ACRIN6691: Monitoring and Predicting Chemotherapy Response Using DOSI
Study Details
Study Description
Brief Summary
RATIONALE: New imaging procedures, such as diffuse optical spectroscopy imaging, may help measure a patient's response and allow doctors to plan better treatment.
PURPOSE: This clinical trial studies diffuse optical spectroscopy imaging in monitoring and predicting response in patients with locally advanced breast cancer undergoing chemotherapy before surgery.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
OBJECTIVES:
Primary
- To determine whether the percentage change in the diffuse optical spectroscopy imaging (DOSI) measurement of the tumor/normal (T/N) tissue optical index (TOI) from baseline to mid-therapy is predictive of the final pathologic response of the primary tumor in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy.
Secondary
-
To investigate whether change of TOI measurements from baseline to post-therapy are predictive of the final pathologic response in these patients treated with this regimen.
-
To investigate whether baseline TOI measurements are associated with final pathologic response in patients treated with this regimen.
-
To investigate whether TOI measurements at baseline, change from baseline to mid-therapy, and change from baseline to post-therapy correlate with available MRI volumetric imaging measurements.
-
To investigate whether changes on TOI measurements from baseline to mid-therapy, and from baseline to post-therapy, correlate with other standard-of-care imaging and/or any MRI-imaging measurements.
-
To explore whether additional optical endpoints and indices obtained during DOSI measurements can be used to predict final pathologic response in patients treated with this regimen.
-
To determine a cutpoint for the percent change of TOI from baseline to mid-therapy that is predictive of pathological complete response in patients treated with this regimen.
OUTLINE: This is a multicenter study.
Patients undergo diffuse optical spectroscopy imaging (DOSI) at baseline, 5-10 days after initiation of neoadjuvant chemotherapy, during early- and mid-neoadjuvant therapy, and within 21 days after completion of neoadjuvant therapy. Results are compared to standard-of-care imaging (e.g., MRI, ultrasound, mammography). Patients then undergo surgery.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: DOSI Pre-Surgery Participants undergo approximately four assessments of breast health using the DOSI technology during treatment and prior to surgery for breast cancer. |
Procedure: DOSI
Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, tissue oxygen saturation (StO2), and TOI (ctHHb x tH2O/lipid) were acquired on both breasts up to four times during neoadjuvant chemotherapy (NAC) treatment.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict Pathologic Response (pCR +/-) [From baseline to mid-therapy]
This measure will look at the Accuracy of % change in DOSI measured Tumor Optical Index (TOI) from baseline to mid therapy to predict pathologic response (pCR+ v pCR-) Pathologic response (dichotomized into responders (pCR+) and non-responders (pCR-) based pathologic assessment) will be used as the reference standard and Accuracy will be determined using receiver operating characteristic (ROC) analysis to determine the ROC Area Under the Curve (AUC).
Secondary Outcome Measures
- %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Progesterone Receptor (PR) Status (Positive, Negative, Unknown ) [baseline to mid-therapy]
Pathologic Complete response vs Non-Complete response, by PR status Progesterone Receptor Status (positive, negative, unknown ) is determined at pathological assessment of the tumor sample. %change in TOI is evaluated from baseline to mid-therapy.
- Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Oxygen Saturation (St02) [baseline to mid-therapy]
subset analysis, subjects were stratified using the median tumor StO2 %change TOI Between Baseline and Mid-therapy dichotomized at -40% stratified by the set evaluable subjects with baseline tumor StO2 dichotomized at 76.9%. (i.e. population median). Accuracy will be determined using ROC analysis to determine the ROC Area Under the Curve (AUC).
- Estimate the Optimal Cutpoint for %Change in TOI From Baseline to Mid-therapy to Predict pCR [baseline to mid-therapy]
Determine the optimal cutpoint for %Change in TOI ratio (T/N) to maximize sensitivity and specificity in the predication of pCR , as calculated by maximizing the Youden-index.
Eligibility Criteria
Criteria
Inclusion Criteria
-
Pathologically confirmed diagnosis of invasive breast cancer, determined to be a candidate for primary systemic (neoadjuvant) therapy and for surgical resection of residual primary tumor following completion of neoadjuvant therapy;
-
Tumor size >2cm, measured on imaging or estimated by physical exam;
-
No contraindications for primary chemotherapy;
-
Planned definitive breast surgery (mastectomy or lumpectomy/breast conservation) following completion of neoadjuvant therapy;
-
Age 18 years or older;
-
ECOG Performance Status ≤ 2 (Karnofsky ≥ 60%; see Appendix II);
-
Normal organ and marrow function as follows:
-
leukocytes ≥ 3,000/μl;
-
absolute neutrophil count ≥ 1,500/μl;
-
platelets ≥ 100,000/μl;
-
total bilirubin within normal institutional limits;
-
AST(SGOT)/ALT(SGPT) ≤ 2.5 times the institutional upper limit of normal;
-
creatinine within normal institutional limits; OR
-
creatinine clearance ≥ 30 mL/min/1.73 m2 for patients with creatinine levels above institutional normal;
-
If female, postmenopausal for a minimum of one year, OR surgically sterile, OR not pregnant, confirmed by a pregnancy test as per institutional Standard of Care (SOC), and willing to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation;
-
Able to understand and willing to sign a written informed consent document and a HIPAA authorization in accordance with institutional guidelines;
Exclusion Criteria
-
Previous treatment (chemotherapy, radiation, or surgery) to involved breast; including hormone therapy;
-
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements;
-
Medically unstable;
-
Under age 18;
-
Pregnant or nursing;
-
Previous malignancy, other than basal cell or squamous cell carcinoma of the skin or in situ carcinoma of the cervix, from which the patient has been disease free for less than 5 years.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Chao Family Comprehensive Cancer Center at University of California Irvine Medical Center | Irvine | California | United States | 92617 |
| 2 | Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center | Lebanon | New Hampshire | United States | 03756-0002 |
Sponsors and Collaborators
- American College of Radiology Imaging Network
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Bruce J. Tromberg, MD, Chao Family Comprehensive Cancer Center
Study Documents (Full-Text)
None provided.More Information
Additional Information:
- National Cancer Institute's clinical trials database
- For additional information about the ACRIN 6691 trial, visit the ACRIN Web site.
Publications
None provided.- CDR0000674337
- ACRIN-6691
- U01CA080098
- U01CA079778
Study Results
Participant Flow
| Recruitment Details | Seven institutions were approved to enroll a total of 60 female breast cancer patients: Enrollment began in June 2011 and completed in June 2013. All institutions activated concurrently, except MD Anderson Cancer Center and Boston University, which joined the study in January and May 2013, respectively. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Diffuse Optical Spectroscopy Imaging (DOSI) |
|---|---|
| Arm/Group Description | Participants undergo approximately four assessments of breast health using the Diffuse optical spectroscopy imaging (DOSI)technology during treatment and prior to surgery for breast cancer. DOSI: Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb x tH2O/lipid) were acquired on both breasts up to four times during neoadjuvant chemotherapy (NAC) treatment. |
| Period Title: Overall Study | |
| STARTED | 60 |
| COMPLETED | 34 |
| NOT COMPLETED | 26 |
Baseline Characteristics
| Arm/Group Title | Diffuse Optical Spectroscopy Imaging (DOSI) |
|---|---|
| Arm/Group Description | Participants undergo approximately four assessments of breast health using the DOSI technology during treatment and prior to surgery for breast cancer. DOSI: Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb x tH2O/lipid) were acquired on both breasts up to four times during neoadjuvant Chemotherapy (NAC) treatment. |
| Overall Participants | 34 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
48.4
(10.7)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
34
100%
|
| Male |
0
0%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
5
14.7%
|
| Not Hispanic or Latino |
29
85.3%
|
| Unknown or Not Reported |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
4
11.8%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
8
23.5%
|
| White |
19
55.9%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
3
8.8%
|
| Histologic findings (Count of Participants) | |
| Invasive (infiltrating) ductal carcinoma (IDC) |
16
47.1%
|
| Invasive lobular carcinoma (ILC) |
3
8.8%
|
| Ductal Carcinoma In Situ (DCIS)/ILC |
11
32.4%
|
| IDC/ILC |
2
5.9%
|
| Other/not available |
2
5.9%
|
| estrogen receptor (ER) status (Count of Participants) | |
| Positive |
24
70.6%
|
| Negative |
7
20.6%
|
| Unknown |
3
8.8%
|
| progesterone receptor (PR) status (Count of Participants) | |
| Positive |
19
55.9%
|
| Negative |
12
35.3%
|
| Unknown |
3
8.8%
|
| cell division marker (Ki67) status (Count of Participants) | |
| Positive |
17
50%
|
| Negative |
2
5.9%
|
| Unknown |
15
44.1%
|
| hormone receptor 2 (Her2/neu) status from Immunohistochemistry (IHC): (Count of Participants) | |
| 0 - HER2-negative |
4
11.8%
|
| 1 - HER2-negative |
8
23.5%
|
| 2 - equivocal |
8
23.5%
|
| 3 - HER2-positive |
4
11.8%
|
| unknown/not available |
10
29.4%
|
| fluorescence in situ hybridization (FISH) status (Count of Participants) | |
| Amplified |
7
20.6%
|
| Non amplified |
14
41.2%
|
| Unknown/not available |
13
38.2%
|
| Areolar tumor (Count of Participants) | |
| Areolar tumor |
17
50%
|
| Nonareolar tumor |
17
50%
|
Outcome Measures
| Title | Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict Pathologic Response (pCR +/-) |
|---|---|
| Description | This measure will look at the Accuracy of % change in DOSI measured Tumor Optical Index (TOI) from baseline to mid therapy to predict pathologic response (pCR+ v pCR-) Pathologic response (dichotomized into responders (pCR+) and non-responders (pCR-) based pathologic assessment) will be used as the reference standard and Accuracy will be determined using receiver operating characteristic (ROC) analysis to determine the ROC Area Under the Curve (AUC). |
| Time Frame | From baseline to mid-therapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| Bedside DOSI images of the tissue concentrations of TOI (ctHHb x tH2O/lipid) acquired on both breasts at baseline and mid-therapy during neoadjuvant chemotherapy (NAC) treatment. |
| Arm/Group Title | Diffuse Optical Spectroscopy Imaging (DOSI |
|---|---|
| Arm/Group Description | Participants undergo approximately four assessments of breast health using the DOSI technology during treatment and prior to surgery for breast cancer. DOSI: Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb x tH2O/lipid) were acquired on both breasts up to four times during NAC treatment. |
| Measure Participants | 34 |
| Number (95% Confidence Interval) [probability] |
0.60
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Diffuse Optical Spectroscopy Imaging (DOSI |
|---|---|---|
| Comments | This analysis will look at the ability of the % change in DOSI measured tumor Optical Index (TOI) from baseline to mid-therapy to predict pathologic response using logistic regression. Pathologic response (dichotomized into responders and non-responders) will be used as the reference standard and %change in TOI ratio (dichotomized at -40%) will be used to estimate pCR (+/-)= alpha + beta1(%change TOI) | |
| Type of Statistical Test | Equivalence | |
| Comments | under the NULL, it is assume that there is no difference between a 40% decrease in TOI, and a less than 40% decrease or an increase in TOI in their ability to predict pCR+ | |
| Statistical Test of Hypothesis | p-Value | 0.059 |
| Comments | 5% alpha threshold for significance. | |
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 4.667 | |
| Confidence Interval |
(2-Sided) 95% 0.95 to 23.04 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Progesterone Receptor (PR) Status (Positive, Negative, Unknown ) |
|---|---|
| Description | Pathologic Complete response vs Non-Complete response, by PR status Progesterone Receptor Status (positive, negative, unknown ) is determined at pathological assessment of the tumor sample. %change in TOI is evaluated from baseline to mid-therapy. |
| Time Frame | baseline to mid-therapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis population consists of the 34 participants with both baseline and mid-therapy TOI measurements. |
| Arm/Group Title | PR+ Participants | PR- Participants | PR? Participants |
|---|---|---|---|
| Arm/Group Description | Participants who are PR Positive (PR+) | Participants who are Progesterone Receptor Negative (PR-) | Participants whose PR status is unknown |
| Measure Participants | 19 | 12 | 3 |
| Mean (Standard Deviation) [percentage change] |
-29.874
(31.349)
|
-14.605
(107.425)
|
-45.701
(25.237)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Diffuse Optical Spectroscopy Imaging (DOSI, PR- Participants |
|---|---|---|
| Comments | The Null is that the odd ratio is the same in both the PR+ and PR- subjects fro the model including %change in TOI form baseline to mid-therapy (dichotomized at <=-40%), PR status (+/-) and the interaction between them. | |
| Type of Statistical Test | Equivalence | |
| Comments | test for the equivalence of %change in TOI ratio (dichotomized at <=-40%), between PR+ and PR- groups, with interaction | |
| Statistical Test of Hypothesis | p-Value | 0.8193 |
| Comments | significance at alpha=0.05 | |
| Method | Regression, Logistic | |
| Comments | p-value represents the interaction between %TOI (dichotomized at <=-40%), and PR status | |
| Method of Estimation | Estimation Parameter | Slope |
| Estimated Value | 0.4463 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.953 |
|
| Estimation Comments | Multivariate logistic regression model using % change in TOI ratio (T/N) (baseline to mid-therapy) dichotomized at -40%, PR status, and the corresponding interaction. | |
| Title | Accuracy of %Change in TOI Between Baseline and Mid-therapy to Predict pCR+; Stratified by Oxygen Saturation (St02) |
|---|---|
| Description | subset analysis, subjects were stratified using the median tumor StO2 %change TOI Between Baseline and Mid-therapy dichotomized at -40% stratified by the set evaluable subjects with baseline tumor StO2 dichotomized at 76.9%. (i.e. population median). Accuracy will be determined using ROC analysis to determine the ROC Area Under the Curve (AUC). |
| Time Frame | baseline to mid-therapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| evaluable subjects with baseline tumor StO2 dichotomized at 76.9%. (i.e. population median) and %change TOI dichotomized at -40% |
| Arm/Group Title | StO2 Negative | StO2 Positive |
|---|---|---|
| Arm/Group Description | Evaluable subjects with measurable baseline tumor oxygen saturation StO2 <= 76.9%. (i.e. population median) | Evaluable subjects with measurable baseline tumor oxygen saturation StO2 > 76.9%. (i.e. population median) |
| Measure Participants | 17 | 17 |
| Number (95% Confidence Interval) [probability] |
0.38
|
0.83
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | PR- Participants |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.043 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 16.5 | |
| Confidence Interval |
(2-Sided) 95% 1.09 to 250.15 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Diffuse Optical Spectroscopy Imaging (DOSI |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.406 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 2.86 | |
| Confidence Interval |
(2-Sided) 95% 0.24 to 33.90 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Estimate the Optimal Cutpoint for %Change in TOI From Baseline to Mid-therapy to Predict pCR |
|---|---|
| Description | Determine the optimal cutpoint for %Change in TOI ratio (T/N) to maximize sensitivity and specificity in the predication of pCR , as calculated by maximizing the Youden-index. |
| Time Frame | baseline to mid-therapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| participants having TOI ratio (T/N) using tumor breast normal at baseline and mid-therapy and have pathologic response data. |
| Arm/Group Title | Diffuse Optical Spectroscopy Imaging (DOSI) |
|---|---|
| Arm/Group Description | Participants undergo approximately four assessments of breast health using the Diffuse optical spectroscopy imaging (DOSI)technology during treatment and prior to surgery for breast cancer. DOSI: Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb x tH2O/lipid) were acquired on both breasts up to four times during neoadjuvant chemotherapy (NAC) treatment. |
| Measure Participants | 44 |
| Number [percentage change in TOI] |
-32.527
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | DOSI | |
| Arm/Group Description | Participants undergo approximately four assessments of breast health using the DOSI technology during treatment and prior to surgery for breast cancer. DOSI: Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb x tH2O/lipid) were acquired on both breasts up to four times during NAC treatment. | |
All Cause Mortality |
||
| DOSI | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/34 (0%) | |
Serious Adverse Events |
||
| DOSI | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/34 (0%) | |
Other (Not Including Serious) Adverse Events |
||
| DOSI | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/34 (0%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Donna Hartfeil, Director Protocol Management |
|---|---|
| Organization | American College of Radiology |
| Phone | 215-717-2765 |
| dhartfeil@acr.org |
- CDR0000674337
- ACRIN-6691
- U01CA080098
- U01CA079778