Materials Breast Cancer Adjuvant Therapy

1. Case Study 11The Intent to Treat Principlebeing - two examples of why ITT is a good idea; - followed by a surgical pain example where we excuse ourselves from following it; - proceeding with a hypothetical acute asthma study, - ending with a lesson from the NPC case study.

2. Materials Breast Cancer Adjuvant Therapy Redmond et al. The methodologic dilemma in retrospectively correlating the amount of chemotherapy received in adjuvant therapy protocols with disease-free survival: A commentary. Cancer Treatment Reports 67 (1983); 519-526. The APPROVE Trial of Rofecoxib in CV prevention NEJM 355:203-05 (2006) and accompanying editorial. The On-Q Surgical Pain Study Kushner, DM, R LaGalbo, JP Connor, JC Schink, R Chappell, SL Stewart, LS Harris and EM Hartenbach. The ON-Q pain management system in gynecologic oncology: A randomized, placebo-controlled trial.  Obstetrics & Gynecology106 (2005), 227-233 and accompanying editorial.

3. Key Words: Data analysis; Intent to treat principle; post-randomization exclusions; comparative effectiveness vs. efficacy. Rick Chappell, Ph.D. Professor, Department of Biostatistics and Medical Informatics University of Wisconsin Medical School Stat 542 – Spring 2018

4. Outline: Preliminary comments on ITT Bias in Breast Cancer (Redmond) Bias in Colon Cancer Prevention via Vioxx (APPROVE Trial) Pain in Gynecological Surgery (the ON-Q Device Trial) A Hypothetical (?) Acute Asthma Study When to start measuring survival times? Example using the NPC case study.

5. A. Preliminary comments on ITT • ITT Principle All patients accrued to a trial will be analyzed in the treatment group to which they were assigned, and all events will be counted. • Account for all participants randomized • Account for all events during follow up • “Modified ITT”? • Be careful!

6. Debate: Two types of trials 1. Management - "Intent to Treat" Principle - Compare all subjects, regardless of compliance 2. Explanatory - Estimate optimum effect, understand mechanism - Analyze subjects who fully comply

7. Violations of ITT: 1. Patient INELIGIBLE, withdrawn • After randomization, discover some patients did not in fact meet entry criteria (e.g., staging) • Concern ineligible patients may dilute treatment effect, so withdraw them • Withdrawal of ineligible patients, post hoc, may introduce bias

8. Violations of ITT: 2. Withdrawal for NONCOMPLIANCE • After randomization, note that some patients did not receive intended treatment • Problem: the reason for noncompliance may not be known and could easily be related to outcome • Withdrawals or adjustments for noncompliance may lead to bias

9. B. Bias in Breast Cancer: Adjuvant TherapyProbability of Disease Free Survival for Years Post Mastectomy (Method I) Redmond et al (1983) Cancer Treatment Report

10. Breast Cancer Adjuvant TherapyProbability of Disease Free Survival for Years Post Mastectomy (Method II) Redmond et al (1983) Cancer Treatment Report

12. C. Violations of ITT C: Dropping Patients“Off Drug ≠ Off Study” • ITT requires inclusion of • All patients randomized • All events during follow up • Exclusion of either patients or events can lead to bias of unknown direction • If all events not captured, no way to tell if it makes a difference • Censoring for going off intervention (e.g. after 7, 14 or 30 days) may cause bias

13. Bias in Colon Cancer Prevention via Vioxx (APPROVE Trial) • References • NEJM 2005 Primary Paper • NEJM 2006 Editorials • Lancet 2008 Approve+1 • A trial of Vioxx (Rofecoxib) for colon cancer prevention • 2005 Paper suggested an increase in CV events

14. Debate over 18 month “honeymoon” NEJM 2006; 355:203-05

15. Approve + 1(Lancet, 2008) • In initial design, patients who went off drug were not followed after 14 days • Pressures caused sponsor/investigators to conduct an additional year of follow-up on all patients randomized • An independent analysis was conducted at U. Wisconsin • Results with additional year of FU did not confirm the 18 month honeymoon for CV risk

16. NEJM 2006; 355:203-05

17. Pain in Gynecological Surgery (the ON-Q Device Trial) From the Abstract: Objective: ... to evaluate the safety and efficacy of ... bupivacaine continuous wound infusion system in gynecologic oncology patients undergoing laparotomy. Methods: A prospective, randomized, double-blind, placebo-controlled trial was performed. After closure of the fascia, flexible soaker catheters were placed in the deep subcutaneous space. The infusion pump was filled with 290 mL of either 0.5% bupivacaine or normal saline, to infuse over 72 hours. Daily assessments of pain scores utilized the Wisconsin Brief Pain Inventory.

18. Pain in Gynecological Surgery (the ON-Q Device Trial) We want to avoid missing outcomes among randomized patients. When should we randomize?

19. Pain in Gynecological Surgery (the ON-Q Device Trial) We want to avoid missing outcomes among randomized patients. When should we randomize? As late as possible. Unfortunately, it wasn’t practical to randomize them during or immediately before surgery. Here, patients were randomized after consent, their infusion (placebo or bupivacaine) stored in the research pharmacy in a “brown paper bag” (blinded). Once surgery started, a student “ran” to the pharmacy to get it.

20. Pain in Gynecological Surgery (the ON-Q Device Trial) It wasn’t practical to randomize them during or immediately before surgery. Instead, patients were randomized after consent, their infusion (placebo or bupivacaine) stored in the research pharmacy in a “brown paper bag” (blinded). Once surgery started, a student “ran” to the pharmacy to get it. Is this as good as randomizing “while on the table”?

21. Pain in Gynecological Surgery (the ON-Q Device Trial) From ”Materials and Methods”: “The primary outcome was mean current pain over the 5 days of hospitalization. Secondary efficacy outcomes included mean maximum pain and oral and intravenous pain medicine use.” But: 1. One subject was included twice; she received placebo both times. What to do? 2. Two randomized patients weren’t treated or followed, and this occurrence was completely ignored (though admitted).

22. Pain in Gynecological Surgery (the ON-Q Device Trial) From ”Materials and Methods”: “The primary outcome was mean current pain over the 5 days of hospitalization. Secondary efficacy outcomes included mean maximum pain and oral and intravenous pain medicine use.” But: 1. One subject was included twice; she received placebo both times. What to do? 2. Two randomized patients weren’t treated or followed, and this occurrence was completely ignored (though admitted). ??? !!! ???

23. Pain in Gynecological Surgery (the ON-Q Device Trial) From ”Materials and Methods”: “Two patients were randomized, but because of communication errors [the usual nurse was sick], pumps were not inserted and data were not collected or analyzed. Because the blinds were completely preserved, this would not be expected to induce bias.” To ignore randomized patients, the fact of their missingness must be completely unrelated to both their treatment and their outcome. Was that the case here? See Figures 2 & 3 for results.

24. An Editorial (Same Issue), Invoking the “Efficacy” vs. “Comparative Effectiveness” Divide

25. An Editorial (Same Issue), Invoking the “Efficacy” vs. “Comparative Effectiveness” Divide “The trial appears to be an effectiveness trial, because 1) there were only four inclusion or exclusion criteria, 2) nearly all gynecologic oncology patients were eligible regardless of the type of incision, and 3) the trial was managed by personnel within the gynecologic oncology division.” “The primary outcome for the sample size calculation was a pain score rather than the quantity of analgesic used. Analgesic use would be the most clinically relevant outcome …”

26. An Editorial (Same Issue), Invoking the “Efficacy” vs. “Comparative Effectiveness” Divide My opinion: I don’t care much about making a distinction between “efficacy” and “comparative effectiveness”, but I do understand the logic behind choosing analgesic use as a primary outcome rather than pain scores. What are the considerations behind this choice?

27. A Hypothetical (?) Acute Asthma Study Anecdotal from Richard Gelber, Harvard University. • Suppose you want to improve the treatment of acute pediatric asthma patients who are brought to the emergency room. • These patients are (mostly) a known community, so: • They were pre-consented, randomized, & their medication (one of 2) placed in “brown paper bags” (double-blinded) in the local ER.

28. A Hypothetical (?) Acute Asthma Study • They were pre-consented, randomized, & their medication (one of 2) placed in “brown paper bags” (blinded) in the local ER. • Outcome was time to attack’s resolution. But: • Many or most randomized patients won’t have an attack. • Thus most subjects’ outcomes will be missing. • Under what assumptions can we ignore them?

29. All three trials in the Nasopharyngeal Carcinoma cases study • Trial NPC-9901, e.g., investigated adding concurrent chemotherapy to standard surgical treatment/radiation for NPC. • What is the baseline? (I.e., from when do we start timing the outcomes?) • Since all patients are supposed to receive RT, why not measure survival from RT’s termination?

30. Nasopharyngeal Carcinoma case study • Since all patients are supposed to receive RT, why not measure survival from RTs termination? • What kind of patients don't complete radiation? • Concurrent chemotherapy starts before radiation is finished. • What kinds of biases could this induce?

31. Nasopharyngeal Carcinoma case study • Since all patients are supposed to receive RT, why not measure survival from RTs termination? • What kind of patients don't complete radiation? • Concurrent chemotherapy starts before radiation is finished. • What kinds of biases could this induce? • The rule of “no post-randomization exclusions” also implies measuring times from the point of randomization.

32. Nasopharyngeal Carcinoma case study General Rule: For survival analyses and "after vs. before" (e.g., weight loss, cholesterol change, etc.) outcomes: Baseline should be the time of randomization.