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January 15, 2007

Predicting Recurrence
By Beth W. Orenstein
Radiology Today
Vol. 8 No. 1 P. 20

Researchers at Tufts-New England Medical Center are seeking a mathematical model to assess which women are likely to have their cancer return in an effort to safely spare some unnecessary radiation therapy.

Some women with early-stage breast cancer may only minimally benefit from radiation therapy, yet choosing who those patients are is clinically very difficult. Researchers at Tufts-New England Medical Center in Boston are working on a computer tool that may help solve this dilemma. The tool in development uses risk factors associated with breast cancer recurring in the same breast after breast-conserving surgery (BCS) to predict the likelihood of that happening.

Mona Sanghani, MD, lead author of the abstract, presented this work at the 48th annual meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO) in Philadelphia in November 2006. Their paper was titled “Predicting the Risk of Local Recurrence in Patients With Breast Cancer: An Approach to a New Computer Based Predictive Tool.”

“There are some patients who are at extremely low risk of the cancer coming back,” Sanghani says. “This might help identify who those patients are.”

Sanghani adds that when discussing treatment options with patients, physicians may feel more comfortable if they have such a tool. Also, the tool could help patients decide their course of treatment. “Maybe looking at more concrete numbers might help them decide one way or another,” she says.

Even though the tool may be available online, Sanghani says, it is not intended for patients to make a decision on their own, but for them to use it when discussing the benefits of radiation treatment with their physicians.

According to the American Cancer Society, breast cancer is the most common type of cancer in American women. Every year, more than 210,000 women and 1,700 men are newly diagnosed with breast cancer.

If caught early, breast cancer can often be cured; approximately 80% of patients with breast cancer remain free of the disease 10 years after being diagnosed. Thanks to public education and proactive screening programs, small tumors are being found earlier in a greater percentage of women.

Breast cancers are considered early stage—stages 1 and 2—if they are not fixed to the skin or muscle. Also, if lymph nodes are involved, the nodes are not fixed to each other or to underlying structures.

Current Options
If the cancer is in its early stages when discovered, the current standard treatments are mastectomy or BCS followed by radiation therapy to kill any remaining cancer cells. External beam radiation therapy involves six to eight weeks of daily treatment. BCS is regarded as preferable to mastectomy and axillary dissection in most cases because studies have shown that survival rates are equivalent and BCS preserves the breast.

Standard breast-conservation therapy includes radiation therapy (typically external beam radiation, but sometimes brachytherapy procedures are used to shorten the radiation treatment) because studies have shown a higher recurrence rate in women who do not receive radiation. The Tufts studies compared randomized trials of women who had BCS with radiation therapy with randomized trials of women who had BCS without radiation therapy.

Radiation therapy has side effects. While most are manageable, Sanghani says, side effects can include fatigue, which often increases as the treatments progress. Also, changes and burns can occur in the breast skin and occasionally, and the breast can change color or size or can become permanently firm. Radiation therapy also increases the woman’s risk of developing other cancers, such as soft tissue malignancies known as sarcomas. Sanghani says probably the biggest drawback of radiation therapy is that it is a significant investment of time for the patient.

Still, Sanghani adds, the researchers were not as concerned about avoiding the side effects of radiation, or the time for treatment, as they were about having women undergo the treatment when they would not necessarily benefit from it.

“We found that in speaking with people in the oncology community about it, it seems that patients are really walking the fine line as to attribution, whether or not they will get significant benefit from radiation therapy,” Sanghani says. “The benefit does vary from person to person. So I think the tool will be most useful when you are looking at patients who are uncertain as to whether or not they want radiation and may be looking for data to back their choices.”

Researchers developed the formula by looking at the following seven risk factors associated with recurrence in the same breast after BCS:

• patient age;

• margin status;

• lymphovascular invasion (LVI);

• tumor size;

• tumor grade;

• use of chemotherapy; and

• use of the drug tamoxifen.

Finding Key Variables
To study the risk factors, researchers reviewed all available randomized trials of BCS alone vs. BCS plus radiation therapy. They also reviewed meta-analyses and institutional reports. “We preferred to use randomized trials in breast-conserving therapy. However, we did include single institutions and retrospective trials if we felt like they added value to our knowledge,” Sanghani says.

The studies had been published in the last 10 to 15 years, she says, and they had, on average, eight to 10 studies for each risk factor.

In the model, patient age groups are under the age of 40, then five-year increments up to the age of 70, and then age 70 and older. Margin status is: positive, 0 to 2 millimeters or greater than 2 millimeters. LVI is yes or no. Tumor size is less than 1 centimeter or greater than 1 centimeter. Tumor grade is low, intermediate, or high. Use of chemotherapy and use of tamoxifen is also yes or no.

Each risk factor was given a weight—the higher its importance in predicting recurrence, the higher it was weighted. “Then we combined all the risk factors in a mathematical model that we could use to predict the rate of recurrence for each patient,” Sanghani says. When the patient’s data is entered into the model, it predicts the likelihood of local recurrence within nine years.

For example, if a 48-year-old woman with a 1.8 centimeter, grade 2 tumor, with no LVI, margin status of 1 millimeter, who had chemotherapy and was taking tamoxifen and had radiation therapy, the model predicted a 7% chance of local recurrence with radiation therapy and a 36% chance without it. In that case, she would meet the benefit requirements. A second case is of a 75-year-old woman with a tumor size of 0.4 millimeters, grade 1 tumor, no LVI, margin status of 2 millimeters, no chemotherapy and no tamoxifen; the model predicted a local recurrence rate of 2% with radiation therapy and 8% without. That may be a case where the woman would not see a significant enough benefit to warrant undergoing radiation therapy.

Defining Additional Benefit
Sanghani says radiation oncologists like to see at least a 10% benefit from the therapy. “If the patient is only going to see a 2% to 3% benefit, it may not be an important treatment, and she may wish to consider not having it,” she says.

The next step is to validate the study. “Now that we developed the model, it must be validated by independent clinical data. Only then can it be widely used,” Sanghani says.
Carol L. Kornmehl, MD, FACRO, is a board-certified radiation oncologist at Passaic (N.J.) Beth Israel Regional Medical Center and author of The Best News About Radiation Therapy: How to Cope and Survive. She is also a clinical assistant professor of radiation oncology at Hahnemann University Hospital in Philadelphia.

Kornmehl believes that once the model is validated, it will become a valuable tool to radiation oncologists and their breast cancer patients.

“Once there is enough data—tens of thousands of women on the study—then we can have a comfort level with the tool,” she says. “Until then, I think it would be premature to recommend not following BCS with radiation therapy.”

Kornmehl expects it will take at least five to 10 years for the data to be acquired and of value. If cancer recurs in the same breast, it usually does so in two to three years, “but there can be recurrences after that,” she says.

Because of that possibility, Kornmehl would like to see the data for five years and beyond. “If you have 10,000 women who are disease-free for a year, that doesn’t mean anything; but if they are disease-free for 10 years, you would feel more comfortable recommending they might not want to undergo radiation therapy because the data would support that decision.

“I think I would feel comfortable saying to a patient, ‘We have 10-year data that suggests your risk factors are X, Y, and Z, and so the computer model shows chances of local recurrence without radiation therapy [are] slim, and you might consider not having it,’” she says.

Meanwhile, she says, she would not be comfortable recommending against follow-up radiation therapy. “I think the greatest risk is not taking one. Clearly, doing radiation is not a free lunch. It puts women at risk for other cancers later on, and there are other side effects. Also, it is inconvenient.” However, the data that is currently available shows it is still the best course of treatment, Kornmehl says.

If the computer model proves that it can clearly identify the subset of women who are not likely to benefit from radiation therapy, then it could change standard practice, Kornmehl adds.

— Beth W. Orenstein is a freelance health writer and a regular contributor to Radiology Today. She writes from her home in Northampton, Pa.