Optimal Sequence Of Chemotherapy Research Articles

Multidimensional Transcriptomics Unveils RNF34 as a Prognostic Biomarker and Potential Indicator of Chemotherapy Sensitivity in Wilms' Tumour.

Nephroblastoma, colloquially known as Wilms' tumour (WT), is the predominant malignant renal neoplasm arising in the paediatric population. Modern therapeutic approaches for WT incorporate a synergistic combination of surgical intervention, radiotherapy, and chemotherapy, which substantially ameliorate the overall patient survival rate. Despite this, the optimal sequence of chemotherapy and surgical intervention remains a matter of contention, with each strategy presenting its own strengths and weaknesses that could influence clinical decision-making. To make some headway on this clinical dilemma, we deployed a multidimensional transcriptomics integration approach by analysing bulk RNA sequencing data with 136 samples, as well as single-nucleus RNA sequencing (snRNA-seq) and paired spatial transcriptome sequencing (stRNA) data from 32 WT specimens. Our findings identified a distinct elevation of RNF34 expression within WT samples, which correlated with unfavourable prognostic outcomes. Leveraging the Genomics of Drug Sensitivity in Cancer (GDSC), we simultaneously revealed that patients with high expression of RNF34 have higher sensitivity to commonly used chemotherapy drugs for WT. Furthermore, our analysis of snRNA and stRNA data unveiled a reduced proportion of RNF34 expression in neoplastic cells after chemotherapy. Moreover, stRNA data delineated a significant association between a higher proportion of RNF34 expression in cancer cells and adverse features such as anaplastic histology and tumour recurrence. Intriguingly, we also observed a close association between elevated RNF34 expression and a characteristic exhausted tumour immune microenvironment. Collectively, our findings underscore the pivotal role of RNF34 in the prognostic prediction potential and treatment sensitivity of WT. This comprehensive analysis can potentially inform and refine clinical decision-making for WT patients and guide future studies towards the development of optimized, rational therapeutic strategies.

Effect of radiotherapy sequence on long-term outcome in patients with node-positive breast cancer: a retrospective study

The optimal sequence of chemotherapy (CT) and radiotherapy (RT) after surgery in breast cancer patients is unclear. There is a lack of literature on RT given between anthracycline and taxane administration. We evaluated the effect of RT sequence on long-term outcome in breast cancer. Two hundred patients who underwent surgery between January 2009 and December 2012 for node-positive breast cancers were evaluated retrospectively. All patients were treated with doxorubicin and cyclophosphamide (AC) followed by taxane. Sandwich RT group that received RT between AC and taxane was compared to the group that received RT after CT. The mean follow-up period was 105.4 months. The locoregional recurrence (LRR) rate was lower in sandwich RT group (P = 0.012) and there was no significant difference in distant metastasis between the two groups. The RT sequence was an important predictor for LRR in multivariable analysis (P = 0.017). For luminal A subtype, disease-free survival (DFS) was better in sandwich RT group than in CT followed by RT group (P = 0.001). The overall survival did not correlated with RT sequence regardless of subtype. Sandwich RT can offer DFS benefit in luminal A subtype breast cancer. A tailored approach of sequencing chemotherapy and radiotherapy would be needed considering the factors that can influence outcome.

Utilization of neoadjuvant chemotherapy in high-risk, node-negative early breast cancer.

BackgroundControversy exists regarding the optimal sequence of chemotherapy among women with operable node‐negative breast cancers with high‐risk tumor biology. We evaluated national patterns of neoadjuvant chemotherapy (NACT) use among women with early‐stage HER2+, triple‐negative (TNBC), and high‐risk hormone receptor‐positive (HR+) invasive breast cancers.MethodsWomen ≥18 years with cT1‐2/cN0 HER2+, TNBC, or high recurrence risk score (≥31) HR+ invasive breast cancers who received chemotherapy were identified in the National Cancer Database (2010–2016). Cochran‐Armitage and logistic regression examined temporal trends and likelihood of undergoing NACT versus adjuvant chemotherapy based on patient age and molecular subtype.ResultsOverall, 96,622 patients met study criteria; 25% received NACT and 75% underwent surgery first, with comparable 5‐year estimates of overall survival (0.90, 95% CI 0.892–0.905 vs 0.91, 95% CI 0.907–0.913). During the study period, utilization of NACT increased from 14% to 36% and varied according to molecular subtype (year*molecular subtype p < 0.001, p‐corrected < 0.001). Women with HER2+ (OR 4.17, 95% CI 3.70–4.60, p < 0.001, p‐corrected < 0.001) and TNBC (OR 3.81, 95% CI 3.38–4.31, p < 0.001, p‐corrected < 0.001) were more likely to receive NACT over time, without a change in use among those with HR+ disease (OR 1.58, 95% CI 0.88–2.87, p = 0.13, p‐corrected = 0.17).ConclusionAmong women with early‐stage triple‐negative and HER2+ breast cancers, utilization of NACT increased over time, a trend that correlates with previously reported improved rates of pCR and options post‐neoadjuvant treatment with residual disease. Future research is needed to better understand multidisciplinary decisions for NACT and implications for breast cancer patients.

Evaluation of the optimal sequence of chemotherapy and radiation therapy in the treatment of advanced endometrial cancer

Evaluation of the optimal sequence of chemotherapy and radiation therapy in the treatment of advanced endometrial cancer

Clinical outcomes of first-line FOLFIRINOX versus gemcitabine plus nab-paclitaxel in metastatic pancreatic cancer at the Yale Smilow Healthcare System.

769 Background: FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GN) are established first line (1L) therapies for metastatic pancreatic cancer (MPC) but real-world data on their comparative effectiveness is limited. Methods: All cases of MPC treated with 1L FFX or GN at Yale Smilow Cancer Hospital and the affiliated community care centers (CCC) from January 2011 – April 2019 were reviewed. Patient (pt) demographics, prior therapy, initial and subsequent dose reductions (DR), time to treatment discontinuation (TTD), overall survival (OS), and second line (2L) treatment data were manually abstracted from the electronic medical record. Categorical and continuous variables were compared between 1L FFX and GN cohorts via the Chi-squared and Wilcoxon rank-sum tests. Median OS was calculated by the Kaplan-Meier method. Results: We identified 363 MPC pts treated with 1L FFX or GN; 269 (74%) pts were treated with FFX and 94 (26%) with GN as 1L therapy. 204 (56%) pts were treated at the main campus and 159 (44%) at a CCC. Demographics and baseline characteristics (FFX/GN) were as follows: gender (male) 55% / 41%; race (white) 82% / 77%; age &lt; 76 90% / 71% ( P &lt; 0.001). 332 (91%) of pts received no prior therapy; 21 (6%) had prior surgery plus adjuvant gemcitabine and 10 (3%) had surgery alone. 98% of FFX-treated pts were treated with upfront DR, compared to 78% of GN-treated pts ( P= 0.003). 78% and 53% of FFX-treated and GN-treated pts, respectively, had subsequent DR ( P&lt; 0.001). Median TTD was 4.8 months with FFX and 3.4 months with GN ( P= 0.0029) and the median OS was 11.3 months with FFX versus 7.2 months with GN ( P &lt; 0.0001). After 1L, 33% and 61% of FFX- and GN-treated pts, respectively, received no further chemotherapy ( P&lt; 0.001). Conclusions: In the largest manually abstracted retrospective analysis to date, MPC pts treated with 1L FFX were younger, more likely to receive 2L therapy, and had increased survival compared to pts treated with GN. The OS of pts treated with FFX was similar to the OS reported by Conroy et al despite upfront dose attenuations in 98% of pts. A randomized trial is needed to confirm optimal sequencing of chemotherapy in MPC.

Resistance to chemoimmunotherapy in non-small-cell lung cancer

Recent clinical trials evaluating the combination of chemotherapy with immune checkpoint inhibition for the primary treatment of lung cancer showed increased progression-free and overall survival compared with chemotherapy alone. However, the combination of these two modalities is less than additive and the mechanisms of resistance to this therapeutic intervention are discussed here. So far, the conventional biomarkers for immunotherapy, namely programmed death-ligand 1 expression or tumor mutational burden are poor predictors of the efficacy of immunochemotherapy, and the optimal sequence of chemotherapy and immunotherapy has yet to be defined.

Optimal sequencing of chemotherapy with chemoradiotherapy based on TNM stage classification and EBV DNA in locoregionally advanced nasopharyngeal carcinoma

Optimal sequencing of chemotherapy with chemoradiotherapy based on TNM stage classification and EBV DNA in locoregionally advanced nasopharyngeal carcinoma

Abstract P1-16-08: Response to subsequent therapy after dual immune checkpoint blockade in metastatic breast cancer

Abstract Introduction: While initial studies have found that combining chemotherapy with immune checkpoint blockade (ICB) can augment responses, additional toxicity has been observed. The optimal sequencing of chemotherapy and ICB has not yet been described. Sequential responses to chemotherapy after ICB have been reported in various tumor types; however, data is limited, and this has not been described in breast cancer to date. Methods: We identified patients (pts) from a small pilot study in HER2-negative metastatic breast cancer (MBC) who received at least 1 cycle of durvalumab (PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor). We excluded pts without follow up data or if they did not receive subsequent systemic therapy. Comparison of differences between subgroups was calculated by Fisher's exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. Time to treatment failure (TTF) of subsequent therapy and overall survival (OS) were assessed by the Kaplan-Meier method and differences between breast cancer subtype were compared by log-rank tests. Results: Twenty-three pts received at least 1 cycle of ICB of whom 14 pts were eligible for this analysis. Nine had estrogen receptor positive (ER+) BC and 5 had triple negative (TN) BC. There were no statistically significant differences between the ER+ and TN subgroups in age, race, ethnicity, ECOG performance status (PS) at end of ICB, or sites of metastatic disease except for more lymph node metastases in the TN cohort (p=0.003). Overall response rates to ICB in this cohort was higher in TN vs ER+ (40% vs 0%, p=0.11). Pts received a median of 4 lines of systemic therapy for MBC prior to ICB. Subsequent therapy after ICB was eribulin in 29%, carboplatin/gemcitabine in 21%, palbociclib + endocrine therapy (ET) in 14%, anthracycline in 14%, ixabepilone +/- capecitabine in 14%, and paclitaxel in 7%. Clinical response was seen in 8 pts (57%), of whom 5 had ER+ BC and 3 had TNBC. The median TTF of subsequent therapy was 3.0 mo (1.9, 5.5), which compared to a median TTF for therapy prior to ICB of 2.5 mo. The median OS was 12.3 mo (2.3-13.3). There were no significant differences between the ER+ and TN cohorts (log-rank test p=0.74 and 0.90 for TTF and OS, respectively. Subsequent therapy was discontinued due to progressive disease in 44%, decline in PS in 19%, liver failure in 6%, treatment related adverse event in 6%, and unknown cause in 13%. Two pts remain on subsequent therapy with palbociclib + ET beyond 6 mo without disease progression. There were no statistically significant differences between TTF &amp;gt;3 mo (n=5) and TTF &amp;lt;3 mo (n=9) subgroups. Pts with TTF &amp;gt;3 mo were numerically more likely to have a PS 0-1 (100 vs 78%), liver metastases (80 vs 56%), and ER+ BC (80 vs 56%). Pts with TTF &amp;lt;3 mo had more lymphopenia (66% vs 20%) and more lines of prior systemic therapy for MBC (median 6 vs 4). Conclusions: While median duration of response on subsequent therapy was short, a subset of pts had significant clinical responses. These findings provide rationale for prospective validation as they provide strategies for sequencing ICB with standard therapies. Citation Format: Shah AN, Yalamanchili A, Helenowski I, Bhole S, Woodman J, Gradishar WJ, Cristofanilli M, Santa-Maria CA. Response to subsequent therapy after dual immune checkpoint blockade in metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-16-08.

Abstract CT090: Neoadjuvant chemotherapy of FOLFIRI with or without radiotherapy in the treatment of marginally resectable recurrent rectal cancer exposed to oxaliplatin: A cohort study

Abstract Background FOLFIRI is the standard second-line chemotherapy for recurrent rectal cancer previously exposed to oxaliplatin. For resectable recurrent rectal cancer, the optimal sequence of chemotherapy and resection is still unknown. We carried out a cohort study to evaluate the efficacy and feasibility of neoadjuvant chemotherapy of FOLFIRI in this setting. Patients and Methods Patients aged from 18 to 80 year-old with histologically confirmed and resectable recurrent rectal adenocarcinoma previously exposed to oxaliplatin were recruited. Resectability was decided by three colorectal surgeons. Eligible patients received six preoperative and six more postoperative FOFIRI regimens (irinotecan 180mg/m2 , folinic acid 400mg/m2 and fluorouracil 2800mg/m2, repeated every 14 days). Tumor response was assessed after 3 and 6 cycles. The primary end point was R0 resection rate and the second end points were grade 3 or 4 toxicity and tumor regression grade (Ryan). All the patients signed written informed consent. Result 65 eligible patients were enrolled in this trial. According to RECIST criteria, 22 ( 33.8%) cases had partial remission, 18 ( 27.7%) cases had stable disease, 24 ( 36.9%) cases had progression disease and 1 patient refused to evaluate and quit study. 21 ( 32.8%) patients achieved R0 resection with 5 cases of TRG 1, 11 cases of TRG 2 and 5 cases of TRG 3. 25 patients received concurrent radiotherapy. Grade 3 or 4 toxicity was seen in 4 (6%) patients. One patient had intestinal perforation and one had bowel obstruction during chemotherapy. No one died during treatment. Conclusion Neoadjuvant chemotherapy of FOLFIRI in resectable recurrent rectal cancer can be well tolerated. But more active regimen is still needed for this setting to accomplish better outcome. Funding: This study was supported by 5010 Project of Clinical Research of Sun Yat-sen University (2010012) Citation Format: Jian Xiao, Zerong Cai, Yingxin Tan, Yufeng Chen, Yanhong Deng, Yifeng Zou, Xiaojian Wu, Ping Lan. Neoadjuvant chemotherapy of FOLFIRI with or without radiotherapy in the treatment of marginally resectable recurrent rectal cancer exposed to oxaliplatin: A cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT090.

The docetaxel-abiraterone acetate sequence compared to the abiraterone acetate-docetaxel sequence in metastatic castration-resistant prostate cancer patients with a response to previous castration superior to 12 months.

353 Background: With the approval of the multiple new life-prolonging treatments for men with metastatic castration-resistant prostate cancer (mCRPC), the optimal sequencing of chemotherapy and androgen-receptor (AR) targeting agents remains unclear. Although response duration to castration could influence decision choice for second hormonal therapies, we do not know whether chemotherapy efficacy could be similar to AR targeting agents such as abiraterone acetate (AA). Methods: A retrospective analysis of mCRPC patients treated at Jolimont Hospital is reported. Patients included were castration-resistant PC with a response to castration superior to 12 months. They were treated with sequential docetaxel and AA, in either order. The combined progression-free survival (combined PFS: PFS1 + PFS2) of AA followed by docetaxel is compared to the reverse sequence (docetaxel followed by AA). Baseline characteristics are reported prior to the start of the first agent in the sequence. Results: Forty-two patients who started treatment for mCRPC between January 2013 and February 2017 were identified: 22 were in the docetaxel-AA sequence (Group A) and 20 were in the AA-docetaxel sequence (Group B). The median duration of response to castration was 16 months in Group A and 18 months in Group B. Proportion of Gleason &gt; 8 was higher in group A (60% vs 50%). Visceral or lymph node disease was more important in group A (35% vs 16%). Median pre-treatment PSA was similar in the two groups (27 and 30). In the group A, PFS1 was 9 months and PFS2 was 8 months, resulting in a combined PFS of 17 months (range 5 to 47months). In the group B, PFS1 was 8 months and PFS2 was 7 months, resulting in a combined PFS of 15 months (range 4 to 45 months). Conclusions: We do not observe differences in clinical outcomes based on alternative sequencing of AA and docetaxel in men with mCRPC with a previous response duration to castration longer than 12 months.

The Addition of Chemotherapy to Radiation Therapy Improves Survival in Elderly Patients with Stage III Non-Small Cell Lung Cancer.

Elderly patients account for the majority of lung cancer diagnoses but are poorly represented in clinical trials. We evaluated the overall survival (OS) of elderly patients with stage III NSCLC treated with definitive radiation compared with that of patients treated with definitive chemoradiation. We conducted a comparative effectiveness study of radiation therapy versus chemoradiation in elderly (≥70 years old) patients with stage III NSCLC not treated surgically diagnosed from 2003 to 2014; the patients were identified by using the National Cancer Database. Two cohorts were evaluated: patients (n= 5023) treated with definitive radiation (≥59.4 Gy) and patients (n= 18,206) treated with definitive chemoradiation. Chemoradiation was further defined as concurrent (radiation and chemotherapy started within 30 days of each other) or sequential (radiation started >30 days after chemotherapy). We compared OS between the treatment groups by using the Kaplan-Meier method and Cox proportional hazards regression before and after propensity score matching (PSM). Treatment with chemoradiation was associated with improved OS versus that with radiation both before PSM (hazard ratio [HR]= 0.66, 95% confidence interval [CI]: 0.64-0.68, p < 0.001) and after PSM (HR= 0.67, 95% CI: 0.64-0.70, p < 0.001). Relative to concurrent chemoradiation, sequential chemoradiation was associated with a 9% reduction in the risk for death (HR= 0.91, 95% CI: 0.85-0.96, p= 0.002). We found that definitive chemoradiation resulted in a survival advantage compared with definitive radiation in elderly patients. Sequential chemotherapy and radiation was superior to concurrent chemoradiation. Although prospective trials are needed, this analysis suggests that chemoradiation should be strongly considered for elderly patients and the optimal sequencing of chemotherapy and radiation remains an unanswered question for this patient population.

Responses to chemotherapy in patients with metastatic urothelial cancer (MUC) after frontline immunotherapy.

e16004 Background: The effect of prior immune checkpoint inhibition therapy (CI) on the efficacy of subsequent chemotherapy is largely unknown in MUC. The identification of the optimal sequence of chemotherapy and IO is yet to be determined, but may influence outcomes. Methods: A retrospective audit and comparison of patients who progressed after first and second line CI and received subsequent standard chemotherapy was performed. Date was collected across a broad spectrum of CI. We report on patient’s characteristics and response rates of 28 sequential patients collected from two institutions who received chemotherapy after CI. Patients were separated into 2 cohorts. Cohort A had not previously received chemotherapy (n = 14), cohort B had previously received at least 1 chemotherapy regimen (n = 14). Central radiology review was performed. We assessed objective response rate by RECIST v 1.1. Kaplan Meier method was used. Results: Median age for the whole cohort was 64 yrs (45-80). ECOG was 0/1 in 89,3% and 2 in 10,7% at the time of starting chemotherapy. The commonest chemotherapy regimen in cohort A and B were carboplatin-gemcitabine (71%) and carboplatin paclitaxel (50%) respectively. 75% of the patients were intermediate risk group. In Cohort A 63% responded to chemotherapy whereas in cohort B only 3 patients showed response. The median change in target lesions in the front line immunotherapy cohort was -60% (-81 to +1%). Both patients who responded to 2nd line chemotherapy after CI had a long interval between first and 2nd line chemotherapy (9-24 months). Conclusions: Chemotherapy maintains its efficacy after front line CI with deep responses. Although numbers are modest, results strongly suggest patients should be offered chemotherapy in this setting.

High responses to chemotherapy in patients with metastatic urothelial cancer (MUC) after frontline immunotherapy.

377 Background: The effect of prior immune checkpoint inhibition therapy (CI) on the efficacy of subsequent chemotherapy is largely unknown in MUB. The identification of the optimal sequence of chemotherapy and IO is yet to be determined, but may influence outcomes. Methods: A retrospective audit and comparison of patients who progressed after first and second line CI and received subsequent standard chemotherapy was performed. Date was collected across a broad spectrum of CI. We report on patient’s characteristics and response rates of 20 sequential patients collected from one institution who received chemotherapy after CI. Patients were separated into 2 groups. Group A had not previously received chemotherapy (n=10), group B had previously received at least 1 chemotherapy regimen (n=10). Central radiology review was performed. We assessed objective response rate by RECIST v 1.1. Kaplan Meier method was used. Results: Median age for the whole cohort was 64 yrs (45-80). The commonest chemotherapy regimen in group A and B were cisplatin-gemcitabine (80%) and carboplatin paclitaxel (70%) respectively. Results are summarised in the table. The median change in target lesions in the front line immunotherapy cohort was -49% (-81 to +8%). Only two patients (20%) in group B responded to chemotherapy and both presented a long interval between first and 2ndline chemotherapy (9-12 months); compared to 56% responding in group A. Conclusions: Chemotherapy maintains its efficacy after front line CI with deep responses. Although numbers are modest, results strongly suggest patients should be offered chemotherapy in this setting. [Table: see text]

NICE Chemotherapy Guidelines in Advanced Breast Cancer (ABC) in Practice: Experience of Mount Vernon Cancer Centre

Purpose: There is uncertainty with regards to the optimal chemotherapy schedules and sequencing in ABC. In the absence of randomised data on the optimal sequencing of chemotherapy in this setting, NICE has issued guidance recommending a specific sequence: anthracycline, taxotere, capecitabine, vinorelbine, seemingly based on the chronology of licensing approval of these drugs in ABC. In this retrospective audit we reviewed the sequence of chemotherapy schedules given in ABC at the Mount Vernon Cancer Centre.

Defining the Optimal Sequencing of Chemotherapy (Cx) and Radiation (RT) in Patients With Locally Advanced Pancreatic Cancer

Defining the Optimal Sequencing of Chemotherapy (Cx) and Radiation (RT) in Patients With Locally Advanced Pancreatic Cancer

Update Erstlinien- und Rezidivchemotherapie beim Hodentumor

Germ-cell cancer (GCC) is still the most common cancer diagnosis in men between the ages of 20 and 45 years with an increasing incidence. Due to effective and standardized algorithms that have been developed to stratify patients into different risk groups, remarkable progress has been made in the medical treatment of testicular cancer with an overall cure rate of 88%. The application of surgery, radiotherapy and chemotherapy, the choice of chemotherapy agents as well as treatment duration is defined in international consensus guidelines. The guidelines are based on histology, tumor stages and presence or absence of already known and well-established risk factors. These stringent parameters guarantee the optimal curative treatment options for each GCC patient and can avoid overtreatment as well as undertreatment. For patients with early stage disease, careful consideration between possible side effects due to an adjuvant therapy and the expected relapse rate must be made, whereas in advanced tumor stages the optimal sequence of chemotherapy, surgery and radiotherapy is the focus. In patients who progress or relapse after first-line therapy, the issue of optimal treatment represents a particular challenge and is far more complex. It needs to take into account the analysis of special prognostic variables for a further risk-tailored therapy. A careful weighting between the chosen regimen and the often higher rate of treatment failure in contrast to increased toxic side-effects is mandatory.The disregard of accurate risk stratification and application of accepted treatment standards for patients with GCC at the time of initial diagnosis or at relapse is associated with developing more extensive disease and more intensive treatment. It also results in lower cure rates with the need for further therapy or leads to death of the patient without ever having had a chance for cure.

Adjuvant and Neoadjuvant Therapy for Gastric Cancer

To improve outcome of resectable gastric cancer, several treatment strategies have been evaluated. These include adjuvant chemotherapy, adjuvant chemoradiotherapy, and perioperative chemotherapy. The US Intergroup 0116 trial reported the benefit of postoperative chemoradiotherapy using 5-FU/leucovorin in a U.S. population. In this study, only 10 % of patients received D2 resection. For Korean patients after D2 resection, the ARTIST trial failed to show any benefit from adding radiotherapy to adjuvant chemotherapy in terms of 3-year disease-free survival. The MAGIC trial compared perioperative chemotherapy with surgery alone and reported a prolonged 5-year overall survival in the perioperative chemotherapy arm. In resectable gastric cancer, the benefit of adjuvant chemotherapy compared with surgery alone has been clearly demonstrated. After D2 dissection, S-1 adjuvant chemotherapy improved the overall survival (ACTS-GC trial) and capecitabine/oxaliplatin combination chemotherapy improved 3-year disease-free survival (CLASSIC trial). To date, for resectable gastric cancer, the use of chemotherapy in addition to surgery is beneficial for the reduction of recurrence and to improve overall survival. The optimal sequence of chemotherapy and surgery, as well as optimal chemotherapeutic agents, should be further studied. In D2-resected gastric cancer, the addition of radiotherapy to chemotherapy does not appear to provide any additional benefit.].

Abstract S4-4: SECRAB: The Optimal SEquencing of Adjuvant Chemotherapy (CT) and RAdiotherapy (RT) in Early Breast Cancer (EBC), Results of a UK Multicentre Prospective Randomised Trial

Abstract Background: The optimal sequence of CT and RT for women with EBC has yet to be defined. SECRAB aimed to determine i) if synchronous (Syn) CT-RT improves loco-regional relapse rates (LRR) and ii) whether the treatments could be given together without increased toxicity or compromising the dose intensity of either CT or RT. The first endpoint of this study is presented in this abstract. Methods: SECRAB was a prospective, randomised trial comparing sequential (Seq) to Syn CT-RT. Permitted RT schedules included 40Gy/15F over 3 weeks, 45Gy/20F over 4 weeks and 50Gy/25F over 5 weeks. Syn RT was administered between cycles 2 and 3 for CMF or 5 and 6 for anthracycline-CMF. Syn patients treated using 15F were treated predominantly using a sandwich schedule while those receiving &amp;gt;15F were treated concurrently with CT. Seq RT was delivered on CT completion. Key eligibility criteria were completely excised EBC, fit for and requiring adjuvant CT and RT. The trial was powered to produce a definitive event driven analysis: 150 loco-regional relapses having 85% power to detect 4% 2-sided differences in the primary endpoint of overall LRR. Results: Between Jul 98 and Mar 04, 2296 women were randomised. Baseline characteristics were well balanced. 63% of patients were node positive indicating a high risk population. 2 patients did not receive CT and 23 did not receive RT. 5 patients in the latter group had a loco-regional relapse prior to planned RT (Seq n=3). With a median follow-up of 8.8 years there were 93 and 76 loco-regional relapses in the Seq and Syn arms and 5-year LRR were 7.4% (95% CI 5.9-9.1) and 5.4% (95% CI 4.2-7.0) respectively. There was no significant difference in overall LRR (HRSyn 0.82; 95% CI 0.6-1.1; p=0.19). There was a trend for benefit for Syn treatment which was consistent across different subgroups (grade, lymph node status, tumour size, vascular invasion and excision margin). In an unplanned subgroup analysis, a trend for benefit for Syn treatment was seen predominantly in patients with the presence of lymphovascular invasion (LRR 11.9% Seq vs 8.2% Syn) and also in patients with 0 and 1-3 positive nodes (LRR 7.8% Seq vs 5.2% Syn) but not in those with 4 or more positive nodes. Similar rates were observed for distant recurrences (22.2% vs 22.2%), contralateral recurrences (2.9% vs 2.7%), and new primary cancers (2.9% vs 2.6%) in the Seq and Syn arms respectively. There was also no significant difference in overall survival which was 83% and 82% in the Syn and Seq arms respectively at 5-years (HRSyn 0.99; 95% CI 0.8-1.2; p=0.87). Modest differences in acute skin toxicity and telangiectasia were observed between the two study arms. There was no difference in other late toxicities. The second primary endpoint of safety, toxicity and dose intensity is described in detail elsewhere (abstract no 850168). Conclusions: SECRAB is the largest sequencing trial in EBC to date. Delivering Syn CT-RT using CMF or anthracycline-CMF and a 3 weekly RT fractionation shortens the overall treatment time. Although not statistically significant there was a trend to improved locoregional control with Syn treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-4.

Abstract P4-11-05: Acute and Late Toxicity Results from the SECRAB Trial: The Optimal SEquencing of Adjuvant Chemotherapy (CT) and RAdiotherapy (RT) in Early Breast Cancer (EBC)

Abstract Background: SECRAB is a large multicentre randomised controlled trial designed to determine the optimal sequence of CT and RT for women with EBC. The second objective of this trial was to determine if CT and RT treatment modalities could be given together without increased toxicity or compromising either modality. See abstract no 851519 for details of CT and RT scheduling. Methods: Data on acute skin reaction was collected on completion of RT and graded as mild, moderate or severe. Late toxicity data was collected annually and included lymphoedema, telangiectasia, severe subcutaneous fibrosis, brachial plexopathy, rib fracture, ischaemic heart disease, symptomatic lung fibrosis, and clinical radiation pneumonitis. Results: Between Jul 98 and Mar 04, 2296 women were randomised. Acute toxicity data was collected on 2267 patients who received RT. The distribution of RT schedules was balanced across treatment arms, with the majority of patients (67%) receiving 40Gy/15F (15F). Significantly more patients in the Syn arm experienced a delay of &amp;gt;10 days in CT delivery (11% vs 5%, p &amp;lt; 0.0001). Very few patients experienced a &amp;gt;7 days delay in RT in either arm (Syn n=12 vs Seq n=3). In a sub-set of 880 patients dose intensity of CT was not significantly different between the two arms. Percentage skin toxicities for the Syn and Seq arms respectively were: None 22.9 vs 36.3; Mild 52.4 vs 48.1; Moderate 20.2 vs 13.6; Severe 3.8 vs 1.1. A significantly (p &amp;lt; 0.001) higher proportion of patients on the Syn arm suffered a moderate or severe skin reaction compared to those on the Seq arm. An unplanned exploratory analysis by duration of RT showed that patients receiving &amp;gt;15F (45Gy/20F or 50Gy/25F) had a significantly worse acute skin reaction than those receiving 15F (25% vs 16%, p=&amp;lt;0.001). 5 patients on the Syn arm were admitted to hospital as a result of a severe RT reaction, 3 received &amp;gt;15F. Acute radiation pneumonitis was 0.3% in both arms (n=5 in total). Percentage late toxicities for the Syn and Seq arms respectively were not significantly different for: moderate/severe lymphoedema 6.1 (n=70) vs 5.5 (n=64); severe subcutaneous fibrosis 1.3 (n= 15) vs 0.6 (n=7); brachial plexopathy 0.2 (n=2) vs 0.1 (n=1); rib fracture 0.6 (n=7) vs 0.4 (n=5); ischaemic heart disease 0.4 (n=5) vs 0.4 (n=2); symptomatic lung fibrosis 0.3 (n=15) vs 0.3 (n=7); and late clinical radiation pneumonitis 0.1 (n=1) vs 0.1 (n=1). Howevermoderate/severe telangiectasia was 2.5% vs 1.3% in the Syn and Seq arms respectively (p =0.05). This difference was not seen in patients receiving 15F. Conclusions: The delivery of Syn CT-RT in the adjuvant treatment of EBC is associated with an increase in acute skin toxicity however the percentage of severe reactions is less than 5%. These skin reactions were seen predominantly in patients treated with concurrent RT (&amp;gt;15F). An increase in late skin telangiectasia was also seen in patients receiving &amp;gt;15F. There was no difference in other late toxicities recorded. Syn CT-RT is feasible in the adjuvant treatment of EBC and does not result in a reduction in dose intensity of delivered CT. The optimal schedule is 40Gy/15F which is now the standard regime used in the UK. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-05.

Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: A final report

4050 Background: We conducted a prospective randomized trial to define the optimal sequence of chemotherapy and radiotherapy of postoperative adjuvant treatment in stage II and III rectal cancer. Methods: Three hundred eight patients were enrolled onto the study. We randomly assigned 155 to arm I (early radiotherapy group) and 153 to arm II (late radiotherapy group). Treatment included eight cycles of chemotherapy at 4-week intervals and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on day 1 of the first chemotherapy cycle in arm I and on day 1 of the third chemotherapy cycle in arm II. The chemotherapy regimen consisted of fluorouracil 375 mg/m2/d and leucovorin 20 mg/m2/d. Chemotherapy was administered for 3 days per cycle in two cycles during the period of radiotherapy and for 5 days per cycle in the remaining six cycles. (J Clin Oncol 2002 20:1751- 8) Results: Twenty patients in arm I and 14 in arm II were not eligible. We included 274 patients in the analysis. With a median follow-up of 94 months for surviving patients, there was a trend for improved disease-free survival(DFS) in arm I compared with arm II, although it was not reached statistical significance (72% v. 63% at 7 years; P =.157). Especially, in patients who received abdominoperineal resection (APR), DFS was prolonged in arm I compared with arm II (66% v. 41% at 7 years; P=.033) Thirty six recurrences (26.7%) occurred in arm I and 49 (35.3%) in arm II (P =.151). Overall survival was not significantly different between arms I and II (71% v. 68% at 7 years; P =.855). Conclusions: With a long-term follow-up, this study failed to show a significant survival advantage for early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer. In patients with APR, significant improvement in DFS for arm I was observed. No significant financial relationships to disclose.