Effective neoadjuvant therapy prior to metastasectomy: a new paradigm.

These two single institution experiences describe the results of using tyrosine kinase inhibitors followed by resection for metastatic gastrointestinal stromal tumor (GIST) and are great examples of a combined modality approach to a malignancy that attempts to define the biology of the disease. These two centers are defining if and when patients with metastatic GIST should be taken to the operating room for metastasectomy. In the article by DeMatteo et al, they describe the results of 40 patients with metastatic GIST who were treated with tyrosine kinase inhibitors and then resected. They found that patients with responsive disease had better progression-free and overall survival than those who had one site of drug resistance or who had multiple sites of drug resistance. They conclude that selected patients with metastatic GIST who have responsive disease or only focal resistance to tyrosine kinase inhibitor therapy may benefit from surgical resection, whereas those who have multifocal resistance may not. In the article by Gronchi et al, they describe the results of 38 patients with metastatic GIST who were treated with the tyrosine kinase inhibitor imatinib mesylate and then resected. They found that patients with unresponsive disease did not appear to have any major benefit from surgery and that the progression of disease was more related to acquisition of mutations causing resistance to drug therapy. The patients who responded to therapy and then underwent surgery and recurred seemed to do so because of their discontinuation of therapy rather than acquisition of resistance mutations. First, it must be clearly stated that these studies in no way prove that patients placed on tyrosine kinase inhibitors who have a response derive a benefit from surgery. It can be argued that surgery had no bearing on their longer survival but that they had better biology and were just responsive to the medical therapy. The only way to clearly prove the benefit of surgery in this setting is to perform a randomized clinical trial, and this was pointed out by both sets of authors. What both studies do clearly point out is that patients with tumors that are resistant to therapy are much less likely to benefit from surgical intervention. Traditionally, surgery is effective at controlling localized disease, whereas systemic therapy is used for metastatic disease. There are multiple examples, however, of patients with metastatic disease who are cured with metastasectomy. Colorectal cancer metastatic to the liver is an example of this. The problem, however, is that many of the patients who undergo metastasectomy will recur with disease anyway; and for many patients, the surgical intervention will have no bearing on their longevity. It may even subject them to an unnecessary surgical procedure for which they incur risks, pain, and recovery time with no benefit. In the two studies previously presented, the two sets of authors subdivide patients with metastatic GIST who are potential candidates for metastasectomy into those who may benefit from surgical intervention and those who will likely not. Hopefully, one day we will have molecular therapy that is as effective against other metastatic diseases, such as lung, breast, and pancreas cancer. The paradigm of giving a neoadjuvant approach prior to metastasectomy is now sometimes used with colorectal cancer but not with lung, breast, or pancreas cancer, which in general cannot be cured by metastasectomy. The National Comprehensive Cancer Network guidelines for patients with primary colon or rectal cancer with resectable hepatic metastases give the option for systemic chemotherapy prior to resection of the primary and or metastatic disease as they do with GIST (Clinical Practice Guidelines in Oncology, version 3.2006; available at: http://www.nccn.org. Accessed December 10, 2006. To view the most recent and complete version of the guideline, go online to www.nccn.org). The rationale, of course, in this situation is to quickly, systemically treat patients who are at high risk of systemic micrometastatic disease and also to select out the patients most likely to benefit from surgical intervention and to spare those who already have systemic disease and are unresponsive to chemotherapy. As more effective therapies become available for other metastatic cancers, this paradigm will be more commonly used. These two studies are relative clear on the lack of significant benefit of elective metastasectomy of patients with metastatic GIST who progress on tyrosine kinase inhibitor therapy. The real question is: do patients with metastatic GIST who have disease responsive to tyrosine kinase inhibitors benefit from surgery, or are we just picking the patients with the best biology to take to the operating room? This question should be answered with a randomized clinical trial in which subjects with potentially resectable metastatic GIST are recruited and given a defined period of tyrosine kinase inhibitor therapy. Resectable subjects with responsive, partially responsive, or stable disease should then be randomized to surgery or no surgery, both with continued medical therapy. The primary endpoints of the trial should be progression-free and overall survival. A further interesting point to study and possible secondary endpoint is whether surgical resection decreases the number of further mutations and whether these patients are more responsive to second-line tyrosine kinase inhibitors once they do progress on imatinib mesylate.