Introduction
Thanks to the use of adjuvant irradiation and simultaneos systematic chemotherapy, or "chemoradiation," rectal cancer treatment has progressed toward more conservative surgical management. This review covers three aspects of infusional chemoradiation in the management of patients with rectal cancer:
- First, differing chemoradiation schedules are compared with respect
to various outcomes, including survival and acute, perioperative, and late
treatment-related morbidity. This discussion focuses mainly on the use
of systemic chemotherapy when given with conventionally fractionated radiation
(1.8 to 2.0 Gy/d). Although there is much more to learn about altered fractionation
radiation schedules (ie, giving more than one radiation treatment per day),
a discussion of this issue is beyond the scope of this review (for details,
see reference 1). However, "accelerated" radiotherapy treatment
schedules have shown much promise, with results paralleling those obtained
with chemoradiation. Some of the biologic reasons for this are considered
below.
- Another area that may widen the therapeutic window for patients with
cancer of the rectum is the sequence in which adjuvant chemoradiation is
given relative to surgery. Both post- and preoperative irradiation sequences
are now being investigated prospectively in national trials. The pros and
cons of both chemoradiation sequences are explored.
- Finally, infusional chemoradiation for rectal cancer is placed in perspective by discussing it in the context of other effective infusional chemoradiation programs, such as those used for esophageal or anal cancers, since recent breakthroughs in the management of these cancers are helping to chart new directions. One new direction, the use of radical (nonoperative) infusional chemoradiation, may have a role in the management of locally advanced rectal carcinoma.
Adjuvant Pelvic Irradiation
The results of standard surgical treatment reveal that local recurrence rates in pathologically staged T3, N0-N1 rectal cancers range from ~30% to 50%.[2] Some workers believe that the high rates of local recurrence do not reflect truly modern surgical practice, and argue that these high recurrence rates can be reduced markedly by patient selection and meticulous surgical excision of the mesorectum.[3] Although local recurrence rates after surgery alone in all large, multicenter, randomized trials and large single-institution series do not support this claim, reexamination of the utility of surgery alone is being proposed. The clinical hypothesis that surgical excision can provide adequate local control will be tested further in a Scandinavian multicenter trial.[4]
Mainstream clinical research efforts in North America and western Europe have accepted the problem of pelvic recurrence after surgery and have focused attention on adjuvant therapy for these patients. Nonrandomized trials have shown that adjuvant postoperative irradiation lowers recurrence rates.[5,6] Moreover, several randomized, multicenter trials have demonstrated clearly that local failure is lower after postoperative irradiation than after surgical excision alone.[7,8]
In the Gastrointestinal Tumor Study Group (GITSG) protocol GI-7175, a statistically significant reduction in local recurrence was noted in those who received pelvic irradiation, as compared with those who were not irradiated.[7] Similarly, the local recurrence rate in the National Surgical Adjuvant Project for Breast and Bowel Cancers (NSABP) protocol R-01 was 16% when 50 Gy of radiation was given postoperatively, as opposed to 25% after surgery alone.[8]
These local failure rates are relatively high in comparison to the 6% to 8% rate reported in nonrandomized, single-institution studies.[5,6] These differences may reflect patient selection and the fact that higher total doses were used in the nonrandomized studies.
Irradiation has a relatively steep dose-response curve for the eradication of subclinical (microscopic) disease in numerous tumor sites,[9] making changes in total dose potentially important. Postoperative irradiation to total doses of 45 to 50.4 Gy in daily fractions of 1.8 to 2.0 Gy are usually very well tolerated. "Boost" doses to ~55 Gy are now routinely used in nearly all patients treated with adjuvant postoperative irradiation as long as the small intestine can be eliminated from the radiation field.[10]
Doses to the pelvis higher than ~ 55 Gy risk the development of severe small bowel damage but may be necessary when there is residual microscopic (R1) or macroscopic (R2) disease.[11-13] However, low morbidity from adjuvant treatment has been achieved in patients with no residual disease (R0) by strict adherence to protocol requirements[14] and by the use of techniques that shift the small bowel away from the radiation field.[10, 15,16] An awareness of the multiple biologic and technical factors contributing to late radiation morbidity has also lowered late morbidity.
In the future, irradiation techniques using three-dimensional treatment planning and conformal radiotherapy will be applied more frequently in the treatment of gastrointestinal malignancies. Today, these newer approaches are being used to escalate radiation doses to more than 75 Gy safely in patients with prostate cancer, thus paving the way for future trials in rectal cancer.[17]
Adjuvant Chemoradiation
One criticism of the use of postoperative pelvic irradiation is that there is little evidence for improved survival with this single modality. As with the use of chest-wall irradiation alone after mastectomy, single-modality adjuvant therapy adds relatively little to overall survival. When both adjuvant systemic chemotherapy and irradiation are given, a real increase in survival has been obtained, and the methods by which these two modalities can be combined are many.
The interdigitation of chemotherapy and irradiation is under intense study, and many radiation and medical oncologists have expressed concern over the potential for delayed utilization of the "full dose" of one modality caused by the other. One reason that radiation oncologists regularly raise this concern is the issue of the "rapidly proliferating clonogen."[18] Since cancer is a dynamic system, a cytotoxic insult from either radiotherapy or chemotherapy can create a form of "kinetic" treatment resistance resulting from the proliferative response of surviving clonogenic cells.[19]
Indirect evidence that the radiocurability of human cancer can be altered by a tumor's proliferative response to therapy is well illustrated by Durand's elegant laboratory studies ascribing treatment "resistance" to altered tumor cell kinetics rather than to genetic mutation.[20] Indeed, Durand demonstrated the emergence of "treatment resistance" while individual cell sensitivity to a cytotoxic agent was actually increasing! In other words, the apparent treatment resistance observed in this system was accounted for by the tumor simply outgrowing the treatment.
Clinical support for this concept comes from other studies in which the prolongation of radiation treatment time clearly has detrimental effects. For example, delays in the irradiation of head and neck squamous cell cancers "wastes" dose, resulting in higher failure rates[21]; similar adverse effects of prolonged treatment time occur in the treatment of uterine cervical cancers.[22] The success of accelerated radiotherapy schedules (in which the treatment is given in a relatively short time span) probably is based on this phenomenon. Measurements of tumor growth have suggested that improved outcomes of accelerated radiotherapy occur in patients with highly proliferative tumors.[23]
In combined-modality therapy, the effect of prolonged radiotherapy is less clear. In this setting, there are some indications that treatment prolongation may be less hazardous, at least according to one randomized trial that studied continuous irradiation vs split-course irradiation combined with infusional fluorouracil(Drug information on fluorouracil) (5-FU) and mitomycin(Drug information on mitomycin) (Mutamycin).[24] In this trial, each arm had identical survival rates, as well as equal acute and late treatment-related morbidity. One interpretation of these results is that the detrimental effect of the treatment split was made up for by the use of concomitant infusional chemotherapy.
In surgically treated rectal cancer, local recurrence occurs relatively quickly after potentially curative surgery in comparison to the formation of overt distant metastasis, suggesting accelerated repopulation.[25] However, there are no data to indicate that poor local control occurs when adjuvant pelvic irradiation is delayed after surgery when combined with systemic chemotherapy. The currently used adjuvant treatment schedule of two cycles of systemic chemotherapy followed by chemoradiation followed by two more chemotherapy cycles appears to be well suited for continued investigation.
What Is the Best Infusion Schedule?
Adjuvant postoperative chemoradiation for operable rectal cancer continues to be evaluated. Since the best results have been obtained with 5-FU-based regimens, many permutations of 5-FU-based chemotherapy have been examined in randomized trials over the last three decades. Important data were first reported in a GITSG trial that terminated early because of the rapid appearance of a survival benefit in those treated with chemoradiation; although the improvement in 5-year survival with chemoradiation was statistically significant, neither irradiation nor chemotherapy alone had a significant effect on survival when compared to the surgical controls.[7] This study found improved survival with combined-modality treatment, which produced good control of distant metastasis and a reduction in the incidence of local recurrence.
A follow-up trial performed by the North Central Cancer Treatment Group incorporated two major changes in trial design[26]: First, radiotherapy was administered after two cycles of systemic chemotherapy rather than immediately after surgery, thus introducing the delay mentioned above. Second, the total duration of systemic chemotherapy was reduced from 18 to 6 months. Neither change adversely affected the treatment results. Indeed, because this trial showed a major survival benefit from the use of adjuvant postoperative chemoradiation, the 1990 National Institutes of Health (NIH) Consensus Development Conference stated that patients with operable rectal cancer should have "adjuvant postoperative combined chemotherapy and radiotherapy because local control and survival for stage II and III patients are improved."[27]
Protracted 5-FU Infusion--A subsequent trial by O'Connell et al reported that administration of 5-FU by protracted venous infusion (PVI) during irradiation significantly increases survival when compared to "standard" 5-FU bolus injection during irradiation.[28] In patients treated with PVI 5-FU at a dosage of 225 mg/m2 for 7 days per week throughout irradiation, improved local control (P = .08) and overall survival (P = .02) were obtained. These benefits were achieved without an increase in late treatment morbidity, indicating an improvement in therapeutic gain with infusional chemoradiation. This same study found no evidence that the use of semustine (methyl-CCNU) added to survival.
The trial by O'Connell et al verified preclinical 5-FU dose-scheduling studies showing the strong time dependency of this drug for cytotoxicity [29] and radiation enhancement[30,31]; prolongation of exposure to 5-FU beyond the cell-cycle time increases the activity in both roles. In the clinic, the optimal tumoricidal concentration-time product of 5-FU infusion is unknown, but laboratory studies suggest that as long as a primary cytotoxic effect is observed, radiosensitization occurs, suggesting that any number of infusion schedules may be beneficial.
One 5-FU infusional chemoradiation schedule commonly used in other sites employs a dosage of 1,000 mg/m2/d over 5 days. When this short 5-FU infusion is combined with irradiation, normal tissue toxicity in the rapidly dividing cell compartments can be markedly increased, which may re- quire an interruption of chemoradiation (Figure 1). One potential risk of this interruption may be the emergence of kinetic resistance (mentioned above).
In contrast, protracted infusional chemoradiation usually results in uninterrupted irradiation treatment schedules since this approach produces a different spectrum of normal tissue reactions. There is also the suggestion that, in the treatment of advanced rectal cancer, the protracted schedule produces better tumor control than shorter infusional chemoradiation schedules.[32]
"Biomodulation" of 5-FU--Another regimen used to treat colorectal cancer is "biomodulation" of bolus 5-FU by leucovorin.[33] This regimen is based on preclinical evidence showing that the inhibitory effects of 5-FU increase in the presence of leucovorin and that this could potentially produce an effect similar to protracted exposure to 5-FU but without the cost and inconvenience of PVI therapy. However, preliminary data from a large, randomized postoperative adjuvant trial show that bolus 5-FU with leucovorin and levamisole(Drug information on levamisole) (Ergamisol) plus irradiation confers no additional benefit over bolus 5-FU alone chemoradiation, and also results in increased toxicity.[34]
Based on the above data, the best 5-FU administration schedule in the adjuvant treatment of rectal cancer appears to be a protracted infusion to maximize control of both local and distant micrometastatic disease.
