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Doc, Shouldn’t We Be Getting Some Tests?

From the Mayo Clinic, Rochester, MN; Georgetown University Medical Center, Washington, DC; and Massey Cancer Center, Richmond, VA.

Address reprint requests to Charles L. Loprinzi, MD, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; email cloprinzi{at}mayo.edu

HERE’S THE CASE: Mrs. Smith presents herself to a medical oncologist. She had been treated by oncology colleagues down the street (whose clinical abilities are respected). Having presented in the recent past with node-positive, hormone receptor–negative breast cancer, she subsequently completed all planned antitumor therapy, including breast-conserving surgery, adjuvant doxorubicin/cyclophosphamide chemotherapy for four cycles, adjuvant paclitaxel chemotherapy for four cycles, and primary breast radiation therapy.

She transferred her care to the present oncologist because she was concerned that her prior oncologist, although performing what she thought were detailed histories and physical examinations and recommending yearly mammograms, wasn’t recommending any other follow-up surveillance tests. She knew she still had an appreciable risk of cancer recurrence, and she knew other women from her support group who were getting regular follow-up tests, including chest x-rays and serum marker tests.

Which of the following two options should this oncologist choose?

1. Initiate follow-up to include regular chest x-rays, liver function tests, and serum marker tests.

2. Explain American Society of Clinical Oncology (ASCO) guidelines for why her initial oncologist was correct, despite what other members of her support group were receiving (including, maybe, giving the patient a copy of this article or the new patient version of the guidelines, available at http://www.asco.org).

The first of the above two choices is certainly the most expedient thing to do in terms of initially satisfying the patient while utilizing the least amount of patient contact time. This presentation, to no surprise to the reader now, will argue that the latter choice is more appropriate and should lead to better patient care.

RECURRING CONSULTATION

To further introduce this discussion, let’s go to another clinical scenario. This one represents a recurring phone call to breast cancer physician specialists. "Doctor, I have a patient with a previously resected and curatively treated breast cancer (a variety of details are here presented regarding stage, primary therapy, and administered adjuvant therapy). I have been observing this woman for (variable follow-up periods here provided, ranging from months to years). She has been feeling well and has always had normal examinations and yearly mammograms. Nonetheless, her follow-up has included serial chest x-rays, liver function tests, blood counts, and tumor markers assessments. Over the past few months, the tumor marker (eg, carcinoembryonic antigen, CA 15–3, or CA 27–29) has increased to (variable amounts ranging from 1.5 to 10 times the upper limit of normal). In response, I have completed a thorough workup (usually a several thousand dollar evaluation spanning a period of weeks to months). My workup has been completely negative and my patient is now very anxious. What should I now do?"

Although some may argue with the style, one response to this question is to ask several leading questions (being nice enough, however, to help with the answers to the queries):

Are There Data Available to Demonstrate That Surveillance Tests Such as Tumor Markers and X-Rays Can Improve the Quality of Life of Such Patients?
No. In fact, available data could be used to support the opposite viewpoint: such surveillance tests might negatively influence quality of life.^1-8

How Is It That Follow-Up Surveillance Tests Might Negatively Influence Quality of Life?
Although it is often claimed that follow-up surveillance tests can be reassuring for patients, and this may be true if all of the tests are completely normal every time, is it reassuring for a patient to hear that "the liver test is a little elevated (a couple points above the upper normal limit) and this probably does not mean that you have recurrent breast cancer, but we’ll just recheck it in a couple of months to make sure it isn’t going up and more strongly indicate that it might be from breast cancer and (2 months later when it is two points higher) we’ll check a computed tomography (CT) scan next week... "? Do any of us even remotely think that this scenario, which is not an uncommon one, reassures a patient during these waiting times?

Are There Data to Suggest That Obtaining Surveillance Tests—Other Than History, Examination, and Mammograms—Can Improve Survival in Such Patients?
No. In reality, two well-conducted randomized trials reported a lack of any suggestion of benefit for liver function tests, chest x-rays, and liver imaging.^5,6 Admittedly, there are not randomized data to address the value of specific serum tumor markers in this situation, but the available uncontrolled data do not suggest that tumor markers would lead to survival benefit in patients with curatively treated primary breast cancer.^9-11

Does the Use of These Tests Seem to Be a Way to Reduce the Cost of Care of Such Patients?
No. It most certainly increases costs.

Do Patients Want Follow-Up Tests?
If you ask patients whether they would like to get tests to detect whether their breast cancer is reoccurring, most patients may reply in the affirmative.⁶ This is at least in part because well-meaning health care providers have told the patient that they should undergo frequent testing to detect early recurrences. This seems to be because of a number of false assumptions that many people have, including the following:

The American Cancer Society recommends such frequent follow-up tests. (The truth is that the American Cancer Society recommends evaluation for early detection of primary curable cancers, not tests to detect recurrent widely metastatic disease.)

If we catch recurrent cancer early, we can cure it. Although this is true for recurrent localized disease, it does not seem to be true for established metastatic disease.

Given this, the more appropriate question to now ask is: Will patients want follow-up surveillance tests if they understand that the presently available data fail to suggest that they improve survival or quality of life? The following two examples provide some indication as to how informed patients respond to truthful information about getting follow-up surveillance tests. The reader is first referred to an eloquently written letter by a breast cancer survivor, entitled "To Test or Not to Test: Where is the Truth?"¹²

A second example is provided by explaining an event that occurred in 1995. One of the authors (C.L.L.) had the opportunity to present information regarding follow-up surveillance testing in breast cancer survivors to a group of approximately 100 breast cancer survivors and their families/friends. Before this presentation, and again just after it, the audience was asked the following question: "In the follow-up of curatively treated breast cancer survivors, how important are follow-up tests such as chest x-rays and blood tests?" Responses to this question are listed in Table 1. In concluding this presentation, the audience was asked to help the presenter understand what they thought physicians should do with the information that had just been presented. Was it best to be honest with patients, telling them that the experts believe that the follow-up tests were not helpful (and admitting, if asked, that picking up widely metastatic disease a few weeks to months early did not allow such patients to be cured or to improve their quality of life), or was it best to not admit such, get the follow-up surveillance tests, and reassure patients when they were all normal? When the audience was asked for a show of hands regarding this question, the former response received what looked like a unanimous affirmation. When the audience was then asked if there were any in attendance who felt otherwise, the presenter detected two hands which meekly signaled, in a clandestine manner, that they felt physicians should get the tests anyway. When it was then announced to the audience that there were a couple of people who felt that physicians shouldn’t be so honest, there was an instantaneous and resounding response from three different sections of the audience: "No, you can’t be deceiving!" "You’ve got to be honest!" "Tell us the truth!" This convinced the presenter that the vast majority of informed patients can understand the limits of follow-up testing.

What About Patients With Higher Recurrence Risks?
There are scant data that support that medical oncologists are more likely to change their practices and recommend against follow-up surveillance tests for low-risk women (eg, small node-negative breast cancers) than they are for patients with higher-risk disease (eg, a large cancer with 10 to 15 positive lymph nodes).¹³ Are there reasons to support this? Maybe there are, but they are not valid enough to make the ASCO guidelines differentiate between high- and low-risk patients. Although it is true that there may be a greater chance of detecting recurrent disease on follow-up surveillance testing with higher-risk patients,¹⁴ there still is not any strong suggestion that follow-up surveillance testing in asymptomatic high-risk patients will improve survival and/or quality of life. In fact, treatment options are fewer in this situation, as opposed to early-stage disease, because more advanced-stage disease patients, in general, are already treated aggressively in the adjuvant therapy setting.

Do "Tests Beget Tests"?
Yes. Clinicians well know that "normal" test results are the results seen in "most" healthy people, but that there are many healthy people who have tests findings that are outside of the normal range. Along this line, the more tests that are obtained in a normal healthy person, the more likely it is that one or more of the tests will fall outside of the normal range. The following scenario illustrates this point.

A 60-year-old breast cancer survivor comes in for routine follow-up with a chest x-ray and liver function tests. The chest x-ray notes questionable sclerosis in the fifth thoracic vertebrae, and the AST and alkaline phosphatase are both approximately 5% above the upper limit of normal. On the basis of these tests, a bone scan and CT scan are ordered. The bone scan is normal except for some uptake in the fourth lumbar vertebrae (radiology report reading: "probably degenerative joint disease but cannot rule out metastatic disease; x-ray recommended if clinically indicated"). The CT scan shows changes consistent with mild fatty infiltration but also a questionably enlarged area around the head of the pancreas that could be a pancreatic mass or an enlarged lymph node ("ultrasound is recommended for further evaluation, if clinically indicated"). Upon reviewing the results with the patient, both tests are now "clinically indicated," because the patient, her spouse, and her lawyer son are now very anxious about the report and the oncologist is worried about liability. The follow-up lumbosacral spine x-rays show classic degenerative joint disease changes, and the abdominal ultrasound is totally normal. In the end (after 2 weeks time, thousands of spent dollars, multiple office visits requiring multiple workday absences, and many "stress units"), the patient is given partial reassurance that there is not any clear-cut proof of recurrent cancer and that, for the degenerative joint disease and the fatty liver infiltration, she ought to try to lose a few pounds (a recommendation that would have been reasonable after the initial history/examination on day 1, as she was 50 pounds overweight anyway).

Are Physicians Legally Liable If They Don’t Get Tests When Their Colleagues Do?
It is reasonable to argue that the answer to this is no. Past concern regarding this issue was understandable a decade or so ago, when obtaining multiple frequent surveillance tests was more of the national norm. However, the ASCO guidelines, and the vast literature supporting ASCO’s recommendations, should now be considered standard of care.

Do the Above Arguments Substantiate That Oncologists Should Not Perform Follow-Up for Breast Cancer Survivors or That Breast Cancer Survivors Do Not Develop Recurrent Cancers That Are Still Curable?
No. It is important to know that breast cancer recurrences in an irradiated breast, or new contralateral primary breast cancers, are curable, especially if they are caught early. Thus focusing in on this area, including yearly mammograms, are important. In addition, evaluation of new symptoms and evaluating psychosocial and other health concerns are in order.

Are Patients Always Getting the Appropriate Tests Done?
No. Among Blue Cross-Blue Shield enrollees with breast cancer, nearly 20% had not had a repeat mammogram performed in the subsequent 2 years.¹⁵ In this group, approximately 24% and 14% were getting routine bone or CT scans. We would argue that the best use of resources is to ensure that all breast cancer survivors be taught signs or symptoms of recurrence, do breast self-examination, and get mammograms.¹⁰

Are Oncologists Changing and Ordering Fewer Surveillance Tests in This Situation?
It may be that things are slowly changing toward decreasing inappropriate surveillance testing.^13,16 ASCO guidelines and decreased testing requirements in National Cancer Institute–sponsored national adjuvant treatment trials are providing leadership in this area. To date, however, the impact of ASCO guidelines on oncology practice patterns has not been well delineated.

Is There Patient-Friendly Information Available for Patients?
Yes. In addition to ASCO’s publication entitled "A Patient’s Guide: Follow-up Care for Breast Cancer" (available at www.asco.org), some institutions have developed their own brochures, and other things that can be provided to patients include this article and the previously described patient letter.¹²

How About the Answer to the Phone Caller’s Question About What to Do in the Case of an Elevated Tumor Marker and an Otherwise Normal Workup?
In this situation, it is recommended that the referring physician be told the same thing that should be told to patients who present to us after such a scenario. We recommend telling them that this elevated tumor marker means that there is a risk that clinical evidence of recurrent breast cancer will become apparent in the months or years to come. It is then noted that the same statement would have been true for a similar patient who had a normal tumor marker level. Being honest, it is reasonable to note that the risk of recurrence is higher in the patient with the elevated tumor marker than in someone with a normal marker, but this should not generally affect follow-up clinical strategies for the two patient scenarios. Both patients should be followed-up by history, examination, and yearly mammograms, and worrisome symptoms and/or signs should be appropriately evaluated.

Lastly, it is important to stress to patients that not performing blood tests is not therapeutic nihilism. There simply are not blood tests shown to improve quality or quantity of life. It is important to make sure those things that work—mammograms, good preventive care, and healthy lifestyle, including diet and exercise—are performed regularly.

REFERENCES

1. Gulliford T, Opomu M, Wilson E, et al: Popularity of less frequent follow-up for breast cancer in randomised study: Initial findings from the hotline study. Br Med J 314:174-177, 1997[Abstract/Free Full Text]

2. Grunfeld E, Yudkin P, Adewuyl-Dalton R, et al: Follow-up in breast cancer: Quality of life unaffected by general practice follow-up. Br Med J 311:54, 1995 (letter)[Free Full Text]

3. Dewar J: Follow-up in breast cancer. Br Med J 310:685-686, 1995[Free Full Text]

4. ASCO Breast Cancer Surveillance Expert Panel: Recommended breast cancer surveillance guidelines. J Clin Oncol 15:2149-2156, 1997[Abstract/Free Full Text]

5. Rosselli Del Turco M, Palli D, Cariddi A, et al: Intensive diagnostic follow-up after treatment of primary breast cancer. JAMA 271:1593-1597, 1994[Abstract/Free Full Text]

6. GIVIO Investigators: Impact of follow-up testing on survival and health-related quality of life in breast cancer patients: A multicenter randomized controlled trial. JAMA 271:1587-1592, 1994[Abstract/Free Full Text]

7. Crivellari D, Price KN, Hagen M, et al: Routine tests during follow-up of patients after primary treatment for operable breast cancer. Ann Oncol 6:769-76, 1995[Abstract/Free Full Text]

8. Liberati A: Follow-up in breast cancer: A model case for controlled evaluation of complex interventions. Ann Oncol 6:747-750, 1995 (editorial)[Free Full Text]

9. Smith TJ, Davidson NE, Schapira DV, et al: American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines. J Clin Oncol 17:1080-1082, 1999[Abstract/Free Full Text]

10. American Society of Clinical Oncology: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer: Adopted on May 17, 1996, by the American Society of Clinical Oncology. J Clin Oncol 14:2843-2877, 1996[Abstract/Free Full Text]

11. American Society of Clinical Oncology: 1997 update of recommendations for the use of tumor markers in breast and colorectal cancer: Adopted on November 7, 1997, by the American Society of Clinical Oncology. J Clin Oncol 16:793-795, 1998[Abstract]

12. Gilseth M: To test or not to test: Where is the truth? J Clin Oncol 14:1406-1407, 1996[Free Full Text]

13. Loprinzi CL, Johnston PB, Sloan JA, et al: Have medical oncologists recently modified surveillance testing patterns for melanoma and/or breast cancer survivors? Cancer Res Ther Control 9:205-214, 1999

14. Hayes DF: Evaluation of patients after primary therapy, in Harris JR (ed): Diseases of the Breast (ed 2). Philadelphia, PA,Lippincott Williams & Wilkins, 2000

15. Hillner BE, McDonald MK, Penberthy L, et al: Measuring standards of care for early breast cancer in an insured population. J Clin Oncol 15:1401-1408, 1997[Abstract]

16. Tomiak EM, Diverty B, Verma SH, et al: Follow-up practices for patients with early stage breast cancer: A survey of Canadian oncologists. Cancer Prev Control 2:63-71, 1998[Medline]

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