacy as a valuable instrument in showcasing survival probability of functional cure.

EP.08F.14 Outcomes of Durvalumab Consolidation Treatment in Stage III Unresectable NSCLC: A Retrospective Real-World Study

EP.08F.14 Outcomes of Durvalumab Consolidation Treatment in Stage III Unresectable NSCLC: A Retrospective Real-World Study

Safety Profile of Durvalumab (D) as Consolidation Treatment (tx) in Limited-Stage Small-Cell Lung Cancer (LS-SCLC) in ADRIATIC: Focus on Pneumonitis and Immune-Mediated Adverse Events (imAEs)

Safety Profile of Durvalumab (D) as Consolidation Treatment (tx) in Limited-Stage Small-Cell Lung Cancer (LS-SCLC) in ADRIATIC: Focus on Pneumonitis and Immune-Mediated Adverse Events (imAEs)

Comparative Studies on Nanocellulose as a Bio-Based Consolidating Agent for Ancient Wood

In this work, nanocellulose aqueous dispersions were studied as a bio-inspired consolidating agent for the recovery and conservation of ancient wood and compared with two of the most used traditional consolidants: the synthetic resins Paraloid B-72 and Regalrez 1126. The morphology of crystalline nanocellulose (CNC), determined using Scanning Electron Microscopy (SEM), presents with a rod-like shape, with a size ranging between 15 and 30 nm in width. Chemical characterization performed using the Fourier-Transform Infrared Spectroscopy (FT-IR) technique provides information on surface modifications, in this case, demonstrating the presence of only the characteristic peaks of nanocellulose. Moreover, conductometric, pH, and dry matter measurements were carried out, showing also in this case values perfectly conforming to what is found in the literature. The treated wood samples were observed under an optical microscope in reflected light and under a scanning electron microscope to determine, respectively, the damage caused by xylophages and the morphology of the treated surfaces. The images acquired show the greater similarity of the surfaces treated with nanocellulose to untreated wood, compared with other consolidating agents. Finally, a colorimetric analysis of these samples was also carried out before and after a first consolidation treatment, and after a second treatment carried out on the same samples three years later. The samples treated with CNC appeared very homogeneous and uniform, without alterations in their final color appearance, compared to other traditional synthetic products.

Flexible-rigid hybrid siloxane network for stone heritage conservation

Flexible-rigid hybrid siloxane network for stone heritage conservation

Consolidating Lime Mortar with Nanolime: The Effect of the Ethanol:Water Ratio

ABSTRACT Over the last twenty years, more research has been conducted on the application of nanolime as a consolidant. However, a limitation in consolidation with nanolime is the back-migration of the product to the absorption surface during the drying phase, resulting in insufficient product deposition in depth. In this paper, a solvent composition is adapted to the substrate properties to examine the theory that a nanolime with low kinetic stability should be applied to prevent back-migration to the absorption surface for a substrate with large pore size. The common solvent composition of 100% ethanol has a kinetic stability considered too high. Nanolime dispersions (CaLoSiL® E 20 g/L) with different ethanol:water (100:0, 95:5, 90:10, 80:20) ratios were tested on lime mortar samples. The treated samples were subjected to several test methods to evaluate the effectiveness of the consolidation treatment. After comparing the results, the theoretical propositions were substantiated: a back-migration was noticeable in samples treated with the nanolime containing 100% ethanol, while no back-migration was observed in the other solvent compositions. Samples treated with a nanolime dispersion with the addition of 10% deionised water showed promising results regarding mechanical strength, product deposition over the entire depth profile of the sample, and porosity properties.

Combination of rituximab and methotrexate followed by rituximab and cytarabine in elderly patients with primary central nervous system lymphoma.

The optimal treatment strategy for newly diagnosed primary central nervous system lymphoma (PCNSL) has yet to be established, especially in the elderly. In the current study, we conducted a phase II study to evaluate the efficacy and safety of rituximab plus high-dose MTX followed by rituximab plus cytarabine in patients aged ≥60 years newly diagnosed with PCNSL. Patients received an induction treatment of high-dose methotrexate plus rituximab followed by two cycles of a consolidation treatment of cytarabine plus rituximab. The primary end-point was a 2-year progression-free survival (PFS) rate. A total of 35 patients were recruited, and their median age was 73 (range: 60-81). After induction treatment, the complete and partial responses (PRs) were 56% and 20% respectively. Twenty-six patients proceeded to the consolidation treatment; the complete and PRs were 59% and 9% respectively. After a median follow-up duration of 36.0 months, the 2-year PFS rate was 58.7%. Treatment was generally well-tolerated as only three patients were withdrawn from the study due to toxicity, and no treatment-related mortality was reported. The 2-year overall survival rate was 77.9%. The current study may suggest the feasibility of administering high-dose MTX plus cytarabine in PCNSL patients aged ≥60 years and the potential role of additive rituximab.

The effect of traditional processing craft on the hygroscopicity of palm leaf manuscripts

Palm leaf manuscripts, which are crucial carriers of historical, religious, scientific, and artistic information in East and Southeast Asia, specifically encapsulate significant aspects of Buddhist culture and thus require comprehensive research and preservation efforts. The base material of palm leaf manuscripts is processed palm leaves, which are hygroscopic and profoundly affected by environmental humidity. Currently, there is a research gap regarding the impact of traditional processing crafts and natural aging on the hygroscopicity of palm leaf manuscripts. Utilizing dynamic water vapor sorption (DVS), the hygroscopic properties of palm leaves from various years were assessed before and after traditional processing in Yunnan Province, China. The results show that traditional processing slightly increases the equilibrium moisture content (EMC) in environments with 0 to 60% relative humidity (RH), but significantly lowers EMC in high humidity environments, with reductions up to 19.01%. Additionally, hysteresis doubled post-processing, indicating enhanced stability under fluctuating humidity conditions. Sorption models suggest that traditional processing increases the number of adsorption sites while reducing physical adsorption or capillary condensation. FT-IR (Fourier-transform infrared spectroscopy) analysis indicates that the relative contents of cellulose and hemicellulose were reduced by 39.90% and 3.97%, respectively. Degradation occurring in both the crystalline and amorphous regions of cellulose. After natural aging, the hygroscopicity of processed palm leaves improved across the entire humidity range of 0 to 95%, and there was a slight increase in hysteresis. This is due to the increase in both adsorption sites and physical adsorption capabilities. FT-IR results also indicate that the relative contents of cellulose and hemicellulose were decreased by 57.52% and 19.83% after nature aging, respectively. These findings confirm that traditional processing improves the writability and humidity resilience of the leaves, while natural aging enhances their overall hygroscopic properties. This research contributes to our understanding of how humidity damages palm leaf manuscripts. aids in determining optimal RH ranges for storage, and assesses the effectiveness of consolidation treatments in their long–term preservation.

Association Between PD-L1 Score and the Outcomes of Consolidation Durvalumab in a Large Nationwide Series of Patients With Stage III NSCLC Treated With Chemoradiotherapy

The Pacific trial reported improved outcomes when durvalumab was administered following concurrent chemoradiotherapy (CRT) for stage III NSCLC. Post-hoc subgroup analysis did not show favorable results for PD-L1 negative cases. We compared nationwide survival data with the trial outcomes, and evaluated the influence of PD-L1. Data from the Netherlands Cancer Registry were queried regarding patients with clinical stage III who underwent CRT, either by concurrent or sequential administration. Predictors for the use of consolidation treatment with durvalumab were evaluated by tabulations and logistic regression analysis. Overall survival (OS) was calculated from start of radiation or start of durvalumab and was stratified by PD-L1 score. Between 2017 and 2021, application of consolidation durvalumab increased from 2% to 21%, 40%, 57%, 62%, respectively. In the period 2020-2021, durvalumab use was more frequent among patients with younger age, concurrent CRT, better performance score and proton radiation, but was irrespective of PD-L1 score. For patients receiving durvalumab (n = 1639), the 4-year OS was 53% overall (95%CI 50-57), and it was 56% (95%CI 52-60) after concurrent CRT. Four-year OS was considerably better for the PD-L1 subgroup ≧50% at 67% (95%CI 59-73), and it was similar for PD-L1 subgroups 0 and 1-49, at 51% (95%CI 42-58) and 46% (95%CI 39-54), respectively. In real-world clinical practice, survival outcomes were equivalent to results from trial series. Overall survival in patients with negative PD-L1 was similar to the survival in patients with PD-L1 1-49, questioning the restrictions imposed by the European Medicines Agency.

Standard or high dose chemoradiotherapy, with or without the protease inhibitor nelfinavir, in patients with locally advanced pancreatic cancer: The phase 1/randomised phase 2 SCALOP-2 trial

The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel. In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL). High dose CRT did not improve OS (16.9 (60% confidence interval, CI 16.2-17.7) vs. 15.6 (60%CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60%CI 0.91-1.40; p=0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60%CI 9.9-10.2) vs. 11.1 (60%CI 10.3-12.8) months; adjusted HR 1.71 (60%CI 1.38-2.12; p=0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n=11/46 (23.9%) vs. n=15/45 (33.3%)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment. Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS.