Effect Of Treatment Sequence Research Articles

The order of surgery and chemotherapy matters: Multimodality therapy and stage-specific differences in survival in gastric cancer.

Multimodality treatment improves survival for gastric cancer (GC). However, the effect of treatment sequence by stage remains unclear. We aim to compare outcomes between patients receiving neoadjuvant(neoadj) and adjuvant chemotherapy (adj). Nonmetastatic GC patients with clinical stage ≥ T2N0 who underwent both resection and neoadj or adj were identified using the National Cancer Database (2005-2014). Multivariable Cox regression analyses were performed on propensity score-matched (PSM) cohorts stratified by stage to compare overall survival (OS). We identified 11 984 patients; 55% stage I (SI), 76% stage II (SII) and 57% stage III (SIII) received neoadj. Unadjusted analysis showed worse survival among SI neoadj patients (hazard ratio [HR] 1.195, confidence interval [CI] 1.04-1.38) and improved survival for SII (HR 0.93 CI 0.87-0.998) and SIII (HR 0.75, CI 0.68-0.84). After PSM, SI patients with neoadj had worse OS with increased risk of death compared to Adj (HR 1.186, CI 1.004-1.402). SII patients had no difference in OS (HR 0.98, CI 0.91-1.07) and SIII patients had improved OS (HR 0.78, CI 0.69-0.90). In patients who received surgery and chemotherapy, the benefit of neoadj was limited to SIII with worse survival for SI. A clinical trial to examine the optimal sequence of chemotherapy is warranted.

Being Transparent About Brilliant Failures: An Attempt to Use Real-World Data in a Disease Model for Patients with Castration-Resistant Prostate Cancer.

BackgroundReal-world disease models spanning multiple treatment lines can provide insight into the (cost) effectiveness of treatment sequences in clinical practice.ObjectiveOur objective was to explore whether a disease model based solely on real-world data (RWD) could be used to estimate the effectiveness of treatments for patients with castration-resistant prostate cancer (CRPC) that could then be suitably used in a cost-effectiveness analysis.MethodsWe developed a patient-level simulation model using patient-level data from the Dutch CAPRI registry as input parameters. Time to event (TTE) and overall survival (OS) were estimated with multivariate regression models, and type of event (i.e., next treatment or death) was estimated with multivariate logistic regression models. To test internal validity, TTE and OS from the simulation model were compared with the observed outcomes in the registry.ResultsAlthough patient characteristics and survival outcomes of the simulated data were comparable to those in the observed data (median OS 20.6 vs. 19.8 months, respectively), the disease model was less accurate in estimating differences between treatments (median OS simulated vs. observed population: 18.6 vs. 17.9 [abiraterone acetate plus prednisone], 24.0 vs. 25.0 [enzalutamide], 20.2 vs. 18.7 [docetaxel], and 20.0 vs. 23.8 months [radium-223]).ConclusionsOverall, the disease model accurately approximated the observed data in the total CRPC population. However, the disease model was unable to predict differences in survival between treatments due to unobserved differences. Therefore, the model is not suitable for cost-effectiveness analysis of CRPC treatment. Using a combination of RWD and data from randomised controlled trials to estimate treatment effectiveness may improve the model.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-022-00294-7.

Effect of treatment sequence on mortality in advanced-stage endometrial cancer

<h3>Objectives:</h3> The aim of this study was to assess for an association between the sequence of surgical and systemic treatment and overall survival in patients with Stage IV endometrial cancer, as well as to identify prognostic factors for mortality. <h3>Methods:</h3> The National Cancer Database (NCDB) was queried for cases of endometrial cancer diagnosed between 2006 and 2015. These cases were further narrowed to include only International Classification of Diseases for Oncology (ICD-O) histologic codes of adenocarcinoma or endometrioid adenocarcinoma and FIGO stage IV disease. Exclusion criteria were: reference date prior to date of diagnosis; unknown treatment sequence; intraoperative chemotherapy use; and hormonal or immunotherapy as first-line systemic therapy or unknown hormonal or immunotherapy use. Three groups were defined according to sequence of administration of surgery and systemic therapy. Overall survival (OS) was compared by calculating hazard ratios for death via Cox regression analysis. The Incomplete Treatment (IT) group received surgery alone, systemic therapy alone, or no treatment. The Primary Surgery (PS) group received surgery before systemic therapy. The Interval Surgery (IS) group had neoadjuvant systemic therapy followed by surgery, with or without further systemic therapy after surgery. Subanalyses were performed to assess the impact of post-IS systemic therapy, age, ethnicity, insurance status, and Charlson-Deyo score on OS. Analysis was performed using STATA.16. <h3>Results:</h3> A total of 8,520 cases of FIGO Stage IV endometrial adenocarcinoma were identified using the criteria above. Median OS in months for each treatment sequence group was 7.2 for IT, 35.7 for PS, and 30.7 for IS. Regardless of treatment sequence, receiving both surgical and systemic therapy improved OS compared to receiving only one or neither treatment. The hazard ratio (HR) for death for PS compared to IT was 0.38 (95% CI 0.36-0.40) and for IS compared to IT was 0.41 (95% CI 0.36-0.47), p<0.0001 for both. There was no significant difference in survival for IS compared to PS (HR 1.10, 95% CI 0.96-1.24, p=0.18). Stratification of IS cases by administration of further systemic therapy after surgery yielded the same result. Patient groups with worse OS (p<0.0001 for all) included: age >50 years (HR 1.18, 95% CI 1.08-1.30), non-Hispanic Black compared to non-Hispanic White (HR 1.27, 95% CI 1.17-1.37), and presence of medical comorbidities reflected by Charlson-Deyo score of 1 or more. Patients with private insurance had better OS than uninsured patients (HR 0.80, 95% CI 0.71-0.90, p<0.0001) but the same was not true for government insurance. <h3>Conclusions:</h3> This retrospective survival analysis of NCDB data for FIGO Stage IV endometrial adenocarcinoma illustrated a benefit to receiving both systemic and surgical treatment over receiving only one or neither form of therapy. No difference in mortality was identified between primary surgery with adjuvant systemic therapy and neoadjuvant systemic therapy with interval surgery, even when accounting for additional chemotherapy after surgery. The decision whether to begin treatment with surgery or chemotherapy will thus depend on nuanced clinical factors specific to each patient. Patient factors associated with worse mortality included age >50 years, Non-Hispanic Black ethnicity, lack of insurance, and presence of medical comorbidities. These findings indicate a need to address the socioeconomic determinants of health contributing to these disparities in mortality.

New Strategy to Enhance Transfer printing and Functional Finishing of Polyester fabric

This research work is aimed to upgrade the transfer printability, the UV-protection and antibacterial functionalities of polyester woven fabric via alkali-treatment followed by post-loading of functional agents namely PVP, Triclosan, Chitosan, metal oxide nano particles MO-NPs i.e. TiO2, ZrO2, ZnO-NPs individually. The modified fabric samples were subsequently transfer printed with certain disperse dyes. The effect of treatment sequence and type of the used additive on the printability and functionality of the polyester prints were investigated. The results revealed that the creation of hydrophilic active sites namely carboxyl and hydroxyl end groups at the fabric surface, as well as loading and fixation of the used functional agents onto the finish/fabric matrix brought about polyester prints with a darker depth of shades, excellent antibacterial activity, and higher UV-protecting functionality compared with the untreated one.

The effect of treatment sequence on overall survival for men with metastatic castration-resistant prostate cancer: A multicenter retrospective study.

238 Background: We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy. Methods: We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naïve prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival. Results: The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio: HR 0.84, P = 0.530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR 0.82, P = 0.650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR 1.58, P = 0.384). Conclusions: The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.

The Effect of Treatment Sequence on Overall Survival for Men With Metastatic Castration-resistant Prostate Cancer: A Multicenter Retrospective Study.

We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy. We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naive prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival. The median age was 71 years. A total of 35patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, and 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n= 68) and first-line docetaxel (n= 78) therapies (hazard ratio [HR], 0.84; P= .530), between the ART-ART (n= 35) and docetaxel-mixed (n= 111) sequences (HR, 0.82; P= .650), and between the first-line abiraterone (n= 32) and first-line enzalutamide (n= 36) sequences (HR, 1.58; P=.384). The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.

Effect of treatment sequence on survival in stage IV rectal cancer with synchronous and potentially resectable liver metastases.

The optimal treatment sequence in stage IV rectal cancer (RC) with synchronous liver metastases (SLM) remains undefined. Here, we compared outcomes between patients treated with the bowel-first approach (BFA) or the liver-first approach (LFA). Consecutive patients diagnosed with stage IV RC with SLM and who underwent complete resection were included. Both groups were matched using propensity scores. Differences in postoperative outcome, local control, and long-term survival were studied. In addition, a decision analysis (DA) model was built using TreeAge Pro to define the approach that results in the highest treatment completion rate. During a 12-year period, 52 patients were identified, 21 and 31 of whom underwent the BFA and the LFA, respectively. Twenty-eight patients were matched; patients treated with the BFA experienced a longer median OS (50.0 vs 33.0 months; P = .40) and higher 5-year OS (42.9% vs 28.6%). The DA defined the BFA to be superior when the failure threshold (ie, no R0 resection, treatment discontinuation regardless of cause) for colectomy is less than 28.6%. In stage IV rectal cancer with SLM, either the BFA or the LFA result in similar long-term outcomes. Treatment should be tailored according to clinicopathological variables.

A Novel Mechanism of High Dose Radiation Sensitization by Metformin.

Introduction: Metformin, the most widely used treatment for diabetes, is lethal to cancer cells and increases in toxicity when used in combination with radiation. In addition to various molecular and metabolic mechanisms that have been previously proposed, the studies presented provide evidence of an additional, novel mechanism of sensitization following high dose radiotherapy; the magnitude of sensitization depends on the microenvironmental levels of glucose and oxygen which are in turn affected by high dose radiation.Methods: Cancer cells (A549 and MCF7) were studied in vitro under various controlled conditions. Endpoints included clonogenic cell survival and ROS expression measured by DHE and DCFDA. CD1 nu/nu athymic mice implanted with A549 cells received metformin alone (200 mg/kg, i.p.), radiation alone (15 Gy) or a combination of metformin and radiation; the effect of treatment sequence on efficacy was assessed by tumor growth delay and histology. In a separate set of experiments, tumor blood flow was measured using a tracer clearance technique using SPECT after the administration of metformin alone, radiation alone and the combined treatment.Results: In vivo, metformin provided equally effective tumor growth delay when given 24 h after radiation as when given 1 h or 4 h before radiation, an observation not previously reported and, in fact, unexpected based on published scientific literature. When drug followed radiation, the tumors were histologically characterized by massive cellular necrosis. In vitro, cancer cells when glucose depleted and/or hypoxic were preferentially killed by metformin, in a drug dose dependent manner. A549 cells exposed to 5.0 mM of metformin was reduced seven fold in survival when in a glucose deprived as compared to a low-glucose medium (0 vs. 1.0 g/L). Finally, using a SPECT detector to follow the washout of a radioactive tracer, it was shown that a high single dose of radiosurgery (15 Gy) could dramatically inhibit blood flow and presumably diminish glucose and oxygen.Discussion: Insight into the best timing of drug and radiation administration is gained through an understanding of the mechanisms of interaction. A new mechanism of metformin sensitization by high dose radiation is proposed based on the blood flow, glucose and oxygen.

Effect of treatment sequence in combined intrastromal corneal rings and corneal collagen crosslinking for keratoconus

To compare 2 sequences of combined intrastromal corneal ring segment (ICRS) implantation and ultraviolet/riboflavin-mediated corneal collagen crosslinking (CXL) in progressive keratoconus. Dunya Eye Hospital, Istanbul, Turkey. In this prospective comparative randomized consecutive study, CXL was followed by ICRS implantation (Group 1) or ICRS implantation was followed by CXL (Group 2). Uncorrected (UDVA) and corrected (CDVA) distance visual acuities, spherical equivalent (SE), manifest cylinder (cylinder), and mean keratometry (K) were compared preoperatively and postoperatively. The mean interval between treatments was 7 months +/- 2 (SD) (mean follow-up, 13 +/- 1 months). The mean UDVA and CDVA improved in both groups (UDVA: 0.07 +/- 0.09 to 0.25 +/- 0.12, Group 1, and 0.11 +/- 0.09 to 0.32 +/- 0.21, Group 2; CDVA: 0.24 +/- 0.11 to 0.41 +/- 0.20 and 0.22 +/- 0.16 to 0.55 +/- 0.2, respectively). The mean SE, cylinder, and mean K values decreased in both groups (SE: -7.13 +/- 3.34 D to -2.98 +/- 2.33 D, Group 1, and -7.05 +/- 5.54 D to -2.81 +/- 4.08 D, Group 2; cylinder: -4.38 +/- 2.03 D to -2.62 +/- 1.93 D and -4.68 +/- 2.60 D to -2.20 +/- 1.67 D, respectively; mean K: 52.47 +/- 4.01 D to 48.31 +/- 3.65 D and 52.06 +/- 4.93 D to 48.08 +/- 4.13 D, respectively). Overall, there was more improvement in CDVA, SE, and mean K in Group 2 than in Group 1. Implantation of ICRS followed by CXL resulted in greater improvement of keratoconus.

Effect of treatment sequence with radiotherapy and the antiestrogen EM 800 on the growth of ZR 75 1 human mammary carcinoma in nude mice.

We demonstrated previously that continuous administration of EM-800, a SERM having pure antiestrogenic activity in the mammary gland and endometrium in combination with monthly radiotherapy caused a greater inhibition of human ZR 75 1 tumor growth in nude mice than either therapy used alone. To further optimize therapy, we have now examined the effect of various treatment sequences to determine the optimal treatment regimen in the same model. EM 800 was given at the maximally effective oral dose of 300 microg daily. External beam radiation therapy (RTX) was carried out (2 Gy/tumor/day, 5 days per week for 3 weeks) for a total of 30 Gy/tumor delivered directly to the tumor while shielding the rest of the animal body. There was no evidence of RTX-related morbidity. Continuous treatment with EM 800 was initiated either 3 weeks before or at the same time as RTX, immediately after RTX, or 3 weeks before and immediately after RTX. After 156 days of treatment, EM 800 alone caused a 75% decrease in average tumor area, an effect equivalent to that achieved by ovariectomy. RTX alone, on the other hand, caused a transient 30% decrease in tumor area regardless of treatment sequence, whereas combined treatment with EM 800 and RTX was superior to either treatment alone. Combined treatment with EM 800 and RTX both started on Day 1 caused the greatest (88%), most rapid (50% in 2 weeks) and sustained decrease in tumor size. The present data indicate that optimal reduction in breast tumor size is achieved by continuous administration of EM 800 and RTX started simultaneously on Day 1.

Preclinical and clinical aspects of biomodulation of 5-fluorouracil

Although single agent 5-FU has for many years been the standard therapy for advanced colorectal malignancies, a number of recent clinical trials show higher response rates with biomodulation of 5-FU by several different agents. In general, trials of leucovorin, methotrexate, interferon, and PALA given in biomodulatory doses and sequences with 5-FU have demonstrated comparable response rates over a broad range. However, in the absence of controlled direct comparative phase III trials, final judgement on clinical superiority of a particular regimen must be reserved. Nevertheless, on the basis of current data, certain approaches appear promising and warrant further investigation. Compared to single agent 5-FU, survival benefit has been demonstrated with both low and high dose leucovorin/5-FU regimens and response rates in the 20–50% range appear reproducibly higher than those of 5-FU alone. Low dose and either continuous infusion or repetitive dosing of leucovorin, as well as the effect of treatment sequence and intervals between drugs, require additional investigation. When given 20–24 h before 5-FU, methotrexate achieves response rates similar to leucovorin modulated 5-FU, but the potential role of rescue leucovorin used in many of the trials makes definitive interpretation difficult. Interferon/5-FU regimens attaining response rates of 30–40% are promising but need to be carefully and rationally designed. Low dose PALA with effective doses of 5-FU achieving responses in 35–45% of patients represent a marked improvement in earlier trials of high dose PALA, but additional studies with higher doses not compromising 5-FU dose intensity should be considered. Certainly, the concomitant use of multiple modulating agents also needs further investigation. While many such trials already performed attained results no better than single agent biomodulation, the preliminary results obtained by Grem and colleagues with IFN/LV/5-FU in untreated patients, and by Conti et al. using TMTX/LV/5-FU in previously treated patients are encouraging. Further understanding of the mechanisms of action and interaction of modulating agents should allow additional rational combinations to be explored clinically. Cisplatin biomodulation of 5-FU has been studied in gastrointestinal and head and neck malignancies achieving excellent results in the latter group. Preclinical evidence exists which suggests, however, that 5-FU modulation of cisplatin may be more effective, especially when 5-FU is administered 24 h or more before cisplatin. Clinical investigation of this sequence is currently lacking. Data to support the clinical promise of AZT, IdUrd, uridine, and the benzylacyclouridines are not yet available, although preclinical and preliminary clinical studies are promising.