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Article in Medical Decision Making · May 2006

DOI: 10.1177/0272989X06288684 · Source: PubMed

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DIAGNOSIS AND PATIENT SAFETY

Implications of Cancer Staging Uncertainties in Radiation Therapy Decisions

Robert C. Lee, MSc, Edidiong Ekaette, MSc, Karie-Lynn Kelly, MD, Peter Craighead, MD, Chris Newcomb, PhD, Peter Dunscombe, PhD

Introduction. Radiation therapy (RT) for cancer is a criti- cal medical procedure that occurs in a complex environ- ment involving numerous health professionals, hardware, software, and equipment. Uncertainties and potential inci- dents can lead to inappropriate administration of radia- tion to patients, with sometimes catastrophic consequences such as premature death or appreciably impaired quality of life. The authors evaluate the impact of incorrectly stag- ing (i.e., estimation of extent of cancer) breast cancer patients and resulting inappropriate treatment decisions. Methods. The authors employ analytic and simulation methods in an influence-diagram framework to estimate the probability of incorrect staging and treatment deci- sions. As inputs, they use a combination of literature

information on the accuracy and precision of pathology and tests as well as expert judgment. Sensitivity and value- of-information analyses are conducted to identify impor- tant uncertainties. Results and conclusions. The authors find a small but nontrivial probability that breast cancer patients will be incorrectly staged and thus may be sub- jected to inappropriate treatment. Results are sensitive to a number of variables, and some routinely used tests for metastasis have very limited information value. This work has implications for the methods used in cancer staging, and the methods are generalizable for quantitative risk assessment of treatment errors. Key words: patient safety; breast cancer; radiation; risk analysis. (Med Decis Making

2006;26:226–238)

R adiation therapy (RT) for cancer is a complex medical procedure involving numerous health

professionals, hardware, software, and equipment.

Received 17 December 2004 from the University of Calgary, Alberta Cancer Board. Financial support for this study was provided by an oper- ating grant from the Canadian Institutes of Health Research. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report. Related work has been presented in posters at the Society for Medical Decision Making (2004) and the Society for Risk Analysis (2004) annual conferences, as well as oral presentations at the International Federation of Operational Research Societies triennial conference (2005), the Institute for Operations Research and the Management Sciences annual conference (2005), and the Canadian Operations Research Society annual conference (2005). Revision accepted for publication 23 November 2005.

Address correspondence to Robert C. Lee, Director, Calgary Health Technology Implementation Unit, Departments of Community Health Sciences and Oncology, University of Calgary, Foothills Medical Centre, South Tower, Room 602, 1403 29th Street NW, Calgary, AB T2N 2T9 Canada; telephone: (403) 944-4343; fax: (403) 944-1090; e-mail: rclee@ucalgary.ca.

DOI: 10.1177/0272989X06288684

Deviations from optimal pathways of care can lead to inappropriate administration of radiation to patients, with sometimes catastrophic consequences such as premature death or appreciably impaired quality of life. As a result, standard and comprehensive quality assurance guidelines have been defined for patient safety in RT. 1 RT facilities, such as the Tom Baker Cancer Centre (TBCC) in Calgary, Alberta (Canada), the site of the present study, employ a variety of risk management procedures and patient safety initiatives aimed at ensuring that currently accepted tolerances are routinely met and that incidents that could poten- tially prove to be harmful to patients and staff are pre- vented. However, these risk management procedures have not necessarily been based on a systematic and quantitative assessment of the RT system. Quantitative health risk analysis methods aid decision makers by informing risk management deci- sions. Risk in this discussion refers to a function that reflects both the probability of a given activity or sys- tem failure and the consequences of such a failure. 2 Misstaging breast cancer patients after primary surgery is one potential cause of inappropriate admin-

226 MEDICAL DECISION MAKING/MAY–JUN 2006

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UNCERTAINTIES IN RADIATION THERAPY DECISIONS

istration of RT. Clinical staging requires a complete physical examination of the breast and lymph nodes, imaging, and examination of biopsy specimens. Patho- logic staging uses all the information available through clinical staging, surgical biopsies, and resec- tion. Pathologic staging provides more histologic certainty regarding invasion state, tumor size, and nodal status as compared to clinical staging. 3 We define misstaging as an error in cancer staging in which the extent of the disease is incorrectly classi- fied and thus the type of RT technique prescribed (based on this information) is not optimal. In this analysis, we are concerned with “imperfect” or uncer- tain processes and tests that can lead to misstaging. We employ 2 modeling methods: analytic methods, where the system is represented via normal mathe- matical formulas, and simulation, to quantify risks that cannot be directly calculated via such formulas. To our knowledge, this is the first attempt at model- ing the cumulative effect of uncertainties associated with all the steps involved in staging breast cancer, as relevant to RT.

BACKGROUND—RADIOTHERAPY

RT is the treatment of cancer with targeted high- energy beams of ionizing radiation such as X-rays. Such radiation injures or destroys cancer cells in the area being treated (the “target volume”), compro- mising the ability of these cells to continue to divide. Although radiation damages both cancer cells and normal cells, the goal of properly administered treat- ment is to keep normal tissue damage at an accept- able level while at the same time destroying the tumor. RT is most beneficial when it is “matched” to the appropriate type and stage of cancer; otherwise, the benefit may be suboptimal. For example, particular types and stages of cancer are treated with “4-field” (i.e., 4 beams) v. “2-field” (2 beams) RT, in an attempt to maximize coverage of the tumor while minimizing coverage of normal tissue. In metastatic cancer, which is not typically curable, palliative treatment is used to control cancer growth and pain in the patient. Our present focus is on breast cancer. Surgery is the primary treatment for breast cancer. Breast-conserving surgery, also known as lumpectomy, is surgery to remove cancer tumors while conserving (as much as possible) healthy breast tissue. Surgery is often fol- lowed by RT. For patients undergoing breast-conserving therapy, studies show that adjuvant systemic therapy (such as chemotherapy and hormonal and biological therapy) cannot at present replace RT. 46 Thus, breast

DIAGNOSIS AND PATIENT SAFETY

RT after lumpectomy is the standard of care for these patients in most facilities. Anatomic regions that are considered for inclusion in the target volume for RT are the breast, chest wall, internal mammary nodes, and the axilla and supra- clavicular fossa. Standard RT is administered through a medial and lateral tangent field arrangement. The axilla and supraclavicular fossa (regional nodes) are nearly always treated with parallel opposed sets of beams. The internal mammary nodes are rarely treated due to the high potential risk to vital organs such as the heart and lungs. Ductal carcinoma in situ (DCIS), a precancerous condition, is treated with 2 fields. For all other invasive breast cancers (except palliative cases), the RT technique depends on the type of surgery that the patient underwent, as well as pathological features of the tumor, including the number of positive lymph nodes, margin status, presence or absence of lymph- vascular invasion, tumor grade, and so on. We represent the RT operational process as a sys- tem that involves assessment, prescription, prepara- tion, treatment, and follow-up. Treatment prescription occurs subsequent to assessment, which includes diag- nosis and staging. Cancer diagnosis is a process in which the physician establishes the fact that a patient has or does not have a particular type of cancer.

BACKGROUND—STAGING

For all patients diagnosed with cancer, the assess- ment of the extent of the cancer, using clinical and/or pathologic findings, is known as staging. Diagnosis always precedes staging and usually takes place out- side an RT administering facility. Staging, on the other hand, is usually carried out within such a facility and is the focus here. Staging guides treatment prescrip- tion by helping determine 1) the extent of cancer, 2) the suitability of RT, and 3) the applicable radiation technique (i.e., 2-field, 4-field, or palliative treatment, in the case of breast cancer) and specifics of treatment. Despite the important roles that diagnosis and staging play, evaluation of their “correctness” (i.e., whether the diagnosis and staging are indeed cor- rect) is difficult. However, this evaluation is critical for the quantification of potential risks associated with RT. Here, we are concerned with 1) the proba- bility of misstaging and consequently in treatment, 2) quantification of the risk involved in the treat- ment decision-making process, and 3) identification of sensitive variables (i.e., those that contribute most to uncertainty in model results). The TNM (tumor size, lymph node involvement, and degree of distant metastasis) classification is a

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LEE AND OTHERS

clinical and pathologic staging system with world- wide acceptance, developed by Denoix. 7 Most cancers are staged using this system. The TNM system classi- fies cancer patients into 5 main stages: stage 0, stage I, stage II, stage III, and stage IV. Pathology reviews are used to determine stages 0 to III of breast cancer, while imaging and biochemical tests are used to determine the presence of metastatic disease, which defines stage IV cancer. The correctness of staging is therefore dependent on the accuracy of the pathology review, imaging, and biochemical tests employed. Determining the statistical accuracy and precision of pathology examinations is difficult, as there is no “gold standard” (other than perhaps autopsy in some cases) to which these reports may be com- pared. The most common approach to this problem is review of pathology reports (i.e., second opinion) in prospective and retrospective studies. However, a difficulty exists concerning who makes the “correct” diagnosis: the primary pathologist or the second- opinion pathologist? Regardless, these reviews help to identify the frequency of change of diagnosis, which is an indirect indication of the uncertainty associ- ated with these reports. Pathology review studies can generally be grouped into prospective studies, 815 where the primary report is reviewed by peers, and retrospective reviews 1618 of slides, frozen sections, and/or autopsies after treat- ment has been delivered to the patient. These studies report discrepancies between the original reports and the reviewed reports that can be classified as either differences in final diagnosis that would have led to different treatment options or differences in diagno- sis with no relevant change in the treatment option. Discrepancies may arise due to incomplete informa- tion (incomplete clinical history, number of nodes, etc.), clerical mistakes (involving spelling, grammar, unclear terminologies, typographical errors), over- sights, and misinterpretations. Two of these studies addressed breast cancer diag- nosis. 10,14 In 1 study, examination of 346 breast can- cers for second opinion resulted in major changes for 7.8% of all cases reviewed. 14 A change was termed as major if it involved 1) failure to confirm the diagnosis of malignancy, 2) a change in diagno- sis from invasive to noninvasive carcinoma or the converse, or 3) a change in diagnosis that would alter the recommended surgical procedure (i.e., mar- gin status positive to negative). In another study, 10 follow-up information and other additional informa- tion were used to confirm the second opinion. This study reports a 1.4% rate of change of diagnosis on second opinion for breast cancer. Changes appear to

228 MEDICAL DECISION MAKING/MAY–JUN 2006

be more common between DCIS (ductal carcinoma in situ) with invasion and DCIS alone. 10,14 Distant metastasis in other organs (the most common sites being the liver, lung, and bone) is classed as stage IV cancer. Patients with distant metas- tases are typically not curable, and thus the aim of treatment is palliative. On average, approximately 40% to 50% of all distant metastases are in the bone. 3 The most commonly used imaging technique for iden- tifying bone metastases is bone scintigraphy. Some- times, scintigraphic findings are further confirmed through bone biopsies or other methods. Magnetic res- onance imaging (MRI) and other advanced means of imaging are more sensitive than bone scintigraphy in detecting bone metastases but are not routinely used in Canada. There are also a number of tumor markers that can guide the physician in his or her diagnosis of distant bone metastases. These include alkaline phos- phatase (AP), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA 15.3). The liver is a relatively uncommon site of first metastases. The most common ways of determining liver metastases are via liver ultrasonography (LUS) or scintigraphy. Hepatic enzyme elevation monitored by liver function tests (LFTs) may serve as indications of liver metastases. However, due to the poor speci- ficity of these tests, other techniques such as comput- erized tomography (CT) scans and LUS are sometimes considered for further evaluation. Some of the more popular LFTs are considered in the present analysis. They are gamma glutamyl transferase (GGT), aspar- tate aminotransferase, and alanine aminotransferase (AST/ALT). CEA tests may also be considered along with these LFTs in the detection of liver metastasis. Another uncommon site of first metastases is the thorax or lungs. Because such metastases are rela- tively rare, the use of routine chest X-rays is typi- cally discouraged. Thoracic metastasis is typically only investigated when there is some physical indi- cation that it may be present. We simulate the staging process using the esti- mated accuracy and precision of pathology reports and tests to generate staging results, influenced by the true stage of the disease. The simulated staging results are then used to evaluate the probability of inappropriate treatment.

METHODS

We built a simulation model 19 (using Lumina Analytica, Palisade DecisionTools, and Microsoft Excel ® ) to quantify the probability that a patient is incorrectly staged (and, conversely, correctly staged)

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UNCERTAINTIES IN RADIATION THERAPY DECISIONS

Pathology staging results Biochemical test results Data Cancer generator staging Imaging test results stage
Pathology
staging results
Biochemical
test results
Data
Cancer
generator
staging
Imaging test
results
stage
Result
RT technique
analysis
prescription
probability (correctly staging patient)
probability (prescribing correct RT technique)

Sample size

Reference data (true cancer stage and required RT) technique)

Assigned cancer

Figure 1

High-level representation of the computational model.

and thus incorrectly prescribed (and, conversely, correctly prescribed) an RT technique for treatment. In the simulation model, we follow a cohort of hypo- thetical patients through the system, assigning uncertainty and potential for error in different sub- systems. The final outcome of the system is com- pared to reference data for each patient to quantify the probability of misstaging. A high-level representation of the model structure is indicated in Figure 1 (further details regarding the model are available upon request). The arrows indi- cate inputs and outputs to and from each computa- tional submodel. The input to the data generator is the hypothetical sample population size—in our case, 500 (assuming that an average of 500 patients present for RT at the TBCC annually). For each hypothetical patient, the simulation model assigns the “true” can- cer stage, required RT treatment technique, and a pathologic cancer stage. Furthermore, all stage IV patients are randomly assigned the site of metastasis based on generated imaging and biochemical test results. The generated results for pathologic staging, imaging, and biochemical tests are sent to the cancer

DIAGNOSIS AND PATIENT SAFETY

staging submodel. The true cancer stage and required RT technique are sent to the result analysis submodel. In the cancer staging submodel, the imaging and bio- chemical test results are combined using Bayes theo- rem (see below) to decide whether a patient is metastatic, in which case he or she is assigned stage IV. Patients who are not metastatic are assigned their gen- erated pathologic stage. Based on the assigned cancer stage, the prescribed RT technique is assigned in the RT technique prescription submodel and forwarded to the result analysis submodel. The result analysis sub- model then calculates the probability of a correct assignment of cancer stage and RT technique pre- scription. Figure 2 summarizes treatment decisions. The combination of evidence from diagnostic pro- cedures (imaging and biochemical tests) for a deci- sion regarding the extent of metastases is modeled using probabilistic influence diagrams. 20,21 Influence diagrams are more efficient than decision trees for complex modeling and also facilitate value-of- information analysis that quantifies the value (in util- ity terms) of different tests and combinations of tests. Latin Hypercube simulation (LHS), a variant of

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LEE AND OTHERS

Cancer

stage

Stage 0 Stage I Stage II Stage III yes Negative lymph nodes? no no Ratio
Stage 0
Stage I
Stage II
Stage III
yes
Negative
lymph nodes?
no
no
Ratio of positive to
removed nodes ≥
3:10?
2-field
yes
Stage IV

Stage IV

Stage IV
Stage IV

Palliative

Radiotherapy

treatment option

4-field

Figure 2

Radiation therapy (RT) decision guide for invasive and noninvasive breast cancer.

Monte Carlo simulation, which focuses sampling on distribution tails, 22 is used to propagate uncertain- ties and to perform sensitivity analysis. We ran 100 iterations of the model (i.e., 2-dimensional LHS, 500 patients) to achieve a reasonable degree of confi- dence in mean results. 23 To calculate the probability of misstaging a patient, we evaluate the staging information that is typically available in a Canadian cancer treatment facility, which is publicly funded and has a fixed annual bud- get (note that different types and amounts of tests may be used in a US facility). All data used for variable definitions were taken from the published literature where possible (references are provided in Table 1 and below; otherwise, assumptions represent expert opinion and standard practice). No patient-specific information was employed. Table 1 represents the sensitivity and specificity distributions used in the influence diagrams. The following are additional key assumptions made in modeling:

1. Studies designed to verify the correctness of surgi- cal pathology and cytopathology and, consequently, the staging and grading system used in generating pathology reports have revealed discrepancies and errors. 2434 Based on the work of Waalkes and others 35 and Hou and others, 36 we define a uniform distribu- tion with the upper bound of the pathologic correct- ness for breast cancer at 98.6% and the lower bound at 93.2%.

2. Pathology examinations of specimens are equally accurate in all stages of the disease (e.g., if the pathol- ogy report has an estimated correctness of 98%, then it has a correctness of 98% for identification of stage 0, stage I, stage II, and stage III). Misstaging is

230 MEDICAL DECISION MAKING/MAY–JUN 2006

more likely to occur between adjacent stages on the

severity scale than between more widely separated stages. For example, a stage I patient is more likely to be misclassified as a stage 0 or stage II patient than as a stage III patient.

3.

Of

the number of patients presenting for RT after

their first lumpectomy or mastectomy, it is assumed that 0.1% may have some other disease other than cancer (stage X), 9.9% would have stage 0 cancer, 45% would have stage I cancer, 30% stage II cancer, 10% stage III cancer, and 5% stage IV cancer. Of the 5% with stage IV cancer, approximately 40% to 50% would have metastases to the bone, 3% to 10% would have metastases to the liver, and 5% to 20% would present with metastases to the chest (with the remainder with metastases to other sites). 3

4.

In

determining bone metastases, a physician may

use results from bone scan (S) and tests such as CA 15.3, CEA, and AP. In determining liver metastases, a physician may use LUS, AST/ALT, CEA, and GGT results. In determining chest metastases, a physi- cian may use chest X-rays or CT scans. CEA tests indicate metastases to a nonspecific site of the body.

5.

All stage 0 and stage I patients will receive 2-field

treatments, and all stage IV patients will receive pal- liative treatment.

6.

To

determine the type of treatment for stage II and

stage III patients, the number of positive lymph nodes

removed during surgery is important. Assuming that 10 or more nodes are removed (per typical guide- lines), patients with fewer than 4 removed positive nodes will be prescribed 2-field treatments, and

patients with 4 or more removed positive nodes will

be

prescribed 4-field treatments.

7.

Seventy percent of stage II patients and 20% of stage

III

patients will be prescribed 2-field treatments;

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UNCERTAINTIES IN RADIATION THERAPY DECISIONS

Table 1

Sensitivity and Specificity of Tests Used for Detection of Metastases in Breast Cancer Patients

Test

Sensitivity to Metastasis

Specificity to Metastasis

S 2428,43,44

LUS 27,2933,45,46

CXR 27,47,48

AST/ALT 27,33

GGT 27,30,35,49,50 AP 27,33,4951 CA 15.3 27,36,5258 CEA 27,36,53,55,57,58 TPA 55,56

Uniform (0.78, 1.00) Uniform (0.58, 0.93) Uniform (0.30, 0.75) Uniform (0.38, 0.53) Uniform (0.60, 1.00) Uniform (0.58, 0.80) Uniform (0.64, 0.92) Uniform (0.40, 0.77) Uniform (0.67, 0.74)

Uniform (0.56, 0.96) Uniform (0.78, 1.00) Uniform (0.86, 0.99) Uniform (0.26, 0.54) Uniform (0.65, 0.98) Uniform (0.39, 0.98) Uniform (0.87, 0.98) Uniform (0.95, 0.99) Uniform (0.79, 0.82)

AP, alkaline phosphate; AST/ALT, aspartate aminotransferase/alanine aminotransferase; S, bone scan; CA 15.3, carbohydrate antigen 15.3; CEA, carci- noembryonic antigen; CXR, chest X-rays; GGT, gamma glutamyl transferase; LUS, liver ultrasound; TPA, tissue polypeptide antigen.

30% of stage II patients and 80% of stage III patients will be prescribed 4-field treatments.

8. We did not attempt to quantify the benefit and harm of the treatment; rather, we simply assess the proba- bility of correct staging and treatment. A correct diag- nosis is assigned a utility of 1, whereas an incorrect diagnosis is assigned a utility of 0.

9. We consider the fact that not every postoperative patient is assessed for metastases. The presence of symptoms discovered during the physical examina- tion of the patient, the size of the tumor, and the number of positive lymph nodes preselect possible candidates for further screening for metastases. In this select group of patients, the prior probability of metastases is much higher than in the general cohort of postoperative patients presenting for RT. Based on expert opinion, we model this prior probability as a uniform distribution between 30% and 70%. This can be interpreted as between 30% and 70% of the patients in this select group will be actually diagnosed with some form of metastases. The stronger the prior evidence for metastases, the higher the prior probability of metastases.

Uncertain variables are represented using uniform distributions, which impose a minimal set of assump- tions regarding parameters and shape. 37 Table 1 pro- vides the sensitivity and specificity values for each diagnostic test used for the detection of distant metas- tases in this model. An influence diagram (e.g., Figure 3) is used to represent each decision context. The actual state of the patient, though uncertain, can be inferred from the results of diagnostic tests. A decision is then made as to whether there has been a spread of breast cancer cells to the site or organ in question. Presently, we do not evaluate the quality of life of the patient or other such “health quality” outcomes of an

DIAGNOSIS AND PATIENT SAFETY

incorrect diagnosis; we are only concerned with the

probability of an incorrect staging and treatment of the patient. Uncertainty associated with imperfect pathology reports is incorporated throughout modeling results,

as this uncertainty can affect all staging assessments.

A detailed sensitivity analysis is conducted to deter-

mine which inputs (Tables 2, 3) are associated with the most variation in the outcome of the assessment of metastasis (Table 4, Figure 4). Spearman’s rank correlation coefficient is used as a measure of the correlation relationship between the uncertain model input values and the measured output (the probability of correct staging). Value-of-information analysis provides decision makers with a tool for evaluating the relative “worth” of information sources. 38 The quantitative value of an information source (prospectively evaluated) is referred to as the expected value of information. In our analysis, the expected value of information is a metric by which we measure the expected improve- ment in the correctness of the staging process that may be directly attributed to the presence of improved information. To analyze the expected value of information, we need 2 baselines: the expected value of the decision context without any information and the expected value of the decision context with perfect informa- tion. Both are represented on scales of 0 to 1.0. An expected value of 0.5 can be interpreted to mean that only 50% of the patients will be correctly staged. A value of 1.0 means that all patients are correctly staged; that is, staging had 100% sensitivity and 100% specificity. The expected value of perfect infor- mation (EVPI) is calculated as the difference between the expected value of having perfect information

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LEE AND OTHERS

p(B) = Lognormal (0.05, 0.005)

Bone metastasis Bone AP Scans CA 15-3 CEA Metastases? Correctness (yes/no)
Bone
metastasis
Bone
AP
Scans
CA 15-3
CEA
Metastases?
Correctness
(yes/no)

p(S+|B) =

Uniform(0.78,0.98)

p(S-|~B) =

Uniform(0.56,0.96)

p(AP+|B) =

Uniform(0.58,0.94)

p(AP-|~B) =

Uniform(0.86,0.98)

p(CA+|B) =

Uniform(0.64,0.92)

p(CA-|~B) =

Uniform(0.87,0.99)

p(C+|B) =

Uniform(0.40,0.77)

p(C-|~B) =

Uniform(0.95,0.99)

M

B

Co

1

0

0

1

M+

B

M+

~B

M-

B

M-

~B

Conditional arc

Informational arc

Figure 3

present or absent, indicated with the symbol “~”; S, bone scans; CA, carbohydrate antigen 15.3 (CA 15.3); C, carcinoembryonic antigen (CEA); AP, alkaline phosphatase (AP); “+” positive test result and “-” negative test result. The results of the decision node may be M+, indicating a positive diagnosis for metastases, or M– for a negative diagnosis. The only value node represents “correctness.” A value of 1 is assigned to a correct staging and 0 to an incorrect staging. Note that node B represents the true state of the patients.

Influence diagram for the detection of metastases to the bone. There are 5 chance nodes: B, bone metastasis, which could be

Table 2

Simulation Results for Staging of Breast Cancer Patients

Physician’s Staging Decision

True Stage

of Cancer

Stage X

Stage 0

Stage I

Stage II

Stage III

Stage IV

Stage X

1.0000 ±± 0.0000

<1E-05

<1E-05

<1E-05

<1E-05

<1E-05

Stage 0

<1E-05

0.8935 ±± 0.0050 0.0880 ± 0.0053 0.0185 ± 0.0032

0.0080 ± 0.0010 0.9808 ±± 0.0015 0.0094 ± 0.0011 0.0009 ± 0.0004 0.0008 ± 0.0003

0.0010 ± 0.0005 0.0279 ± 0.0021 0.9471 ±± 0.0031 0.0117 ± 0.0017 0.0123 ± 0.0014

<1E-05

<1E-05

Stage I

<1E-05

0.0076 ± 0.0019 0.0481 ± 0.0045 0.8193 ±± 0.0066 0.1250 ± 0.0053

<1E-05

Stage II

<1E-05

<1E-05

Stage III

<1E-05

<1E-05

0.0190 ± 0.0070 0.9810 ±± 0.0070

Stage IV

<1E-05

<1E-05

and the expected value of having no information and is equal to 0.5. However, in reality, most tests are imperfect sources of information. The expected value of imperfect infor- mation (EVII) is calculated as the difference between the expected value of having the imperfect informa- tion and the expected value of having no informa- tion. The EVII cannot be greater than the EVPI and

232 MEDICAL DECISION MAKING/MAY–JUN 2006

cannot be less than 0. If an information source does not add any value to a state of having no information, its EVII is said to be 0.

RESULTS

The correctness of the staging procedure and RT technique prescription is reported in Tables 2 and 3.

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UNCERTAINTIES IN RADIATION THERAPY DECISIONS

Table 3

Simulation Results for Radiation Therapy (RT)

Treatment Technique for Breast Cancer Patients

Prescribed Treatment

Required Treatment

None

2-Field

4-Field

Palliative

None

2-field

4-field

Palliative

1.0000 ±± 0.0000

<1E-05

<1E-05

<1E-05

<1E-05

0.9834 ±± 0.0011 0.0149 ± 0.0011 0.0015 ± 0.0004

<1E-05

<1E-05

0.9226 ±± 0.0033 0.0774 ± 0.0033

<1E-05

<1E-05

0.0190 ± 0.0070 0.9810 ±± 0.0070

Inputs

spec_ap

spec_bs

sen_cea

spec_ca15

sen_ca15

sen_bs

spec_cea

sen_ap

prior prob. of bone mets

sen_bs spec_cea sen_ap prior prob. of bone mets 0.985 0.986 0.987 0.988 0.989 0.990 0.991 0.992
sen_bs spec_cea sen_ap prior prob. of bone mets 0.985 0.986 0.987 0.988 0.989 0.990 0.991 0.992
sen_bs spec_cea sen_ap prior prob. of bone mets 0.985 0.986 0.987 0.988 0.989 0.990 0.991 0.992
sen_bs spec_cea sen_ap prior prob. of bone mets 0.985 0.986 0.987 0.988 0.989 0.990 0.991 0.992
sen_bs spec_cea sen_ap prior prob. of bone mets 0.985 0.986 0.987 0.988 0.989 0.990 0.991 0.992
sen_bs spec_cea sen_ap prior prob. of bone mets 0.985 0.986 0.987 0.988 0.989 0.990 0.991 0.992
sen_bs spec_cea sen_ap prior prob. of bone mets 0.985 0.986 0.987 0.988 0.989 0.990 0.991 0.992
sen_bs spec_cea sen_ap prior prob. of bone mets 0.985 0.986 0.987 0.988 0.989 0.990 0.991 0.992

0.985

0.986

0.987

0.988

0.989

0.990

0.991

0.992

Expected value of the probability of a correct diagnosis

Figure 4 Tornado graph of 1-way sensitivity analyses of all model inputs on the expected value of the staging results. Spec_ap, speci- ficity of alkaline phosphatase (AP); spec_bs, specificity of bone scans; sen_cea, sensitivity of carcinoembryonic antigen (CEA); spec_ca15, specificity of carbohydrate antigen (CA 15.3); sen_ca15, sensitivity of CA 15.3; sen_bs, sensitivity of bone scans; spec_cea, specificity of CEA; sen_ap, sensitivity of AP.

The 95% confidence interval for the mean of each result is shown. For example, the probability that a patient will be staged as stage III when the patient is truly stage III is approximately 82% (Table 2), which implies that the probability the wrong stage will be assigned is 18%. The probability that a patient will receive 4-field treatment when 4-field treatment is truly required is approximately 92%, which implies that the probability that the wrong treatment will be prescribed is 8% (Table 3). We find the highest degree of correctness (aside from patients who are told they do not have cancer) with the 2-field prescription. This can partly be attrib- uted to the fact that a greater percentage of the patients seen after a surgical operation are stage 0 (1%) and stage I (45%) patients. If a patient is prescribed a

DIAGNOSIS AND PATIENT SAFETY

4-field treatment, this is largely because more than 4 positive lymph nodes were retrieved during surgery. Thus, the more likely error for patients prescribed 4-field treatment is that the cancer is truly metastatic (thus indicating palliative treatment) but has not yet been detected. The correctness of the treatment pre- scription for palliative patients is directly affected by the correctness of the process of screening for metasta- tic disease (stage IV cancer). According to the sensitivity analysis, the correct- ness of the assessment of metastatic bone cancer is very sensitive to the specificity of AP, the specificity of S/scintigraphy, the sensitivity of CEA, and the sensi- tivity and specificity of CA 15.3 tests. This implies that the relative degree of uncertainty associated with these tests is large. The spread of possible values for

233

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LEE AND OTHERS

Table 4

Sensitivity Analysis of the Process

of Detection of Distant Metastases in the Bone, Chest, and/or Liver

Rank

Variable

Rank Correlation

Coefficient

Bone metastases

1

Specificity of AP

0.462

2

Specificity of S

0.441

3

Sensitivity of CEA

0.412

4

Specificity of CA 15.3

0.310

5

Sensitivity of CA 15.3

0.290

6

Sensitivity of S

0.179

7

Specificity of CEA

0.168

8

Sensitivity of AP

0.109

9

Prior probability of bone metastases

–0.045

Chest metastases

1

Specificity of CXR

0.559

2

Sensitivity of CXR

0.425

3

Specificity of CEA

0.415

4

Prior probability of chest metastases

–0.322

5

Sensitivity of CEA

0.305

Liver metastases

1

Sensitivity of CEA

0.51

2

Specificity of LUS

0.424

3

Sensitivity of LUS

0.392

4

Specificity of GGT

0.366

5

Specificity of CEA

0.216

6

Prior probability of liver metastases

–0.126

7

Sensitivity of GGT

0.079

8

Specificity of AST

–0.066

9

Sensitivity of AST

0.021

AP, alkaline phosphate; AST, aspartate aminotransferase; S, bone scan; CA 15.3, carbohydrate antigen 15.3; CEA, carcinoembryonic antigen; CXR, chest X-rays; GGT, gamma glutamyl transferase; LUS, liver ultrasound.

the specificity of AP tests reported in literature (from 0.39 to 0.98; see Table 1) introduces the largest amount of uncertainty in the expected outcome (Figure 4). The

rank correlation coefficient reported for the variable is

0.462 and is the highest in that group of tests (Table 4).

It is closely followed by a value of 0.441 for the speci- ficity of S. The probability of correct staging, though consistently high for this battery of tests (between

0.985 and 0.992; see Figure 4), is most sensitive to the

specificity of AP and S. Hence, further research and meta-analysis may be desired to narrow the range of their values and subsequently reduce the uncertainty in the model output. Table 4 presents details of the sensitivity analysis for all 3 sites, which includes the rank or order of importance of the input variables, from the one contributing the most uncertainty (rank

234 MEDICAL DECISION MAKING/MAY–JUN 2006

Table 5

Value-of-Information Analysis

for the Process of Detecting Bone Metastases from Breast Cancer

Test Set

Expected

Value

s

EVPI

EVII

No information

0.5

0.5

Perfect information

1.0

0.0

0.5

S

0.825

0.380

0.325

S

+ CEA

0.846

0.361

0.346

S

+ CA 15.3

0.853

0.355

0.353

S

+ AP

0.825

0.380

0.325

S

+ CEA + CA 15.3

0.916

0.277

0.416

S

+ CEA + AP

0.868

0.338

0.368

S

+ CA 15.3 + AP

0.891

0.311

0.391

S

+ CEA + CA 15.3 + AP

0.921

0.269

0.421

AP, alkaline phosphate; S, bone scan; CA 15.3, carbohydrate antigen 15.3; CEA, carcinoembryonic antigen; EVPI, expected value of perfect infor- mation; EVII, expected value of imperfect information.

1) to the one contributing the least uncertainty, as well as the rank correlation coefficient. EVII is not conducted for stages 0 through III, as pathology is the sole source of information in making this determination. We consider EVII for tests used to determine a state of stage IV. We consider 4 test pro- cedures for the detection of bone metastases (Table 5). These are S/scintigraphy, CEA, CA15.3, and AP. S is always carried out to confirm metastases. Given a choice of 2 tests, a combination of CA15.3 and S is of the greatest value. The AP test appears to add little value to the S. A panel of 3 tests is preferred over a panel of 2 tests, as the expected value of information is greater for 3 tests than for 2. From our analysis, the “best” combination of 3 tests would be S, CEA, and CA15.3. A panel of 4 tests (S, CEA, CA15.3, AP) is the best choice, resulting in the highest EVII index. For liver metastases, using a panel of LUS, GGT, and CEA is as valuable as having a panel of LUS, AST/ALT, GGT, and CEA. This indicates that the AST/ALT test is of very little value even when in combination with all the other tests in this panel. This may be due to its very low sensitivity and specificity (Table 1). The LUS test is standard prac- tice for the detection of liver metastases, and thus it is included in all the test panels. Given the choice of only 2 tests in a panel, the best combination from our analysis would be LUS with CEA (Table 6). Thorax metastasis is not as common as bone and liver metastases. It is mainly diagnosed via chest X-rays/radiographs (CXR). CEA is a tumor marker that is not very specific to the site of metastases or the type of cancer, and thus it can alert physicians to the

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UNCERTAINTIES IN RADIATION THERAPY DECISIONS

Table 6

Value-of-Information Analysis

for the Process of Detecting Liver Metastases from Breast Cancer

Test Set

Expected

Value

s

EVPI

EVII

No information

0.5

0.5

Perfect information

1

0

0.5

0.5

LUS

0.8225

0.382

0.323

LUS + AST/ALT

0.8225

0.382

0.323

LUS + GGT

0.838

0.368

0.338

LUS + CEA

0.881

0.324

0.381

LUS + AST/ALT + GGT

0.843

0.364

0.343

LUS + AST/ALT + CEA

0.881

0.324

0.381

LUS + GGT + CEA

0.893

0.309

0.393

LUS + AST/ALT + GGT + CEA

0.893

0.309

0.393

AST/ALT, aspartate aminotransferase/alanine aminotransferase; S, bone scan; CEA, carcinoembryonic antigen; GGT, gamma glutamyl transferase; LUS, liver ultrasound; EVPI, expected value of perfect information; EVII, expected value of imperfect information.

possibility of metastases to the chest. A combination

of CXR and CEA yields a better value of information

than does CXR on its own (Table 7).

DISCUSSION

The fact that uncertainty exists and errors occa- sionally occur during complex health care processes

such as RT creates a need for rigorous risk analysis. This article describes a first step toward the quan- tification of risk in RT administration. We present

a mathematical model that helps decision makers

have a better understanding of the system. To our knowledge, this is the first attempt at modeling the cumulative effect of uncertainties associated with all the steps involved in staging breast cancer, as rele- vant to RT. This approach will be generalizable to many forms of medical treatment. Our analysis indicates that misstaging of cancer,

Table 7

Value-of-Information Analysis

for the Process of Detecting Chest Metastases from Breast Cancer

Test Set

Expected

Value

s

EVPI

EVII

No information

0.5

0.5

Perfect information

1

0

0.5

CXR

0.725

0.447

0.225

CXR + CEA

0.850

0.357

0.350

CEA, carcinoembryonic antigen; CXR, chest X-rays; EVPI, expected value of perfect information; EVII, expected value of imperfect information.

Moreover, the probability of correct staging is most sensitive to the specificity of AP and S. Hence, fur- ther research and meta-analysis may be desired to narrow the range of their values and subsequently reduce the uncertainty in the model output. This analysis, like all modeling exercises, has limitations. Medical practice involves some compo- nent of subjectivity that has not been captured in this model (e.g., we have assumed that the oncolo- gists follow a simple guideline in prescribing the RT technique to be used in treatment). Uncertainty, errors (which are action oriented), and variability in the model inputs should ideally be defined and addressed distinctly; for example, deviations in the pathology reports are analyzed as uncertainty distri- butions around the true staging results. We have not considered the different root causes of typographi- cal, training, and transcription errors as separate. The values shown in Tables 5, 6, and 7 are based on the properties of the individual tests, as shown in Table 1. In reality, several different panels of tumor markers and liver function tests may be used. For example, Nicolini and others 39,40 explore the use of a panel of CEA, CA 15.3, and tissue polypeptideantigen (TPA) for the detection of chest metastases, 39 liver metastases, 40 and bone metastases 39 from breast can- cer. They report sensitivities of 0.91, 0.80, and 0.82

although uncommon, may be associated with an

a

result of treatment). Errors may occur at the very

and specificities of 1.00, 1.00, and 0.96, respectively.

appreciable risk of harm. The potential adverse effects

A

further analysis of the literature and/or solicitation

range from “under-treatment” (i.e., the cancer may

of

expert opinion should ideally reduce the range of

not be effectively treated) to “over-treatment” (i.e., the patient may experience morbidity or mortality as

values for input variables displayed in Table 1. We have not evaluated impacts to patient quality of life or resource constraints. Obviously, the cost of

beginning of the treatment process and thus may be propagated throughout treatment. Information from sensitivity analyses and EVII analyses indicates that, for determination of bone metastasis, a panel of 4 tests (S, CEA, CA15.3, AP) is the best choice, resulting in the highest EVII index.

tests can be quite influential on adoption and ultimate “value.” Incorporation of temporal aspects (such as time-dependent course of disease) would also add realism to the analysis. There are subsequent activi- ties involved in treatment planning, patient prepara- tion, and actual treatment that we have not evaluated

DIAGNOSIS AND PATIENT SAFETY

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235

LEE AND OTHERS

to date. Like all models, this is a simplification of a complex system involving myriads of interactions and information transfer between the system and its environment. We have initially focused on aspects of the system that seem to contribute the most risk to the outcome of the staging process and subsequent treat- ment decisions. Continuing work will evaluate many of the considerations above. The probability of misstaging and the RT tech- nique prescription can be used as performance met- rics to evaluate system behavior when parameters are changed. For example, a physician or adminis- trator could study the following:

1. The effect of improving the correctness of the pathol- ogy review process by introducing measures such as mandatory peer review of all pathology reports, spe- cialized training of pathologists for specific anatom- ical regions and diseases, and so on

2. The effect of using more sensitive diagnostic tests such as positron emission tomography (PET) scans, CT scans, and MRIs for the detection of metastatic disease

3. The effect of different panels of biochemical tests for the detection of disease

Future changes in practice guidelines could be informed by carrying out value-of-information analy- sis. Introduction of resource constraints would allow consideration of tradeoffs between increased confi- dence in correctness of treatment decisions and lim- ited financial resources. The methods used in this analysis have not been routinely used in health care scenarios but may have utility in a wide variety of issues, especially in the field of patient safety. Our further work involves determination of metrics for quantifying the severity of each type of error, the benefits of treatment, and the costs of diagnosis, staging, and treatment. This is required for multiattribute utility 41 and optimization 42 modeling, which will allow us to compare different approaches for improving patient safety and increas- ing health benefit during RT administration consider- ing resource and other constraints.

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