The Possibility to Predict

The role of post-mastectomy radiation therapy (PMRT) in the management of breast cancer was controversial when it was introduced more than 50 years ago. And, a half-century later, this practice continues to stymie cancer experts.

Nevertheless, a large number of studies and trials have demonstrated that PMRT results in a consistent relative risk reduction in local-regional recurrence (LRR) – somewhere between a two-thirds and three-quarters reduction – after surgery. Naturally, the absolute benefit depends on the relative risk of an LRR, which is greatest in those patients at higher risk for LRR.

What has remained central to the controversy is the issue of survival benefit, as many early trials failed to indicate any.

But, international researchers have now developed a model that helps physicians to determine the recurrence of cancer probability in high-risk cancer patients who have undergone both a mastectomy and subsequent radiation therapy.

The study, entitled “Prognostic Index Score and Clinical Prediction Model of Local Regional Recurrence after Mastectomy in Breast Cancer Patients,” was published recently in the International Journal of Radiation Oncology, Biology, Physics.

An Ongoing Debate

“The issue of women as candidates for post-mastectomy radiation therapy has been debated for over 50 years,” says breast surgeon Nancy Elliott, MD, the founder of the Montclair Breast Center in N.J., and an expert in the field of breast disease evaluation and treatment. “I didn’t think there could be another article written on this topic.”

The study was a joint effort that brought together physicians from Taiwan and the United States. Their goal: to develop a clinical prediction model superior to the current benchmark – which is a combination of tumor size and the effect on lymph nodes – for the recurrence of breast cancer in patients who have had a breast removed and undergone radiation therapy.

In the process of assessing the probability of a patient’s cancer returning, the prediction model takes into account five risk factors:

• Status of the lymph nodes near the armpit
• Level of success in the patient’s acceptance of estrogen boosts
• Number of lymph nodes that are affected
• Patient’s age at diagnosis
• Primary tumor size

As a result, the research team found that the prognostic score and predictive index are helpful in the estimation and prediction of recurrence in breast cancer patients after mastectomy. In addition, they discovered that they’re also effective for evaluating the probable benefits of radiation therapy.

The evaluation of these factors would then allow physicians to determine which of three categories of risk of the cancer returning each patient would fall into: high-risk, intermediate-risk or low-risk.

For patients with a high risk of the cancer returning, a course of radiation therapy to keep the cancer at bay would be mandatory. For those in the low-risk category, forgoing the additional treatment would be a safe option. And for patients in the intermediate category, the decision of whether or not to continue radiation therapy would be made after a consideration of all other factors.

“The prediction model is important,” says Skye Hongiun Cheng, MD, a radiation oncologist at Koo Foundation Sun Yat-Sen Cancer Center in Taipei, Taiwan, and the lead author of the study, “because identifying the higher-risk patients sooner will allow physicians to more aggressively treat those cancers in the hopes of giving patients a higher chance for a cure.”

The purpose of the study was to develop clinical production models for local, regional recurrence of breast carcinoma following mastectomy. And the researchers anticipated that it would be more reliable than conventional measures.

“Our current research,” says Cheng, “tries to combine clinical data together with genomic information to generate a more robust prediction of local-regional recurrence at the individual patient level. And initial findings are promising. I just hope that these observations can be validated soon.”

The database consulted in the training and testing of clinical prognostic and prediction models of LRR was formed from the collection of clinical information from 1,143 patients who had undergone modified radical mastectomy as initial treatment for newly diagnosed invasive breast cancer. All patients had received breast cancer treatment at the Koo Foundation’s Sun-Yat Sen Cancer Center between April 1999 and December 2001.

Further, with these models, patients can be divided into low-, intermediate- and high-risk groups on the basis of axillary nodal status, estrogen receptor (ER) status, lymphovascular invasion (LVI) and age at diagnosis.

“The typical factors of primary tumor size greater than or equal to 5 cm or more positive nodes is fairly clear-cut,” explains Elliott. “In the presence of one to three positive axillary lymph nodes, the use of post-mastectomy radiation therapy requires the consideration of other risk factors.”

In the low-risk group, there is no influence of PMRT on either LRR or survival.

Demystifying PMRT

“What the model predicts,” says Cheng, “is that low-risk patients would obtain no benefit from PMRT. Approximately 50 percent of all mastectomy patients could be spared radiotherapy. However, in the subgroup of low-risk patients 38 years old or younger with ER negative and prominent LVI, the risk of local-regional recurrence is about 29 percent. In that case, PMRT would benefit the patient not only in local-regional control, but also in overall survival.”

For intermediate-risk patients, PMRT improves local-regional control but not metastasis-free or overall survival. According to Cheng, intermediate-risk patients would benefit from PMRT “only in local-regional control, but not in overall survival.” However, Cheng cautions that this estimation of benefit is, of course, relative rather than absolute.

“In general, “ he says, “the decision to undergo PMRT for intermediate-risk patients should be individualized. The risk of recurrence ranges from 11 percent to 28 percent. A patient with a risk of approximately 11 percent tends, in general, not to opt for PMRT. But this should be a joint decision between [the] physician and [the breast cancer] patient.”

In contrast, for high-risk patients, PMRT improves both LRR control and metastasis-free and overall survival.

According to Cheng, “This prediction model suggests that high-risk patients undergoing PMRT would improve not only local-regional control, but also overall survival. The improvement of survival by PMRT is associated with the risk estimation of local-regional recurrence. Concordant with the results from meta-analysis in the literature, a patient with a higher risk of local-regional recurrence is more likely to benefit from PMRT.”

Further, Cheng says, “According to our model, factors associated with local-regional recurrence are axillary lymph node involvement, age, ER status, LVI and primary tumor size. In general, patients with node-positive equal to or greater than four would be classified as ‘high-risk.’ However, in this subgroup of patients age 40 or older with estrogen receptor status strongly positive, the risk of local-regional recurrence is about 22 percent.”

Cheng says, according to his model, this risk estimation is moderate. But whether or not the breast cancer patients choose to undergo radiotherapy would depend on their comprehension of the risk.
“In high-risk patients,” Elliott says, “it may be easy to use this model to explain in simplistic terms to a patient why there is a need for post-mastectomy radiation therapy.”

For instance, Elliott says, “In a young patient with one positive node, lympho-vascular invasion and whose tumor is ER negative, you could clearly show her that, since her score is ‘4’ according to this model, the high-risk-category, post-mastectomy radiation therapy would decrease her chance of a local recurrence and also increase her chance of recurrence-free and metastases-free survival.”

Picking Patients

In general, patients are selected for PMRT – and these trials – based on nodal involvement. This term is traditionally grouped as one to three nodes involved or at least four positive nodes. However, an increasing number of involved lymph nodes usually correlate with both the risk of systemic spread and LRR.

“In the study,” adds Elliott, “they found that the most important factors were age (over the age of 40), estrogen receptor status (positive or negative), lympho-vascular invasion (presence or absence) and the presence of positive lymph nodes (one to three). Each factor was given a numerical value of ‘1.’”

Further, Elliott says, “the presence of four to nine lymph nodes was assigned a value of ‘2,’ and those greater than nine were given a value of ‘3.’ When the entire factor values were added, the three risk categories emerged: the low-risk patient’s prognostic score was 0-1, the intermediate-risk score was 2-3, and high-risk score was 4-6.” Interestingly, low-risk patients obtained no benefit from post-mastectomy radiation, whereas patients at high risk experienced both decreased LRR and improved survival.

Elliott sees this as confirming what medical experts already acknowledge. “The authors of the study state that the prognostic score might lead to improved guidelines for selection of patients for post-mastectomy radiation therapy. I don’t find anything new here.”

An expert American Society of Clinical Oncology panel concluded that, although considerable evidence pointed to increased local control in both nodal groupings, the evidence of improvement in disease-free survival and overall survival was more consistent with the group with four or more nodes involved, as opposed to the one-to three-node-positive group.

Moreover, the panel believes that the evidence was “insufficient to make recommendations for the routine use of PMRT in patients with one to three positive nodes.”       

Further, the panel also investigated the influence of other tumor-related characteristics, such as grade, ER status, LVI and primary size, in addition to patient-related factors, such as age and menopausal status. Its conclusions: that evidence, once again, was insufficient to demonstrate just how these characteristics should factor into a decision of whether or not to use PMRT, and that further investigation in this area was strongly recommended.

What experts do know is that a prognostic score and a predictive index for LRR do now exist, and they are based on easily obtainable clinical information. In addition, they seem to provide more information regarding the risk of LRR than one would find by simply dividing patients according to the primary size of the tumor and the number of lymph nodes involved.

This combination of prognostic score and predictive index might lead to improved guidelines in the selection of patients for PMRT, although the confirmation of these results remains highly desirable.

In addition, the ultimate decision of whether or not to undergo PMRT continues to lie with the patient. And it still relates to both the level of risk that the patient finds acceptable and the amount of treatment that he/she is willing to undertake in exchange for a small survival benefit.

According to Elliott, “Modern radiation oncologists are going to look at all the risk factors that are involved in local-regional recurrence, including tumor size and margin width, and will discuss the option of post-mastectomy radiation therapy with their patients even if the prognostic score is low.”

“Ultimately,” concurs Cheng, “patients should always participate in the treatment decision. Not only because the prediction model cannot be 100 percent correct, but also because each patient has [his or her] own tolerance for the risk estimation. In clinical practice, I have met patients with zero tolerance for it. Even the treatment brings in only 1 to 2 percent benefit. Some want to have all.”

Elliott sums it up by saying, “Together, [the] patient and doctor will decide whether the benefits of radiation outweigh the risk involved. And multidisciplinary conferences help with this decision.”
   

— Bill Wine is a freelance writer based in Pennsylvania. Questions and comments can be directed to editorial@rt-image.com.