Treatment

1. Treatment FMED 1531 Lecture 7 Spring 2007 Kim Cooper, Ph.D.

2. Lecture Outline • Introduction • Issues in Treatment Studies • Internal Validity • Results • External Validity

3. Introduction • You are working with female patient who has been diagnosed with breast cancer and is positive for BRCA • What treatment options are available? • How will you and the patient decide which treatment is best?

4. Introduction • Your first step should be to consult clinical guidelines • There are many sources of such guidelines • A good source for cancer treatment guidelines is • NCCN/ACS (National Comprehensive Cancer Network and the American Cancer Society) • They maintain an excellent web-site (www.nccn.org) from which this information can be downloaded free of charge • The site has wonderful documents for both clinicians and patients

5. Introduction • The NCCN treatment guidelines list 5 major types of treatment for breast cancer • Surgery • Radiation therapy • Chemotherapy • Immunotherapy • Hormone therapy • There are several subtypes of each of the above • The guidelines provide a set of “decision trees” to help you and the patient make your decision

6. Introduction • The NCCN patient document lists 10 breast cancer decision trees depending on the specifics of the case • Stage 0: lobular carcinoma in situ (LCIS) • Stage 0: ductal carcinoma in situ (DCIS) • Stage I, II and some stage III breast cancer • Axillary lymph node surgery • Additional treatment (adjuvant therapy) after surgery • Adjuvant hormone treatment • Treatment of large stage II or stage IIIa breast cancers • Stage III locally advanced breast cancers • Follow-up and treatment of stage IV disease or recurrence of disease • Breast cancer in pregnancy

7. Introduction • Let’s assume your patient has been biopsied and found to have DCIS, what does her decision tree look like? Work-Up Medical history & physical exam Diagnostic mammogram (both breasts) Pathology review of biopsy sample Measure hormone receptor of tumor Findings (next page) Stage 0 DCIS

8. Guideline for Stage 0 DCIS Findings Widespread DCIS in two or more areas Margins positive Work-Up Primary Treatment (next page) Complete surgical excision Reexcision Margins negative Patient preferred mastectomy

9. Guideline for Stage 0 DCIS Findings Primary Treatment Widespread disease OR Margins positive after more surgery OR Patient prefers mastectomy Total mastectomy w/o lymph node removal Lumpectomy w/o lymph node removal followed by radiation OR Total mastectomy w/o lymph node removal Margins negative Lumpectomy followed by radiation OR Lumpectomy w/o lymph node removal followed by radiation OR Total mastectomy without lymph node removal Margins negative and tumor is low grade and small (< 1.5 inch)

10. Introduction • Problem: nothing specific about BRCA in guidelines • Now what? • Go to literature • You find the following article Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Haffty et al, The Lancet, 359: 1471-1477, 2002. • Article describes use of breast-conserving therapy (lumpectomy) with adjuvant chemoprophylaxis • Sounds very encouraging to you and your patient • Now you have to decide if the article is any good

11. Issues in Treatment Studies • The ideal study design is the randomized clinical trial (RCT) • For our question, there are no RCT’s so we have to make do with what’s available • Issues to consider in evaluating our study • Internal validity • Did the study adequately measure what they claim to have measured • Results • Are the results statistically and clinically significant • External validity • Can I apply the study to my patient

12. Internal Validity • Was the assignment of patients to treatments randomized? • What’s so important about randomization? • Best way to guarantee that “unknown” confounding factors are equally distributed between treatment groups

13. Internal Validity • Was the assignment of patients to treatments randomized in our study? • Look in the methods section • No • This is a retrospective study • The surgery has already been done (1975-1998) • The women were asked to come and be tested for BRCA status

14. Internal Validity • Were the groups similar at the start of the trial? • Treatment and control groups should be similar for all factors that determine clinical outcome except treatment • Find this information in table 1 of baseline characteristics of patients • When groups are small, chance may place those with apparently better prognoses in one group

15. Internal Validity Table 1

16. Internal Validity • Were the groups similar at the start of the trial in our study? • Look at Table 1 • Are there p-values? • What does a p-value tell you? • Were there any statistically significant differences? • Age (BRCA group younger, 37.3 vs. 33.7) • Family history (stronger in the BRCA group) • Ethnicity (more Jewish ethnicity in BRCA group) • ER status (more ER+ status in sporadic group) • Adjuvant therapy (more in sporadic group)

17. Internal Validity • Was follow-up of patients sufficiently long and complete? • Was follow-up sufficiently long? • Must follow group long enough to have reasonable chance of seeing the outcomes of interest • Was follow-up sufficiently long in our study? • How long was the follow-up? • Interquartile range (middle 50% of patients) was 13 years • Was it complete? • Yes

18. Internal Validity • Were patients analyzed in the groups to which they were randomized? • Patients in randomized trials sometimes forget to take their medicine or even refuse their treatment • Should patients who never actually received their assigned treatment be excluded from analyses? No! • Reasons people don't take medication often related to prognosis • Principle of attributing all patients to the group to which they were randomized called an "intention-to-treat" analysis • Preserves value of randomization: prognostic factors we know about, and those we don't know about, will be, on average, equally distributed in the two groups

19. Internal Validity • Were patients analyzed in the groups to which they were randomized? • There was no randomization in our study

20. Internal Validity • Were patients, health workers, and study personnel “blind” to treatment? • Patients who know they are on a new, experimental treatment are likely to have an opinion about its efficacy, as are their clinicians or other study personnel • These opinions can systematically distort outcome • Best way of avoiding this bias is double-blinding (double-masking) • Achieved by administering a placebo • If patients and treating clinicians cannot be kept blind, investigators should minimize bias by blinding those who assess clinical outcomes

21. Internal Validity • Were patients, health workers, and study personnel “blind” to treatment in our study? • Patients? • No, they weren’t masked • Could they have been? • Clinical evaluators? • Yes, they were effectively masked because they didn’t know the BRCA status at time of evaluation

22. Results • How large was the treatment effect? • Usually, randomized clinical trials report how often patients experience some adverse event • Patients either do or do not suffer an event • Report proportion of patients who develop such events • Example: • A study in which 20% (0.20) of a control group died • Only 15% (0.15) of those receiving treatment died • How can these results be expressed?

23. Results

24. Results • How large was the treatment effect in our study? • Look at table 2 • Can we convert this to the measures in the previous table? • No, because both are receiving same treatment, NNT not relevant

25. Results 20/105 = 0.19 or 19% 9/22 = 0.41 or 41% 0.41 – 0.19 = 0.22 0.41/0.22 = 1.86 NA

26. Results • How precise was the estimate of the treatment effect? • True absolute risk difference can never be known • All we have is estimate of true treatment effect observed in trial • Called a "point estimate" • Confidence interval gives neighborhood within which true effect is likely lies • Usually use 95% confidence

27. Results • How precise was the estimate of the treatment effect in our study? • They didn’t give confidence intervals (CI) • We can calculate them from the following formula

28. Results • CI for sporadic group ipsilateral side at 10 years • CI for genetic group ipsilateral side at 10 years

29. External Validity • Can the results be applied to my patient care? • Would my patient have been enrolled in the study? • Meets all inclusion criteria • Doesn't meet any exclusion criteria • If above not true, is there compelling reason why results should not be applied to my patient • Is the treatment feasible in your setting? • What are our patient’s values and expectations for both the outcome we are trying to prevent and the treatment we are offering?

30. External Validity • What are our patient’s potential benefits and harms from the therapy? • Benefit • Decrease in extent of surgery • Better self-image than with radical mastectomy • Harm • Increased risk of relapse compared with radical mastectomy