Toxicities of Chemotherapy Regimens

used in Early Breast Cancer

CERCIT Workshop February 17, 2012

Carlos H Barcenas, M.D., M.S. Fellow Hematology-Oncology MD Anderson Cancer Center

CERCIT Scholar

1.  Background

2.  Data Sources

3.  Methods

4.  Results

5.  Discussion

Outline  

Siegel et al, CA Cancer J Clin 2012

•  Multidisciplinary approach: surgery, radiation therapy, chemotherapy, hormonal treatment, targeted therapy, or combination of the above

•  Treatment plan depends on several factors, such as stage, tumor biology, receptors

•  Other factors that can influence treatment: age, comorbid conditions, personal preference

Background Treatment  of  Breast  Cancer  

Chemotherapy Benefits in Breast Cancer  

Early Breast Cancer Trialists Group (EBCTG), Lancet 2005

•  Chemotherapy reduces breast cancer (BC) recurrence and mortality •  Shown in randomized control trials and meta-analysis. •  6 months of an anthracycline based chemotherapy reduces the annual BC death rate by 38% for women younger than 50 years of age and by 20% for those of age 50–69 years.

Regimens Used in HER2-Negative Early Breast Cancer

Non-anthracycline: •  CMF x6: Cyclophosphamide + Methotrexate + 5-FU •  TC x4: Docetaxel (Taxotere) + C Anthracycline based: •  TAC x6: T + Doxorubicin (Adriamycin) + C •  AC x4 → weekly Paclitaxel x12 weeks; AC x4 → T •  Dose-dense (q14 days) AC x4 → Paclitaxel x4 •  Dose-dense A-T-C: A x4 → Paclitaxel x4 → C x4 •  FEC (Epirubicin) → T; FEC → Paclitaxel •  Non- taxane: ACx4; FACx6; CAFx6; ECx8; CEFx6

•  Direct comparison of 17 trials of CMF-based vs. anthracycline-containing regimens were made (15,000 women; 4,000 deaths).

•  Anthracycline-containing polychemotherapy produced greater beneficial effects on recurrence and breast cancer mortality than CMF.

•  A minimum of 4 cycles of an anthracycline-based regimen is considered standard.

Anthracycline-based Regimen vs. CMF

Clarke M, Ann Oncology. 2006 Jones SE, et al, JCO. 2006

•  Cardiac damage is irreversible •  Damage extent depends on: cumulative dose, drug combinations, patient factors •  Incidence of CHF increases with cumulative dose >500 mg/m2 of doxorubicin •  The risk of developing CHF with standard doses is between 1.6% and 2.1%

Shift in Pattern of Care •  In pts with age >65 yrs,

anthracycline (A) use peaked in 2005 at 68% and decreased to 32% by 2008; taxane (T) use increased from 12% in 2005 to 51% in 2008.

•  In pts <65 yrs, A use peaked in 2004 at 86% and decreased to 49% in 2008; T use increased from 9% in 2004 to 46% in 2008.

Giordano SH, Lin Y, Kuo Y, et al: Anthracyline use among women with breast cancer. ASCO Meeting Abstracts 29:Abstract 1019, 2011

SAN ANTONIO BREAST CANCER SYMPOSIUM 2005

•  Slamon et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC®T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC®TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study.

•  Jones et al. Final analysis: TC (docetaxel/ cyclophosphamide, 4 cycles) has a superior disease-free survival compared to standard AC (doxorubicin/cyclophosphamide) in 1016 women with early stage breast cancer.

The addition of 1 yr of adjuvant trastuzumab significantly improved DFS and OS among women with HER2-positive breast cancer. The risk–benefit ratio favored the non-anthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia.

•  Estimated Enrollment: 2000 •  Study Start Date: May 2007 •  Estimated Study Completion Date: May 2015

Phase III Clinical Trial TAC vs. TC

Toxicities of Taxanes

•  Myelosuppression (neutropenia) •  Hypersensitivity reactions •  Fluid retention (Docetaxel) •  Peripheral neuropathy (more Paclitaxel) •  Mucositis •  Skin rash

Cancer Chemotherapy Drug Manual 2011 (Chu and DeVita)

Objective

•  To compare differences in toxicities between anthracycline-based and taxane-based breast cancer chemotherapy regimens, using hospitalization information from population-based databases.

•  Surveillance, Epidemiology, and End Results (SEER) Program collects information on incidence, prevalence and survival from specific geographic areas representing 28% of the U.S. population.

•  The SEER-Medicare database links the SEER data with Medicare records for the U.S. population of age 65 years or older.

•  Contains demographical (age, gender, race/ethnicity, marital status, census data), comorbidities, and tumor characteristics (date of diagnosis, stage, hormone receptor status )

Data Sources SEER-­‐Medicare  database  

Potosky AL, et al, Med Care. 1993

•  Proprietary datasets that meet HIPPA requirements for confidentiality, and undergo quality validity checks.

•  Files released when 100% of claims have been paid. •  Commercial Claims & Encounters dataset: large,

nationwide, employment-based database that contains information on medical claims and outpatient prescription claims for employees and dependents.

•  Includes a younger population, comprehensive geographic area, contains demographical and comorbid data from nationwide private medical insurance claims.

•  It does not contain tumor characteristics.

Inclusion / Exclusion Criteria SEER-Medicare and CERCIT

•  Inclusion: 1st DX of breast cancer, age ≥66 years, stage I–III, DX between 2003 and 2007, had lumpectomy or mastectomy; full coverage Medicare Part A and B during 12 months before and after DX, not an HMO member.

•  Exclusion: previous DX of any cancer type, stage IV patients

Inclusion / Exclusion Criteria MarketScan®

•  Inclusion: incident breast cancer DX between 2003 and 2007, aged <65 yrs, who had a lumpectomy or mastectomy, with continuous coverage during 3 months before and 12 months after DX.

•  Exclusion: previous cancer of any type.

Identification of Claims

•  Chemotherapy claims by specific ‘HCPCS J’ codes (anthracyclines: J9000, J9001, J9010, J9178; taxanes: J9170, J9264, J9265)

•  Mastectomy: ICD-9 codes 85.41 to 85.48; CPT Codes 19180, 19182, 19200, 19220, 19240, 19303 to 19307

•  Lumpectomy: ICD-9 codes 85.20 to 85.25 CPT codes 19110, 19120, 19125, 19126, 19160, 19162, 19301, 19302

Groups for Comparison (HER2 neg)

1)  Anthracycline (A) : A, +/- 5-FU, +/- cyclophosphamide (C); no taxanes, no trastuzumab, no other chemo

2)  Taxane (T): docetaxel + C, only 3)  A + T : anthracycline, +/- 5-FU, +/- C,

taxanes (T or paclitaxel), no other chemo

Groups

Hospitalization

•  Number of hospitalization admissions between first chemotherapy claim and 30 days, 6 months and 1 year after

•  Accumulated numbers of days that patients remained hospitalized

MarketScan

SEER - Medicare

CERCIT

Hospitalization due to Toxicities

•  Reason for hospitalization: infection, neutropenia, fever, thrombocytopenia, dehydration, anemia, delirium, adverse effects of systemic therapy Du et al. JCO 2002

MarketScan Specific

Discussion Points •  A + T was the most common chemotherapy

regimen used in all groups •  Non-A (T) regimen use increased after 2005 •  Majority of patients were not hospitalized •  At 30 days the hospitalization rates were not very

different among the groups •  At 6 and 12 months, the hospitalization rates were

higher with A + T, although the length of stay was higher with T in some subgroups

•  Toxicity specific hospitalization was not very different in the MarketScan group

•  Lack of Stage in the MarketScan database

•  Chemotherapy-induced toxicities may be underrepresented by hospitalization data

•  Medicare billing and errors capturing claims can occur.

Limitations

Next

•  Compare differences in medical costs in the initial treatment phase between anthracycline-based and taxane-based chemotherapy regimens.

•  Identify variables associated with short-term toxicities in each type of chemotherapy regimen (anthracycline-based and taxane-based).

Acknowledgements

•  Dr. Sharon H Giordano •  Ning Zhang •  Jiangong Niu •  Yufeng Zhang