Where next with preoperative radiation therapy for rectal cancer?

The basic question for radiation oncologists is what we hope to achieve from treatments that are adjuvant to surgery: better local (pelvic) control and, hopefully, because of that, fewer metastases. Chemotherapy could add to the local effect of irradiation and may also decrease distant metastases directly. Selection criteria for individual treatment could enhance the therapeutic index.

Total mesorectal excision reduces the incidence of local recurrence, but preoperative (chemo) radiation is still indicated for more advanced tumors (T3-T4) and for lymph node involvement. Pelvic recurrences arise from tumor clonogens residual beyond the surgical margins. Thus, the practice of shrinking fields to boost the dose to the primary tumor makes no sense, except for tumors that invade residual structures, such as the sacrum. Subclinical disease beyond the future surgical margins grows more quickly than the primary tumor, and hence treatment should be as intense as tolerable. A short treatment course (e.g. 5 x 5 Gy) is desirable, but this regimen, which is currently the gold standard, should be compared (as in the recently closed randomized Polish trial) with higher-dose, longer-duration chemoradiotherapy regimens. The recently closed EORTC trial 22921 examines the benefit of pre- and postoperative chemotherapy combined with a long schedule of radiation. Likewise, continuous infusion of a cycle-active agent rather than bolus administration is a logical addition to radiation therapy in the treatment of fast-growing subclinical tumor extensions.

The reduction in distant metastasis rates attributable to adjuvant chemotherapy varies greatly among reports. If the reduction is of the order of 10-25%, the efficacy of chemotherapy equates to as little as about 5 to 12.5 Gy and not more than 20 Gy of total body irradiation.

Early excision after preoperative irradiation would be desirable if the primary tumor were still disseminating viable metastatic clonogens. Most tumors do not metastasize until they contain enough viable clonogens to render them clinically detectable. A dose of 10 Gy in 2 Gy fractions reduces at least 30-fold the absolute number of viable clonogens in the primary tumor, to levels that do not yield metastases from the untreated tumor. After a dose of 44-50 Gy in 2 Gy fractions, there is little chance that the surviving tumor clonogens could regrow to a metastasis-yielding volume in any reasonable radiation-surgery interval. Thus there is no tumor-related necessity for early postradiation surgery. The importance of the interval between radiation and surgery is currently being addressed in a Swedish randomized trial.

Tumor volume should be included in the staging system. There are many tumor- and host-related characteristics that can be used to fingerprint the tumor to help select appropriate individual treatment.