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ATLAS Trial: 10 years vs. 5 years of tamoxifen in patients with breast cancer

In ATLAS trial, Davies C et al. randomized 12,894 females with early breast cancer diagnosed and receiving adjuvant tamoxifen to either 10 years continued tamoxifen or 5 years of tamoxifen therapy. The primary goal of the trial was to study breast cancer recurrence and mortality in these patients. The results of the ATLAS trial were significantly in favor of pursuing the 10 years prolong therapy as compared with 5 years. The authors concluded that for women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. The ATLAS trial proved to be a big breakthrough in terms of practice-changing implications. Source

NLST Trial: Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening

Source: NEJM

FREGAT Trial (2019): Minimally Invasive Esophagectomy for Esophageal Cancer

FREGAT Trial

Source: NEJM

FREGAT Trial Key Points

  1. Minimally invasive esophagectomy (MIE) was found to have significantly lower complications and side effects compared to open esophagectomy.
  2. The 3 years survival rate was also higher among patients undergoing minimal invasive esophagectomy.
  3. Open esophagectomy is known to have significant morbidity ranging from 17.9% to 58%, with up to 6% mortality. Therefore, the minimally invasive hybrid procedure is now being utilized to limit the adverse events.

PACIFIC Trial (2017): Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC

PACIFIC Trial visual abstract

PACIFIC Trial Summary (NEJM 2018): Scott J et al. randomized 713 patients with stage III unresectable nonsmall cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy were randomized to either Durvalumab 10mg/kg body weight twice weekly for 12 months (n=473) or matching placebo (n=236). The primary objective was to assess if Durvalumab prolongs survival and increases the time to death or prevent distant metastasis in patients with stage 3 unresectable nonsmall cell lung cancer. The primary outcome of 24-month overall survival rate was significantly higher in the Durvalumab group, 66.3% compared to 55.6% in the placebo group. The authors concluded that Durvalumab therapy resulted in significantly longer overall survival than placebo. No new safety signals were identified.

Source: 2018, Durvalumab in non small cell lung cancer, NEJM

AVERT Trial: Apixaban to Prevent VTE in Patients with Cancer

AVERT trial Apixaban

2018, Apixaban to Prevent Venous Thromboembolism in Patients with Cancer, NEJM

The AVERT trial evaluated the use of apixaban for preventing venous thromboemboli such as deep venous thrombosis and pulmonary embolism in patients with cancer who were scheduled to start chemotherapy. These patients were at high risk of VTE based on the Khorana score.

The point that differentiated AVERT trial from other similar trials of using drugs for prevention of VTE in cancer patients was that it enrolled patients who did not have a history of VTE and the primary target was to lower the first incidence of VTE. In comparison, the CLOT and Hokusai VTE trials studied the use of LMWH for secondary prevention of VTE.

The study did show benefits of apixaban in preventing the first episode of VTE but this was countered by significant increase in bleeding risk. Currently based on guidelines, LMWH are preferred agents of choice for secondary prevention of VTE in patients with cancer. The 2012 CHEST guidelines on antithrombotic therapy recommend:

In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade 2B). In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2B).

Source

AGE: Mammographic screening from age 40 years

 

2006, Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years, The Lancet

NELSON: CT Screening For Lung Cancer in High Risk Population

 

Full trial results to follow the publication. This abstract format was presented at the WCLC 2018.

SOME Trial: Screening for Occult Cancer in Unprovoked Venous Thromboembolism

 

2015, Cancer screening in unprovoked venous thromboembolism, NEJM

STAR Trial: Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes

Source: JAMA

Hokusai VTE Cancer Trial: Edoxaban for Cancer-Associated VTE

edoxaban, hokusai VTE cancer trial visual abstract

Let’s talk methodology…

In this randomized, open-label, non-inferiority trial, the authors analyze a primary composite outcome that includes recurrent VTE and major bleeding in cancer patients taking edoxaban, a factor X inhibitor developed by the study sponsor, Daiichi-Sankyo. They conclude that when compared with LMWH, edoxaban is non-inferior for the aforementioned composite outcome. Because composites occur more often than its components, using composites increase the study efficiency by decreasing the study time and sample size with subsequent costs reduction.

Non-inferiority trials are a useful tool when it is unethical to compare a new drug with placebo because a standard of care is available or because the trial involves serious outcomes such as mortality or in this case recurrence of VTE. Non-inferiority trials are usually confused with equivalence trials but these are different. Equivalence is applied mainly for comparison of generic versus marketed drug preparations to assess for pharmacokinetic differences. Otherwise, equivalence is impossible to be achieved between 2 drugs with different mechanisms of action such as edoxaban and LMWH. A non-inferiority approach may be used when the new treatment – edoxaban – seems to offer advantages such as better compliance, cost or availability over the standard of care – LMWH. Importantly, several considerations need to be accounted for when non-inferiority is part of the study design:

  1. As equivalence cannot be determined, a margin of non-inferiority should be established a-priori. This is defined as an acceptable margin of non-inferiority based on clinical judgment and statistical reasoning and it could be guided by previous trials that compared the control drug (LMWH) with placebo. In this case, the margin was a hazard ratio of 1.5 based on the unmet need for an alternative to parenteral LMWH and the advantages of oral therapy, allowing non-inferiority if the edoxaban population presented the composite outcome at 1.5 times the rate per unit time as the LMWH population or 50% the hazard.
  2. Importantly, the hazard ratio must be interpreted conjointly with time-to-event analysis or Kaplan-Meier curves. In this study, the curves cross for the composite primary outcome indicating non-inferiority, however, when interpretation is performed for each component, edoxaban appears to have less recurrent VTE but more major bleeding events when compared to LMWH. Once these 2 opposing components are combined into a composite, there is a sense of compensation.
  3. Intention-to-treat (ITT) analysis is indicated in superiority trials to preserve randomization – similar characteristics in both groups – avoiding attrition bias, however, including dropouts in non-inferiority trials can lead to bias towards equivalence. For this reason, in non-inferiority trials, it is recommended to perform both ITT and per-protocol analysis and both should demonstrate non-inferiority for it to be concluded. It this study a modified ITT analysis was performed including all patients who underwent randomization and received at least one dose of the assigned drug. These results were confirmed by sensitivity analysis of the primary outcome with a per-protocol approach.

In conclusion, non-inferiority trials should be cautiously executed and interpreted. Further studies with diverse factor X inhibitors are needed to validate these results and physicians must discuss risks and benefits of oral versus subcutaneous anticoagulation in cancer patients for whom quality of life might be the decisive variable.

Daniela Guerrero Vinsard MD.
Internal Medicine Resident at the University of Connecticut Health Center.

Source: NEJM

IRIS trial: Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase CML

Source: NEJM

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