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Infusional Chemoradiation for Operable Rectal Cancer: Post-, Pre-, or Nonoperative Management?

Infusional Chemoradiation for Operable Rectal Cancer: Post-, Pre-, or Nonoperative Management?

ABSTRACT: The use of adjuvant irradiation combined with systemic chemotherapy, or "chemoradiation," in the management of patients with operable rectal cancer has enabled more conservative surgery to be performed. Chemoradiation has been employed in both postoperative and preoperative settings, and also has been used as sole therapy in selected patients. Of the various schedules of postoperative chemoradiation evaluated to date, a protracted infusion of fluorouracil (5-FU) combined with irradiation appears to maximize control of both local and distant micrometastatic disease. Preoperative infusional chemoradiation is highly effective in patients with advanced rectal cancer. Data also suggest that it may be possible to treat selected patients with low-lying rectal cancers with radical chemoradiation alone, thus obviating the need for a permanent colostomy. Future studies of preoperative and nonoperative infusional chemoradiation are warranted. [ONCOLOGY 11(3):295-305, 1997]

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:

  1. 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.
  2. 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.
  3. 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 (5-FU) and 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 (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.

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