Kinder, Gentler Cancer Therapy: Not So Fast

Two articles in this issue of ONCOLOGY-Drs. Das and Minsky’s paper “A Watch-and-Wait Approach to the Management of Rectal Cancer” and Drs. Marin, Master, and Delman’s “Minimizing Morbidity in Melanoma Surgery”-discuss efforts to reduce morbidity in combined-modality treatment for cancer. Originally, treatment modalities were combined in an attempt to cure-or at least control-disease in patients with advanced tumors. The success achieved with combined-modality therapy resulted in this becoming the approach used in most solid tumors today.

Systemic therapy such as irradiation has long been used as an adjuvant to surgical resection for solid tumors. This sequence of modalities permitted the decision of whether or not additional therapy was needed to be made based on the findings of the surgical resection, which provided the best biological information about the tumor extent and type. Then, as neoadjuvant use of systemic therapy demonstrated dramatic reductions in the size of some tumors, it became apparent that less extensive surgery could result from reversing the historic order of the therapeutic modalities.

Two trends have followed. First, surgical techniques have continued to progress to smaller operations and less invasive approaches, guided by superior imaging techniques. Second, many solid tumors have demonstrated complete clinical response to neoadjuvant therapy, particularly when systemic therapy has been used in conjunction with irradiation.

This raises the question: Can the surgical step be avoided completely? Almost certainly in some patients, but which ones? It is widely acknowledged that we overtreat some patients. The trick is to identify which ones, and then use tailored or personalized protocols. And can the patients in whom a particular treatment modality was not used be followed so that those whose disease recurs suffer no greater risk of loss of control than those who were treated with all modalities at once? To be able to answer this latter question in the affirmative requires a follow-up protocol that is validated and that is less onerous and expensive than the omitted treatment.

Drs. Das and Minsky propose omitting surgery in certain patients with rectal cancer. Omitting irradiation in estrogen receptor–positive breast cancer patients over 70 years of age has already been shown to be a reasonable strategy. Selective use of irradiation to the breast in patients with ductal carcinoma in situ, based on genomic definition of risk, is being proposed. A genomic risk score is now commonly performed in patients with estrogen receptor–positive invasive breast cancer in whom cytotoxic chemotherapy is being considered.

However, kinder, gentler cancer therapy is neither of those things if it fails to be as effective in controlling the cancer. When an area of completely clinically regressed cancer is excised, there is commonly residual cancer present. Can needle biopsies and imaging replace excision in providing assuance of a pathological complete remission? And even “path CR” does not assure no residua, only that none was seen.

Clinical trials that address proposals for reducing the morbidity of cancer therapy will be required, not only to assess effectiveness, but comparative patient benefit as well. Were the irradiated patients or the resected patients more pleased with their experience if the outcomes were equivalent? And what of economics and the cost of multiple PET-CT scans, robotic-assisted surgical procedures, or genomic assays and combinations of tailored small molecules?

The questions being asked hold great promise for the patients of tomorrow, but also plenty to do for clinical investigators.