Duration Of Adjuvant Treatment Research Articles

Investigating the patterns of treatment failure in patients with advanced stage III and IV melanoma receiving adjuvant therapy.

e21532 Background: The landscape of treatment of patients with resectable stage III melanoma has evolved considerably given studies demonstrating survival benefit of anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy in the adjuvant setting, as well as surgical changes relating to the Multicenter Selective Lymphadenectomy Trial (MSLT)-II trial. Currently, the decision to treat with anti-PD-1 or BRAF/MEKi therapy in the adjuvant setting is dependent upon patient, provider, and institutional preferences, but no comparative analysis has been done between adjuvant therapy options. Methods: Clinical data from 141 surgically-resected staged III and oligometastatic stage IV patients receiving adjuvant anti-PD-1 (n = 66), BRAF/MEKi (n = 36), or surgery only (n = 39) between 2017 and 2021 was analyzed retrospectively. Primary endpoints were overall survival (OS) and progression free survival (PFS) between the three treatment groups. Secondary endpoints include the duration of adjuvant treatment and reasons for termination of therapy. Results: During a mean follow-up period of 17 months, 33.3% of anti-PD-1 patients and 16.7% of BRAF/MEKi patients experienced recurrence, while 41.0% of the surgery only patients experienced recurrence. In univariate Cox regression analyses of the survival data, patients who received anti-PD-1 (HR = 0.46, 95% CI: 0.25-0.87, p = 0.016) or BRAF/MEKi (HR = 0.44, 95% CI:0.21-0.90, p = 0.024) had significantly improved PFS compared to patients treated with surgery only, but the OS was not significantly different with treatment. A multivariate Cox regression model was performed, adjusting for age, sex, and melanoma disease stage. In this model, anti-PD-1 was still associated with improved PFS (HR = 0.33, p < 0.001), while BRAF/MEKi also trended towards improved PFS, but was not statistically significant (HR = 0.54, p = 0.13). Other associations include males having a significantly worse PFS (HR = 2.32, p = 0.009) and OS (HR = 5.86, p = 0.02), and patients with stage IIIC or worse disease having worse PFS (HR = 4.56, p < 0.001), but not significantly worse OS (HR = 4.84, p = 0.05). The average duration of adjuvant therapy was similar between both groups (250-260 days) with approximately half of the patients completing the treatment course. A larger proportion of BRAF/MEKi patients stopped treatment due to intolerable side effects compared to anti-PD-1 patients (83.3% vs. 64.0%). Conclusions: Adjuvant treatment decreases the chance of recurrence compared to surgery alone, but the benefit on overall survival is still inconclusive. Male and more advanced stage III melanoma prior to initiating adjuvant therapy are factors associated with an increased likelihood of recurrence. Although it appears that more patients terminated BRAF/MEKi therapy early due to side effects compared to anti-PD-1, additional follow-up will be needed to confirm this finding.

Alternative trastuzumab dosing schedules and association with health care greenhouse gas emissions.

e13644 Background: Climate change due to greenhouse gas (GHG) emissions by humans imperils health. Health care is a major source of GHG emissions and thus reducing health care’s environmental impact should be a global priority. GHG emissions associated with the production and administration of cancer drugs, as well the downstream societal costs in human health terms, are undescribed. The extent to which a given cancer drug’s dosing frequency and duration impact GHG emissions is unknown. Methods: Using trastuzumab for HER2-positive breast cancer as a use case, we conducted a case-control simulation study of single, U.S. academic medical center data to estimate the expected reductions in GHG emissions with three alternative dosing strategies (6-month adjuvant treatment duration, extended-interval dosing, and both) using streamlined life-cycle analysis. We estimated the per-patient relative reduction in GHG emissions expected to occur with each of the alternative dosing strategies and, in exploratory analysis, the societal health costs ( e.g., disability-adjusted life-years [DALYs] and excess mortality per kg CO2) associated with therapy-related GHG emissions, using conventional versus alternative dosing strategies. Results: Adoption of 6-month adjuvant trastuzumab reduced expected per-patient GHG emissions in the adjuvant setting by 10%. Adoption of both 6-month adjuvant trastuzumab and pharmacokinetically-supported every 4-week trastuzumab dosing reduced GHG emissions by 4.5%, 18.7%, and 14.6% in the neoadjuvant, adjuvant, and metastatic settings, respectively. An estimated 8.1 DALYs and 4.6 excess lives are lost annually worldwide as a result of U.S.-based administration of conventionally dosed trastuzumab. Adoption of alternative dosing in the U.S. is estimated to enable avoidance of approximately 1.5 DALYs and 0.9 excess lives lost annually. Conclusions: Alternative dosing strategies, suggested to be noninferior by pharmacokinetic and clinical evidence, are estimated to reduce the societal health costs imposed on bystanders that arise from cancer care’s environmental impact. Environmental impact and its resultant societal health costs should be considered in clinical trial design, re-interpretation of previously conducted trials, regulatory decision-making, and health technology assessments of both new and existing cancer therapies.

Gastro-intestinal stromal tumor (GIST): Experience from a tertiary care center in a low resource country.

The aim of this retrospective study was to review the overall survival (OS) and disease-free survival (DFS) of GISTs treated surgically at our center over the past decade. We undertook a 12-year retrospective review of our experience in treating this condition with a focus on long-term outcomes of treated patients in a resource-constrained environment. Incomplete follow-up information continues to be a major problem with studies conducted in low resource settings, and in order to overcome this, we undertook telephonic contact with patients or their relatives to get the necessary information about their clinical status. Fifty-seven patients with GIST underwent surgical resection during this period of time. The stomach was the most common organ involved in the disease, with 74% of the patients. Surgical resection was the main treatment approach, with R0 resection possible in 88%. Nine percent of the patients were given Imatinib as neoadjuvant treatment and 61% were offered the same, as adjuvant therapy. The duration of adjuvant treatment changed from one year to three years over the study period. Pathological risk assessment categorized the patients as Stage I, 33%; Stage II, 19%; Stage III, 39%; and Stage IV, 9%. Of the 40 patients who were at least three years from surgery, 35 were traceable giving an 87.5%, overall three-year survival. Thirty-one patients (77.5%) were confirmed to be disease-free at three years. This is the first report of mid-long-term outcomes of the multimodality treatment of GIST from Pakistan. Upfront surgery continues to be the main modality. OS & DFS in resource-poor environments can be similar to those seen in a better-structured healthcare setting.

The impact of frailty on adjuvant treatment in patients with head and neck free flap reconstruction—A retrospective study using two independent frailty scores

ObjectivesReconstructive surgery may result in prolonged postoperative recovery, especially in frail patients, which in turn may impact delivery of adjuvant therapy. To date, no studies have investigated potential associations between frailty and adjuvant treatment delivery after reconstructive surgery. We examine the impact of frailty on time to initiation, duration, and completion of adjuvant treatment after reconstructive surgery for head and neck cancers (HNCs). MethodsA retrospective review of patients who underwent free flap reconstruction for HNC at a single institution from 2015 to 2021 and received adjuvant radiation was performed. Frailty was assessed using two independent scales: the 11-item modified frailty index (mFI) score and binary Johns Hopkins Adjusted Clinical Groups (ACG) frailty indicator. Timely adjuvant initiation (within six weeks of surgery), duration of adjuvant treatment, and completion were compared between frail and non-frail patients. ResultsOf the 163 patients included for analysis, 52 (31.9%) were identified as frail by the ACG indicator and 24 (14.7%) were identified as frail with an mFI score ≥ 3. Frail patients (mFI score ≥ 3) were significantly less likely than non-frail patients to initiate adjuvant treatment within six weeks (OR:0.21, CI:0.04–0.85, p = 0.046). Frailty designated by either frailty scale was not significantly associated with adjuvant treatment duration. Likelihood of adjuvant treatment completion was significantly lower for frail compared to non-frail patients by both scales: ACG indicator (OR 0.02, CI:9.05 × 10−4–0.25, p = 0.007) and mFI score ≥ 3 (OR:0.01, CI:6.85 × 10−4–0.13, p = 0.007). ConclusionsFrailty is associated with decreased likelihood of timely adjuvant treatment initiation and completion in patients with HNCs after free flap reconstruction.

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial.

Simple SummaryOptimal dosing and duration of adjuvant treatment with PD-1 immune checkpoint inhibitors in melanoma patients have not been established. The investigated low-dose regimen of nivolumab with or without ipilimumab (in a sequential dual-cohort phase II trial), resulted in a 12-months relapse-free survival (RFS) rate and tolerability that was comparable to what has been served with standard dosing of nivolumab or pembrolizumab when patients were matched for stage. The incidence of immune-related adverse events was similar to what has been reported from registration trials in this indication. Immunohistochemical quantification of intra- and peritumoral immune cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. Therefore, low-dose regimes of PD-1 blocking monoclonal antibodies deserve further study as cost-effective alternatives for currently approved standard dosing regimens, with baseline immunohistochemical tumor profiling to be further explored as a promising biomarker.Background: Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. Methods: Following the complete resection of melanoma metastases, patients were treated with a single fixed dose of ipilimumab (50 mg) plus 4 bi-weekly fixed doses of nivolumab (10 mg) (cohort-1), or nivolumab for 1 year (10 mg fixed dose, Q2w x9, followed by Q8w x4) (cohort-2). Twelve-months relapse-free survival (RFS) served as the primary endpoint. Results: After a median follow-up of 235 weeks for cohort-1 (34 patients), and 190 weeks for cohort-2 (21 patients), the 12-months RFS-rate was, respectively, 55.9% (95% CI, 39–72), and 85.7% (95% CI, 70–100). Treatment-related adverse events occurred in 27 (79%), and 18 (86%) patients, with 3 (9%), and 1 (5%) grade 3 adverse events in cohort-1 and -2, respectively. Immunohistochemical quantification of intra- and peritumoral CD3+ T cells and CD20+ B cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. Conclusions: One year of adjuvant low-dose nivolumab could be an effective and economically advantageous alternative for standard dosing, at the condition of further confirmation in a larger patient cohort. A shorter low-dose nivolumab plus ipilimumab regimen seems inferior and less tolerable.

Duration of adjuvant treatment for patients with stage III colon cancer.

In The Lancet Oncology, Thierry André and colleagues1 present data on 5-year disease-free survival and overall survival from the International Duration Evaluation of Adjuvant therapy (IDEA) collaboration on 3 months versus 6 months duration of adjuvant chemotherapy in patients with stage III colon cancer. The authors should be complimented on their efforts, and the results confirm the expectations from the earlier published data on 3-year disease-free survival.2 However, the new data are important because overall survival is generally considered to be the most clinically relevant endpoint for adjuvant trials and therefore these results support the value of 3 months of adjuvant chemotherapy.

Tratamento Efetivo de Gliossarcoma com mais de 5 Anos Livre de Doença. Relato de caso e revisão de literatura

Introdução: O gliossarcoma é raro em adultos (2-3%), incomum em crianças e presente geralmente em homens idosos. A sua histologia bifásica, sarcomatosa e gliomatosa, torna seu manejo complexo e prognóstico sombrio. Relato do Caso: Paciente masculino de 2 anos que iniciou náuseas e vômitos por 6 dias sem melhora, com suspeita de hipertensão intracraniana. À TC, constatou lesão em lobo frontal direito; e à RM, lesão sugestiva para tumor teratoide rabdoide. Após 1 mês, houve ressecção total e constatado gliossarcoma. Quatro meses depois, ocorreu recidiva tumoral tratada com ressecção parcial e radioterapia adjuvante, com vincristina semanal e ciclos de carboplatina e etoposídeo. A duração do tratamento adjuvante foi de 3 meses. Após 6 anos livres de doença, as sequelas atuais são epilepsia residual e sequela cognitiva leve. Discussão: As opções terapêuticas acabam imitando o tratamento disponível para glioblastoma com a terapia trimodal: tentativa de ressecção completa, radioterapia e quimioterapia. Estudos mostram que retirar uma dessas opções reduz a sobrevida dos pacientes. Conclusão: A falta de consenso na literatura é reflexo da falta de dados a respeito dessa raridade. Evidencia-se o valor científico do relato deste caso, com sobrevida excepcional quando comparado aos demais casos descritos em literatura.

LBA30_PR - Analysis of circulating tumour DNA (ctDNA) from patients enrolled in the IDEA-FRANCE phase III trial: Prognostic and predictive value for adjuvant treatment duration

BackgroundctDNA has been recently suggested as a major prognostic factor in resected stage II and III colon cancer patients (pts)1,2. Its predictive value for adjuvant treatment intensity or duration is currently unknown. We have analyzed here ctDNA from pts enrolled in the IDEA-FRANCE trial3, its prognostic value and its predictive value for treatment duration (3 or 6 months). MethodsctDNA was tested by using the detection of 2 methylated markers (WIF1 and NPY) by digital droplet PCR accordingly to a method developed and validated for colorectal cancer 4-6. Comparisons for pts and tumour characteristics and DFS will be done between the ctDNA tested pts and the full study population and between ctDNA positive and negative pts. DFS has been analyzed in the 6 and 3M treatment arms according to ctDNA results. Subgroup analyses for high- and low-risk pts were pre-planned. ResultsOf the 1345/2010 pts that consented to the IDEA translational research program, with available blood sample for ctDNA testing, 805 have been sampled before chemotherapy start and fully analyzed. More PS 0 (77% vs 71%) and more T4 and/or N2 (28% vs 23%) were observed in the 805 pts studied here than in the 1205 pts left. 696 pts were found ctDNA- and 109 ctDNA+(13.5%). ctDNA+ pts were more often T4, poorly differentiated and with tumour perforation. 2-year DFS was 64% vs 82% in ctDNA+ and – pts, respectively (HR :1.75 (95%CI 1.25-2.45) p=0.001). In multivariate analysis including Age, Gender, MSI, perforation, T stage, N stage and treatment arm, ctDNA was confirmed as an independent prognostic marker (adj.HR: 1.85 (95%CI 1.31 to 2.61) p<0.001). Adjuvant treatment for 6 months was superior to 3 months in both ctDNA– (HR :0.69 (95%CI 0.52 to 0.93) p=0.015) and ctDNA+ pts (HR: 0.50 (95%CI 0.27 to 0.95) p=0.033). Interestingly ctDNA+ pts treated 6 months had a similar prognosis to ctDNA- pts treated 3 months. ConclusionsIn this first ctDNA assessment on a large series coming from a phase III clinical trial we found 13.5% of pts with ctDNA post-surgery. ctDNA was confirmed as an independent prognostic marker. In this series, 6 months of treatment seems better in both ctDNA+ and- pts. [1]Tie J, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer.Sci Transl Med. 2016 Jul 6;8(346):346ra92. [2]Schøler LV, et al. Clinical Implications of Monitoring Circulating Tumor DNA in Patients with Colorectal Cancer. Clin Cancer Res. 2017 Sep 15;23(18):5437-5445. [3] André T, et al.Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, phase III Trial.J Clin Oncol. 2018 May 20;36(15):1469-1477. [4] Garrigou S, et al. A Study of Hypermethylated Circulating Tumor DNA as a Universal Colorectal Cancer Biomarker. Clin Chem. 2016;62:1129-1139. [5] Garlan F, et al. Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study). Clin Cancer Res.2017;23:5416-5425. [6] Bachet JB, et al. RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study. Ann Oncol. 2018May 1;29(5):1211-1219. Clinical trial identificationNCT00958737. Legal entity responsible for the studyGercor-Prodige. FundingClinical trial: INCa, GERCOR; Translational project: ARC (Association de Recherche contre le Cancer, Paris, France). DisclosureJ. Taieb: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: pierre fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi. D. Vernerey: Honoraria (self), Advisory / Consultancy: HalioDX; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Janssen. J. Bennouna: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

555P - Impact of the IDEA study on clinical practice for stage III colon cancer patients: A French GERCOR - FFCD - GI UNICANCER national survey

BackgroundThe IDEA study showed that the type and duration of adjuvant chemotherapy in stage III colon cancer (CC) could be adjusted according to level of risk (Grothey et al., New Engl J Med 2018). One year after the publication of IDEA study, we performed an audit of real-life practices in France. MethodsWe conducted an online anonymized nationwide survey from January 30, 2019 to March 31, 2019. An invitation email followed by reminders every 2 weeks was sent to clinicians using the oncology cooperative groups GERCOR, FFCD and GI UNICANCER mailing lists. All of the answers were declarative, individual, and anonymized. Proportions were compared using chi-squared test. ResultsA total of 213 physicians answered the survey: 31% worked in an academic hospital, 27% in a general hospital, 26% in a comprehensive cancer center and 16% in a private clinic. Main responders were gastroenterologists (51%) or medical oncologists (39%). 47% of physicians took care of more than 12 stage III CC patients per year. For low risk stage III CC (T1-T3 and N1), 81% preferred a 3-month duration of treatment, and 74% used capecitabine plus oxaliplatine (CAPOX) as the standard regimen. 66% of CAPOX for 3 months were realized without central venous access device, which was necessary during treatment in less than 25% of cases according to 68% of the responders. Physicians choosing 6-month duration of adjuvant treatment for low risk stage III CC were more often medical oncologists (58% versus 35%, P=0.009) or working in a general hospital (48% versus 22%, P=0.001); no significant difference was observed considering years of professional experience or the number of patients treated per year. For high risk stage III CC (T4 and/or N2), 99.5% of responders considered that adjuvant chemotherapy should be prescribed for 6 months, and 94% with FOLFOX. ConclusionsOne year after the publication of the IDEA study, 3 months of adjuvant chemotherapy with CAPOX has been mainly integrated as a new standard of care for low risk stage III CC patients in daily practice whereas 6 months of FOLFOX remains the standard of care of high risk stage III CC. Legal entity responsible for the studyGERCOR. FundingHas not received any funding. DisclosureB. Rousseau: Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (institution), Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: Gilead; Research grant / Funding (institution), Travel / Accommodation / Expenses: AbbVie. All other authors have declared no conflicts of interest.

Is Increased Time From Diagnosis to Treatment in Advanced Hypopharynx Cancer Associated With Poorer Outcomes: A Single-Centre Analysis

To assess the potential influence of increased time from diagnosis to treatment on survival outcomes in patients with locoregionally advanced hypopharyngeal squamous cell carcinoma (HSCC). Retrospective study of patients with a primary diagnosis of HSCC proposed for primary surgical treatment. The study population included a total of 121 Caucasian patients (121 males) with HSCC. Mean age at diagnosis was 60.4 years (range: 43-83 years). All patients had cT3 or cT4 hypopharyngeal tumors. The sample presented a 5-year overall survival (OS) of 59.6% and a disease-specific survival of 74.9%. Considering univariable analysis (unadjusted), duration of adjuvant treatment (T5), pN, margins, and extracapsular spread (ECS) are factors associated with poorer survival outcomes. An increase in T5 was associated with lower OS. Results revealed that T5 higher than 43 days, pN1, pN2, pN3, no free margins, and presence of ECS were associated with lower OS. These patients have 7.465 higher hazard of death. This study suggests that duration of adjuvant therapy may be more important than other timing metrics from diagnosis to treatment. For locoregionally advanced HSCC, duration of adjuvant therapy after primary surgery higher than 6 weeks is an important feature for worse survival outcome. Preventing strategies in order to avoid radiotherapy or chemoradiotherapy breaks should be developed and optimized.

Body Mass Index and Hormone Receptor Status Influence Recurrence Risk in HER2-Positive Early Breast Cancer Patients

IntroductionA reliable risk stratification on the basis of tumor biology and host factors of HER2-positive (HER2+) early breast cancer (eBC) patients is needed. The aim of our study was to assess the prognostic role of body mass index (BMI) and hormone receptor (HR) expression in this setting. Patients and MethodsWe retrospectively evaluated 238 women with stage I to III HER2+ breast cancer who completed adjuvant chemotherapy (CHT) and 1 year of treatment with trastuzumab. The end point was 3-year distant disease-free survival (3yDDFS). Survival analysis was evaluated using the Kaplan–Meier method. Multivariate analysis was performed using Cox proportional-hazards model adjusting for HR status, BMI, tumor staging, size, nodal status, and type of adjuvant CHT. Association among categorical variables was assessed using χ2 test. ResultsThe early recurrence rate after 3 years resulted as 4.2% (40% HR+ patients and 60% HR− patients). Neither HR status nor BMI alone showed an association with 3yDDFS in multivariate analysis. However, the hazard ratios for patients with HR− tumors who had also BMI ≥25 (3yDDFS 86.9%; 95% confidence interval [CI], 75.0%-97.7%) were amplified compared with patients with HR+ tumors and with BMI <25 (3yDDFS 98%; 95% CI, 94.8%-100.0%) and other subgroups (P = .003). This observation was confirmed in multivariate analysis (hazard ratio, 1.79; 95% CI, 1.04-3.07; P = .03). ConclusionOur real-life data highlight a different risk of eBC recurrence after grouping patients according to HR status and BMI. These results might help clinicians to identify correct treatment strategies. Patients who are HR− and have BMI ≥25 might benefit from escalation approaches, whereas those who are HR+ and have BMI <25 might be eligible for a shorter duration of adjuvant treatment with anti-HER2 agents.

A sequential dual cohort phase II clinical trial on adjuvant low-dose nivolumab with or without low-dose ipilimumab as adjuvant therapy following the resection of melanoma macrometastases (MM).

9585 Background: Optimal dosing and duration of adjuvant treatment with anti-PD-1 checkpoint inhibitors, e.g. nivolumab (NIVO), following complete resection of melanoma (MEL) lymph node metastases has not been established. We investigated a regimen of low-dose NIVO with/without low-dose ipilimumab (IPI) as adjuvant therapy in MEL pts. Methods: After complete resection of MM, pts were treated with IPI 50mg (fixed dose, 1x) plus NIVO 10mg (fixed dose, Q2w x4) (Cohort-A), or NIVO 10mg (Q2w x9, Q8w x4) (Cohort-B). One-year relapse-free survival (RFS) rate served as primary endpoint. Sample size (34 pts) was calculated according to a Fleming one-stage clinical trial design. Recruitment to Cohort-B was closed prematurely following registration of NIVO in the adjuvant setting by EMA. Secondary endpoints were safety, distant metastasis-free survival (DMFS) and overall survival (OS). Quantitative measurement of BRAF/ NRAS mutant circulating tumor DNA (ctDNA), as well as tumor gene expression profiling were performed. Results: 34 pts (15M/19F, 31 stage III/3 stage IV) and 22 pts (12M/10F, 21 stage III/1 stage IV) were enrolled in Cohort-A/-B, respectively. After a median follow-up of 86w for Cohort-A and 36w for Cohort-B, estimated 12 months (m) RFS-rate was respectively 55% (95% CI, 39–72) and 78% (95% CI, 73-82), 12m OS-rate was 97% (95% CI, 94-100) and 100%, and 12m DMFS-rate was 79% (95% CI, 92-65), no distant metastases occurred in Cohort-B. Median RFS for Cohort-A was 84w (95%, CI 28-139), not-reached in -B. Median DMFS and OS had not been reached at time of analysis in either cohort. All grade treatment-related adverse events were observed in 21 (61%)/17 (77%) with 3 (8%)/1 (4%) grade 3 irAE in Cohort-A/-B, respectively. One patient in Cohort-A had a detectable level of ctDNA at baseline and relapsed 33w after initiating treatment. Tumor profiling is ongoing at time of submission. Conclusions: The investigated adjuvant low-dose regimens have an acceptable safety profile. Survival rates resemble those of standard regimens. These regimens could be economically advantageous alternatives for pts without access to standard regimens. Clinical trial information: NCT02941744.

The Optimal Duration of Adjuvant Therapy for Stage III Colon Cancer: the European Perspective

The International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration was created to pool data from different studies worldwide in order to assess whether a shorter duration of adjuvant treatment in colon cancer could maintain the expected benefit while reducing toxicity. The results of the IDEA trials were clinically relevant. They confirmed a two- to sixfold reduction in neurotoxicity for the shorter duration across trials. Overall, the 3-year disease-free survival was very similar: only 0.9% lower for the 3months group. However, the results were partially unexpected, because they revealed a difference among chemotherapy regimens (CAPOX better than FOLFOX) and risk groups within stage III. The similar outcome between 3 and 6months of CAPOX coupled with the substantial reduction in toxicity makes us use the CAPOX regimen for 3months for most stage III patients. An exception to this general rule is the patient with very high risk, i.e., either T4N1b-T4anyN2 or anyTN2b where we use 6months of CAPOX. Our take from the trial results is also that FOLFOX should never be given for 3months and preferably not used at all in the adjuvant setting. The conduction of the IDEA enterprise was truly global. The European contribution was major with three fourths of patients enrolled in the four European trials. Herein, we review the results of the "3 versus 6" trials and the literature regarding the interpretation of the collected data in Europe and in the rest of the world.

Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on perioperative outcomes of breast reconstruction

Hormone (anti-estrogen) therapy (HT) plays a major role in hormone receptor-positive breast cancer management. The latest guidelines propose to extend the duration of adjuvant treatment from 5 to 10 years. The association between HT and thromboembolic or microvascular complications during breast reconstruction has been investigated. However, while estrogens play a crucial role in wound healing, no study has assessed the impact of tamoxifen or aromatase inhibitors on other postoperative complications, including wound healing complications. This study aimed to assess the impact of HT on surgical outcomes after breast reconstruction. All patients who underwent breast reconstruction between January 2012 and December 2013 were reviewed. Rates of wound healing complications, prosthesis complications, microvascular thrombosis, flap failures, and venous thromboembolism were retrospectively compared between patients treated and not treated with HT at the time of surgery. A total of 233 operations were performed: 78 free flaps, 12 autologous latissimus dorsi flaps, 47 implants, 42 lipofilling, and 54 secondary symmetrization. At the time of surgery, 38% of patients were treated with HT. Those who received HT experienced significantly more wound healing complications (61% versus 28%; p<0.001), including fat necrosis (26% versus 8.3%; p<0.001), infections (15% versus 2.8%; p<0.001), delayed wound healing (49% versus 13%; p<0.001), and grade III/IV capsular contracture (55% versus 9.1%; p=0.001). No significant difference was observed in the occurrence of microvascular thrombosis and venous thromboembolism. HT seems to be associated with an increased risk of wound healing complications. Currently, there is no guideline on perioperative HT discontinuation. Further investigations are required.

Hormone Therapy in Breast Cancer.

Hormonal therapy is mandatory for all patients with hormonereceptor- positive breast neoplasms. It is active both in adjuvant and metastatic disease. The only active adjuvant hormonal therapy in pre- and postmenopause is Tamoxifen. The adjuvant treatment duration influences disease-free survival, the risk of a contralateral breast cancer apparition and overall survival. The aromatase inhibitors: Anastrozol, Letrozol, Exemestan are only used in postmenopause. Fulvestrant is used in recurrent disease after or during treatment with Tamoxifen. LHRH analogues are used in premenopausal patients in adjuvantcy and sometimes in case of recurrences. Around 50% of hormonereceptor- positive breast neoplasms are or become resistant to hormone therapy. Some molecules involved in some tumour cellular growth pathways reverse the resistance to hormone therapy (Palbociclib, Everolimus).

Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial

The optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with node-positive non-metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety. A total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC → T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography. The 10-year DFS rates were 66.5% in the AC → T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC → T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC → T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy. This 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC → T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity. ClinicalTrials.gov Identifier NCT00312208.

Physician Underestimation of the Risk of Gastrointestinal Stromal Tumor Recurrence After Resection.

Patients with resectable gastrointestinal stromal tumors (GISTs) might not receive the recommended duration of adjuvant therapy if their risk of recurrence is underestimated, which can have an impact on their recurrence-free survival (RFS). To determine the extent of physician underestimation of risk of recurrence after complete primary GIST resection, the impact of underestimation on planned adjuvant treatment duration, and the association among high-risk patients of planned adjuvant treatment duration and RFS. This was a retrospective observational medical record review reported by participating oncologists in 2013. US patients with complete primary GIST resection after 2010 were grouped as underestimated or not if their oncologists' charted risk assessments were lower than assessments based on the Revised National Institutes of Health Consensus Criteria or not. Patients were followed by general community oncologists until death or the end of follow-up. Fisher exact tests compared planned adjuvant treatment duration between groups. Cox proportional-hazards models estimated the impact of planned adjuvant treatment duration on RFS. A total of 109 oncologists reported information on 506 patients with GIST after primary resection (65.8% were high-risk and 8.7% were intermediate-risk). Physicians underestimated risk for 190 patients (37.5%); 30.1% of tumors with an intermediate-level mitotic count (6-10 per 50 high-powered fields) and an intermediate tumor size (6-10 cm) were correctly recognized as high-risk, as were 7.5% of nongastric tumors with an intermediate-level mitotic count and a tumor size of 2 to 5 cm. A smaller proportion of high-risk patients in the underestimated vs not-underestimated groups had at least 3 years of planned adjuvant therapy (36.1% vs 65.9%; P < .001). Planned adjuvant treatment of at least 3 years vs less than 3 years among high-risk patients conferred a lower hazard of recurrence and/or death (adjusted hazard ratio, 0.29; P < .001; 95% CI, 0.14-0.59). Overall, physicians tended to underestimate the risk of recurrence for many patients with GIST, especially for patients with tumors of intermediate size, intermediate-level mitotic count, and nongastric location, which had an impact on planned adjuvant therapy duration. Patients with at least 3 years of planned adjuvant treatment had longer RFS. Improved education on postresection risk assessment and risk reduction is needed.

Gastrointestinal Stromal Tumors (GIST): A Prospective Analysis and an Update on Biomarkers and Current Treatment Concepts.

Gastrointestinal stromal tumors (GIST) are the most common sarcomas of the gastrointestinal tract, with transformation typically driven by activating mutations of cKIT and less commonly platelet-derived growth factor receptor alpha (PDGFRA). Successful targeting of tyrosine-protein kinase Kit with imatinib, a tyrosine kinase inhibitor, has had a major impact in the survival of patients with GIST in both the adjuvant and metastatic setting. A recent modification of treatment guidelines for patients with localized, high-risk GIST extended the adjuvant treatment duration from 1 year to 3 years. In this paper, we review the clinical data of patients with GIST treated in the Oncology Outpatient Unit of “Attikon” University Hospital and aim to assess which patients are eligible for prolongation of adjuvant imatinib therapy as currently suggested by treatment recommendations.

Abstract P2-15-02: Trastuzumab treatment of early breast cancer: Long-term results from a prospective observation study, including a large cohort of elderly patients

Abstract Purpose: Trastuzumab (T; Roche) is part of the standard treatment in patients (pts) of any age with early stage, HER2+ breast cancer, in addition to (neo)adjuvant chemotherapy (CT) and locoregional treatment. After its registration in Germany in 2006, this prospective observation study was started in order to assess the generalizability of the results from the randomized studies, specifically with respect to elderly age cohorts. Methods: 4027 pts were enrolled between 2006 and 2012. 87 were non-eligible due to M1 and/or negative HER2 status. There were no restrictions for recruitment with respect to age or concomitant/sequential adjuvant medication. The long-term relapse/survival status of pts was retrieved by fax forms collected once a year. Safety assessment was limited to the treatment period. Data base cut-off was May 2013. Results: Among the 3940 evaluable pts, there were 1013 elderly pts (EP) ≥ 65 years (y) of age (26%). This contrasts to the pivotal studies, e.g. with a proportion of only 6% beyond 65 y in the NSABP B-31 and NCCTG N9831 studies. The rate of EP steadily increased during the period from 2006 to 2009, remaining stable thereafter. More than half of the pts had pT≥2, with EP more often presenting with a larger tumor (56% vs. 48%,p&amp;lt;.0001). 52% had a grade 3 tumor. Hormone receptor positivity was recorded in 63%. As to be expected, performance status was more impaired in elderly compared to younger pts (ECOG 0: 53 vs 65%,p&amp;lt;.0001). 94% received CT, 78% as adjuvant, 14% as neoadjuvant treatment (in EP only 8%), while 2% received both modalities. In the vast majority (87%), T was administered sequentially to CT, with no differences among the age cohorts. The proportion without any adjuvant CT was higher in EP (8 vs. 5%). 56% of pts were treated with adjuvant endocrine medication, 78% with irradiation. T treatment was stopped prematurely in only 9% of pts, but more often in EP (11% vs 8%, p = .014). After a follow-up period of up to a maximum of 8 y, 370 relapses were reported so far. The estimated recurrence-free survival is 94.7% (95% CI: 94-96%), 89.8% (89-91%), and 82.9% (81-85%) after 2, 3 and 5 y, respectively. Numeric results in EP are only slightly lower with 93.9 (92-96%), 89.3% (87-92%), and 81.6% (78-85%), not statistically significant (p = 0.18, HR = 1.17 [95% CI: 0.93 - 1.47]). Adverse effects with respect to cardiac function were reported in overall 153 pts (3.9%), with the majority of these cases of NCI grade 1 (39%) or 2 (38%). 23% of these events were of grade 3/4, but life-threatening in only 2 pts. Thus, the overall incidence of acute grade 3/4 cardiac function toxicity was 0.9%. In the EP subgroup the incidence across all NCI grades was only slightly increased (4.6%), but grade 3/4 cases were more common (1.6%). Conclusion: Overall, the maturing follow-up data of this observational study confirm the beneficial results from the randomized studies. In addition, the data from more than thousand pts ≥ 65 y of age show that a similar anti-tumor efficiency can be achieved in elderly pts, and suggest that minor age-related differences detected with respect to adjuvant treatment duration, aggressiveness and toxicity do not impair the long-term clinical outcome. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-15-02.

From Evidence-based Medicine to Personalized Medicine

See Article on Page 259-264 Over the last two decades, many studies have shown the role of the adjuvant chemotherapy in stage III colon cancer [1-8]. With the introduction of excellent cytotoxic agents such as oxaliplatin and irinotecan, the median survival of even stag IV disease has been prolonged by more than 24 months. Based on the National Comprehensive Cancer Network (NCCN) guideline and the recently published Korean guideline, the oxaliplatin-based regimen has been the preferred regimen for stage III colon cancer over a single-agent regimen such as the capecitabine or 5-fluorouracil/leucovorin (FL) regimen. However, some concerns exist regarding the toxicity and the efficacy in adjuvant chemotherapy for stage III colon cancer. Because adjuvant chemotherapy means largely prophylactic chemotherapy rather than therapeutic chemotherapy like palliative chemotherapy, the efficacy of adjuvant chemotherapy should be balanced with its possible side effects, such as peripheral neuropathy or febrile neutropenia. For many years, the ideal duration of adjuvant chemotherapy has been under evaluation. Particularly with regard to the cumulative neuropathic adverse effects of oxaliplatin, a further decrease in the treatment duration is warranted. The SAFFA study showed no differences in term of overall survival between six months of a bolus FL regimen or three months of a protracted FL regimen [3]. However, a shorter adjuvant treatment duration is currently under evaluation in the IDEA program, which includes 12,000 patients from six ongoing trials [9]. Recently, the elderly population has grown remarkably worldwide. South Korea is also one of the countries with a fast-growing elderly population. The subgroup analysis of the NSABP C-07 trial showed a trend towards better disease-free survival in patients younger than age 70 (hazard ratio, 0.80; 95% confidence interval, 0.68 to 0.95; P = 0.013), but no positive effect was evident in older patients with the addition of oxaliplatin to the FL regimen [10]. Even the NCCN guideline recommended that the oxaliplatin-based regimen not be used for elderly patients older than 70 years. Conversely, capecitabine showed a constant efficacy even in elderly patients [11]. Lymph node metastasis is the single most important prognostic factor in colon cancer. It also determines the necessity of adjuvant chemotherapy in colon cancer. In the 7th American Joint Committee on Cancer tumor-node-metastasis staging system [12], the 5-year survival of stage IIIA colon cancer was even better than that of stage IIA colon cancer, which raised the concerns about the necessity of and ideal regimen for adjuvant chemotherapy in stage IIIA colon cancer. In this issue of the Journal of the Korean Society of Coloproctology, an article entitled Oncologic Outcome of Stage IIIA Colon Cancer According to Chemotherapeutic Regimen dealt with this specific concern. Although the study was a single-institution-based retrospective review and included a relatively small number of patients (n = 131) to draw a concrete conclusion, single-agent-based chemotherapeutic regimens (capecitabine or FL) showed 5-year disease free and overall survival rates similar to those of oxaliplatin-based regimens. In stage IIIA colon cancer, the depth of invasion is limited to the muscularis propria, and lymph node metastases are minimal (up to 6 metastatic lymph nodes). Among the eight patients who did not receive the adjuvant chemotherapy, three patients had recurrences during the follow-up, which suggested that adjuvant chemotherapy has a role even in stage IIIA colon cancer. This study suggested the need for further clinical trials in Korea to obtain solid evidence for this specific condition. The incidence of stage IIIA disease is very low, so it takes a long time to collect the patients to identify effective chemotherapeutic agents as in this paper (from 1995 to 2008, only 131 patients were collected). During that time in Korea, the governmental insurance policies changed continuously, so it was hard to measure the real value of the different regimens of adjuvant chemotherapeutic agents. However, this study provides possible clues for individualized or personalized chemotherapy. In the near future, I hope the Korean Society of Coloproctology may have a role in addressing this specific question.