What Does It Take To Make It Into Oncology Treatment Guidelines?

Standard oncology treatment guidelines such as the ones published by the the National Comprehensive Cancer Network (NCCN) are extremely influential in the decisions made by oncologists all over the country and even the world at the patient level every day. And the work that goes into these treatment guidelines is not taken lightly.

So what kind of evidence does it take for those behind the guidelines to recommend a treatment as front-line therapy?

Recently, the NCCN updated its guidelines for the treatment of multiple myeloma. In doing so they moved Revlimid (lenalidomide) as maintenance therapy following an autologous stem cell transplant from a category 2A recommendation to a category 1. The difference is significant.

NCCN Categories of Evidence and Consensus

The NCCN uses four categories. Semantically, each category differs from the ones next to it by the addition or omission of no more than one or two crucial words:

Category 1: "Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate."

Category 2A: "Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate."

Category 2B: "Based upon lower-level evidence, there is ["uniform"] NCCN consensus that the intervention is appropriate."

Category 3: "Based upon any level evidence, there is major NCCN disagreement that the intervention is appropriate."

In the guidelines, category 2A recommendations are the default recommendation, meaning if no category is noted for a treatment option, one assumes it's a 2A. Doctors—and insurance companies—don't generally take up recommendations below category 1 unless those treatments fail to work.

Promoting Lenalidomide Maintenance

By moving Lenalidomide maintenance into category 1 status, the National Comprehensive Cancer Network has given the drug an unexpected vote of confidence for this therapy.

Lenalidomide maintenance was first added to the NCCN guidelines for Multiple Myeloma in 2010 (V.3.2010). At that time it was listed as Category 2A and came with a footnote that said, in sum, that such therapy had been evaluated in a number of independent, randomized trials, but that since the data had not been fully peer-reviewed and since the safety had not been determined, it justified inclusion only as a Category 2A.

Among the studies cited in 2010 were the following:

- The Phase III CALGB 100104 trial. This pitted lenalidomide against placebo as maintenance therapy after prior autologous stem cell transplant. Patients in the treatment arm saw a 58% reduction in risk of disease progression. The trial was unblinded accordingly.

- The Phase III Intergroupe Francophone du Myelome 2005-02 trial. Here, patients were given lenalidomide consolidation therapy after transplant then lenalidomide maintenance. This outperformed placebo in terms of progression-free survival.

In the latest version (V.1.2013), significantly more data was included on the two studies:

- The Phase III CALGB 100104 study, we learn, initially involved 617 patients (only 460 could be evaluated). At a median follow-up of 34 months, 37% of patients getting lenalidomide (that's 85 patients out of 231) either had disease progression or had died, compared to 58% given placebo (that's 133 out of 229). Median time to progression in the lenalidomide group was 46 months—much better than in the placebo group, which was 27 months. However, there were three times as many second primary cancers in the lenalidomide group (18, or 8%) compared to the placebo group (6, or 3%).

- In the Phase III Intergroupe Francophone du Myelome 2005-02 trial, the data regarding disease progression and median time to progression was very similar to the CALGB 100104 study. This holds true for the incidence of second primary cancers: of 307 patients in the lenalidomide group., 32 developed second primary cancers (10%), compared to 12 of 307 in the placebo group (4%).

Not surprisingly, lenalidomide maintenance as a category 1 recommendation also comes with a footnote:

"There appears to be an increased risk for secondary cancers, especially with lenalidomide maintenance following transplant. The benefits and risks of maintenance therapy vs. secondary cancers should be discussed with patients."

Notably, the NCCN made the same category change (2A to 1) to lenalidomide maintenance therapy after not-transplant active primary treatment based on the results of a single phase III trial (MM-015).

Final Footnote

It's important for patients to know how, and on what data, their doctors are making treatment decisions for them, and this helps shed some light on the attention to detail given the NCCN guidelines. If you are being treated at a medical center that is associated with the NCCN, you can reliably believe that they are following these guidelines, but no matter where you are, it doesn't hurt to ask whose guidelines your doctor is following, as the NCCN's aren't the only game in town—just the most influential.

[NB: The NCCN has as of late been creating patient-friendly versions of their standard treatment guidelines, and one of the first versions created was for multiple myeloma, which you can access HERE. It doesn't use the categories in its terminology, but the patient-friendly guidelines are as good a patient resource as exists on the internet, if not among the very best.]