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Treatment

Treatment. FMED 1531 Lecture 7 Spring 2007 Kim Cooper, Ph.D. Lecture Outline. Introduction Issues in Treatment Studies Internal Validity Results External Validity. Introduction. You are working with female patient who has been diagnosed with breast cancer and is positive for BRCA

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Treatment

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  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

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