Although the addition of IORT to external-beam radiation therapy and
surgical resection may result in improved local control and possibly
improved survival, long-term follow-up demonstrates an overall
survival rate of less than 20%. Methods for achieving better local
control and preventing distant metastasis are needed. Modulation of
5-FU activity by levamisole [ref: 113,123] or leucovorin [ref:
40,99,116, 132,139,143] or by specialized delivery methods such as
continuous infusion [ref: 133] may provide improved systemic and local
disease control. Investigation of these and other innovative treatment
methods within the context of prospective clinical trials provides the
best hope for improving outcomes in the future. A randomized clinical
trial is planned in Europe to compare external-beam radiation therapy
with and without IORT in patients with locally recurrent and primary
locally advanced disease. Results from this study should provide a
definitive assessment as to whether IORT should have a continuing role
in the treatment of selected patients with colorectal cancer.

Rectal Cancer

Preoperative Irradiation

Low-dose preoperative irradiation using 5 Gy in 1 fraction to 25 Gy in
10 fractions has been compared with surgery alone in several
randomized prospective trials. [ref: 74,127,153] None of these studies
showed improved survival with preoperative radiation therapy
(Fig. 54-7). Retrospective subgroup analysis did suggest a possible
effect of preoperative treatment in two of these trials. In the
Princess Margaret trial, patients with rectal cancer were randomly
assigned to receive surgery either alone or with preoperative
radiation therapy of 5 Gy given in one fraction. Although survival for
all patients in the trial was virtually identical (Fig. 54-7),
retrospective subgroup analysis of patients with Dukes' stage C cancer
suggested a survival advantage for preoperatively irradiated patients.
Based on this observation, the authors recommended that "this form of
preoperative irradiation become routine." [ref: 153]

This conclusion is not justified for several reasons. If, for the
entire group of patients, survival was virtually identical in the two
groups, an apparent positive impact of preoperative irradiation on
survival in some subgroups must be balanced by an apparent negative
impact in other groups. Unfortunately, analysis of subgroups
complementary to the Dukes' stage C patients was not presented.
Moreover, no reliable technique is currently available to identify
Dukes' stage C patients preoperatively. Although useful for generating
hypotheses, retrospective subgroup analysis is generally an invalid
statistical technique for reaching conclusions about treatment
efficacy. [ref: 52,166] The Veterans Administration study group found
better survival among preoperatively irradiated patients (20 to 25 Gy)
who underwent abdominoperineal resection. [ref: 74] The hazard of
retrospective subgroup analysis is illustrated by a later Veterans
Administration trial, which strongly suggested that the original
evaluation favoring the preoperatively irradiated patients resulted
from an imbalance in prognostic factors rather than from any effect of
treatment. [ref: 75]

Analysis of a trial conducted by the Stockholm Rectal Cancer Study
Group suggested a clinically measurable effect of low-dose
preoperative radiation therapy at high dose per fraction, when
compared with surgery alone. [ref: 23] In this trial, the patients
were randomly assigned to receive 25 Gy in five fractions
preoperatively or to receive surgery alone. Survival rates through 5
years of follow-up were virtually identical. Postoperative mortality
was 8% in the preoperatively irradiated patients and only 2% in
patients treated with surgery alone (P < 0.01). Among the patients who
underwent curative surgery, the incidence of pelvic recurrence at 5
years was approximately 18% in the preoperatively irradiated group and
approximately 31% in the surgical control group (P < 0.01). Although
preoperative radiation therapy, as used in this study, appeared to
provide improved local control, the overall benefit to patients was
questionable in view of the lack of survival benefit and increased
morbidity seen with the preoperative regimen.

The most recent test of the value of low-dose preoperative radiation
therapy was a Radiation Therapy Oncology Group (RTOG) trial in which
patients with rectal cancer initially were randomly assigned to
receive either 5 Gy preoperatively or immediate surgery. After
surgery, all patients in both arms who were found to have tumor
penetration beyond the rectal wall or involved nodes received 45 Gy to
the pelvis. No differences in local recurrence, survival, or freedom
from distant metastases were found between the two groups. [ref: 159]
In view of these data, low-dose preoperative radiation therapy should
no longer be used in patients with rectal cancer.

Retrospective studies suggest that higher doses of preoperative
radiation therapy may be associated with improved survival [ref:
49,92,93,148,169] and decreased pelvic recurrence. [ref:
48,148,169,170] Moderate doses (30 to 40 Gy) of preoperative radiation
therapy have been formally tested in several randomized prospective
trials.

At the Rotterdamsch Radio-Therapeutisch, patients with rectal cancer
were randomly assigned to preoperative irradiation (34.5 Gy in 15
fractions to a pelvic and paraaortic field) or to operation alone.
[ref: 17] Freedom from local recurrence and survival were not
significantly different in patients with T2 lesions. For patients with
clinical evidence of T3 or T4 disease, 97% of those in the
preoperative radiation therapy group subsequently had potentially
curative resections, compared with only 68% in the operation-only
group (P < 0.05). Irradiated patients with T3 or T4 tumors also had
better 5-year rates of survival (P< 0.005) and freedom from local
recurrence (P = 0.08).

A larger randomized trial, using the same preoperative
dose-fractionation scheme and field design, was conducted by the
European Organization for Research and Treatment of Cancer. [ref: 54]
Although local recurrence was significantly lower among patients given
preoperative radiation therapy (Fig. 54-8, A), survival was not
affected (Fig. 54-8, B).

In the second randomized trial of neoadjuvant radiation therapy
conducted by the Veterans Administration Surgical Oncology Group, a
preoperative dose of 31.5 Gy in 18 fractions to a pelvic and
paraaortic field was compared with surgery alone in patients with
rectal cancer. [ref: 75] The 5-year survival rate was 50% in both arms
of the study. Overall recurrence (distant and local) was also
virtually identical, although a detailed analysis of patterns of
failure was not reported.

No benefit from low-dose preoperative radiation therapy has been
observed in randomized prospective studies. Most randomized studies
with higher doses of preoperative radiation suggest better local tumor
control but not improved survival.

Postoperative Adjuvant Therapy

The advantage of postoperative adjuvant therapy of rectal cancer is
that it allows consideration of pathologic factors in the selection of
patients for this treatment. In trials of preoperative radiation
therapy, 22% to 37% of patients randomly assigned to surgery alone had
tumors that were limited to the bowel wall and therefore were at low
risk for recurrence. [ref: 24,127,153] An additional 8% to 14% were
found to have distant metastasis at surgery. [ref: 24,53,127,153] A
postoperative approach allows the physician to use pathologic
information to exclude 30% to 50% of patients who are unlikely to
benefit from adjuvant therapy.

A retrospective comparison of adjuvant postoperative irradiation with
surgery alone in patients at high risk for local recurrence was
performed at Massachusetts General Hospital. [ref: 78] For patients
with gross extension of tumor beyond the rectal wall, metastatically
involved lymph nodes, or both, the incidence of local failure was
lower after postoperative adjuvant radiation therapy. Other
retrospective studies suggested that local failure could be decreased
by as much as 20% with the use of postoperative radiation therapy
after resection of modified Astler-Coller B2-B3 and C1-C3 (equivalent
to T3-4 or node-positive) tumors. [ref: 19,55,78,161,176,192] However,
results from these retrospective studies have not been consistently
corroborated by prospective studies. In an RTOG study, for example,
patients with tumors that penetrated the rectal wall and those with
positive nodes received postoperative radiation therapy to a dose of
45 Gy. The rate of local recurrence was 31% among patients who
received 5-Gy preoperative radiation therapy and 34% among those who
did not. [ref: 159] The 31% to 34% rate of local recurrence is not
different from what would have been expected without the use of
adjuvant therapy. In a study from the National Surgical Adjuvant Bowel
and Breast Project, there was a modest nonsignificant difference in
patients who were treated with postoperative radiation therapy,
compared with surgery alone (16% and 25% local recurrence, P = 0.06).
[ref: 44] Two separate randomized studies of postoperative radiation
therapy (50 Gy) versus no adjuvant treatment in patients at high risk
for local recurrence also failed to demonstrate a significant benefit
for either local control or survival among patients who received
postoperative radiation therapy. [ref: 11,173]

Although results of adjuvant postoperative radiation therapy without
chemotherapy have been disappointing, randomized prospective clinical
trials have provided scientific evidence that improved survival and
local tumor control after combined adjuvant postoperative radiation
therapy and chemotherapy can be achieved in patients with T3-4 or
node-positive tumors. The Gastrointestinal Tumor Study Group randomly
assigned patients postoperatively to four groups: no further therapy;
methyl-CCNU and 5-FU; pelvic radiation therapy (40 to 48 Gy); or
pelvic radiation therapy (40 to 44 Gy), methyl-CCNU, and 5-FU. [ref:
50] Overall survival was significantly better among patients receiving
chemotherapy plus irradiation than among those who had no adjuvant
therapy. [ref: 35] Local recurrence rates were 24% in control
patients, 27% in chemotherapy patients, 20% in irradiated patients,
and 11% in patients who received the combination therapy. The results
of this study suggest that both chemotherapy and radiation therapy are
required for adjuvant treatment to have a favorable impact on local
control; neither modality alone had a significant impact on local
control.

The value of adjuvant postoperative radiation therapy and chemotherapy
in T3-4 and node-positive patients was confirmed by a randomized North
Central Cancer Treatment Group (NCCTG) study. After complete surgical
resection, the patients were randomly assigned to receive either
postoperative pelvic radiation therapy or sequential postoperative
chemotherapy (methyl-CCNU and 5-FU) and pelvic radiation therapy.
Disease-free survival, overall survival, freedom from local
recurrence, and freedom from distant recurrence were significantly
improved in patients who received radiation therapy and chemotherapy.
[ref: 98]

The results of the Gastrointestinal Study Group and the NCCTG trials
provided clear evidence that a combination of adjuvant postoperative
chemotherapy and radiation therapy improves local control and survival
in high-risk rectal cancer patients who have undergone complete
surgical resection. A subsequent randomized NCCTG trial was undertaken
to assess the contribution of the relatively toxic drug methyl-CCNU
[ref: 16] to adjuvant therapy and to determine whether continuous
infusion of 5-FU during radiation therapy resulted in better outcome
than bolus administration of 5-FU. An improvement in survival
(Fig. 54-9) was observed in patients who received continuous-infusion
5-FU [ref: 133]; details of the regimen are shown in Figure 54-10.
Methyl-CCNU did not improve survival. A Gastrointestinal Tumor Study
Group randomized study also found that methyl-CCNU did not improve
survival. [ref: 51] Methyl-CCNU is no longer used in the adjuvant
treatment of rectal cancer.

The National Surgical Adjuvant Bowel and Breast Project conducted a
clinical trial to assess the contribution of radiation therapy to
adjuvant combined-modality treatment. Patients were randomly assigned
to receive one of two chemotherapy regimens and either pelvic
irradiation or no irradiation. Initial results from this study showed
no difference in survival for patients who did or did not receive
radiation therapy. The local recurrence rates were 6.7% and 11.3%,
respectively (P = 0.045). [ref: 154] Although this difference was
particularly in view of the potential toxicity associated with pelvic
irradiation. [ref: 94] Longer follow-up is needed to assess
definitively the findings of this study. Further clinical trials may
be needed to evaluate definitively the contribution of radiation
therapy to adjuvant treatment when used in conjunction with modern
chemotherapy.

Several randomized studies support the use of combined adjuvant
postoperative radiation therapy plus chemotherapy in patients with
T3-4 and node-positive rectal cancer. Currently, postoperative
adjuvant combined-modality therapy is preferable to preoperative
radiation therapy on the basis of evidence from randomized prospective
studies that have consistently demonstrated a survival benefit for
this approach and because a postoperative approach to adjuvant therapy
allows exclusion of patients who would achieve little benefit from
such treatment. Preoperative radiation therapy should not be used in
patients with resectable rectal cancer unless a clear advantage of
this approach, relative to postoperative adjuvant treatment, is
demonstrated in a randomized clinical trial.

Locally Advanced Rectal Cancer

External-beam radiation therapy alone or in combination with
chemotherapy provides palliation and modest prolongation of life but
has only minimal curative potential in patients with locally advanced
rectal cancer. At the Mayo Clinic, 65 patients with locally
unresectable carcinoma of the large bowel were treated with
external-beam radiation therapy (35 to 40 Gy) with or without 5-FU in
a randomized prospective study. [ref: 120] Survival free of
progression, median duration of symptomatic control, and overall
survival were better in patients who received 5-FU and radiation
therapy.

Several papers have described results of treating patients with
postoperative radiation therapy after subtotal resection of large
bowel cancer. [ref: 2,19,55,162,181] At the Mayo Clinic, 17 patients
received postoperative radiation therapy with doses of 40 to 60 Gy.
Local failure was observed in 76% of patients, and the 5-year survival
rate was 24%. The minimum follow-up among surviving patients was 5
years. [ref: 162] Other investigators have reported lower local
failure rates (15% to 32%) but similar overall survival. [ref:
2,19,55,181] The reason for the wide range of results for local
control is not clear but may relate to the manner in which local
failure was defined and to the short duration of follow-up in some
series. [ref: 162]

Preoperative irradiation with doses of 45 Gy or more has been used in
patients presenting with unresectable colon and rectal cancer. [ref:
34,39,135,169] Resectability rates after preoperative radiation
therapy vary widely, ranging from about 50% to 75%. After resection,
local failure occurs in approximately 36% to 45% of patients, so
long-term local control is achieved in only 25% to 35% of these
patients. Intraoperative radiation therapy (IORT) may improve these
results.

In most cases, patients who are considered for combined radical
operation and IORT are given preoperative chemotherapy and
external-beam radiation therapy. Theoretically, preoperative
irradiation may provide tumor shrinkage, improve resectability, and
potentiate IORT effects. Typically, between 45 and 55 Gy in 1.8-Gy
fractions over 5 to 6 weeks is given, often in conjunction with
5-FU-based chemotherapy. After completion of external-beam radiation
therapy and a 3- to 5-week recovery period, patients are reevaluated
for metastatic disease and prepared for operation. Usually, aggressive
surgical resection and IORT are performed only in patients without
distant metastases.

At operation, exploration is performed initially to detect the
presence or absence of metastatic disease. If no evidence of
metastatic disease is detected, tumor resection is performed. An
attempt is made to perform a complete resection. Areas of suspected or
known residual disease are evaluated jointly by the surgeon and the
radiation oncologist to determine the feasibility of IORT. Sites of
adherence or residual disease are then fitted with a suitably sized
translucent cone designed specifically for delivery of the electron
beam. The IORT dose is selected according to the amount of disease
subsequent to surgical resection and ranges from 10 to 20 Gy. The two
largest groups of patients in whom IORT has been used are patients
with locally recurrent rectal cancer and those with primary
unresectable disease.

Details of therapy with external-beam radiation therapy, surgical
resection, and IORT at the Mayo Clinic have been reported [ref: 65]
and recently have been updated for 116 patients with recurrent
colorectal cancer. [ref: 66] At 5 years, the survival rate was 18%,
and the local failure rate was 40%. In an analysis of 106 patients
treated with palliative surgical resection alone, palliative resection
with external radiation therapy, palliative resection with IORT with
or without external-beam radiation therapy, or palliative resection
with brachytherapy, the use of IORT was associated with significantly
improved survival (Fig. 54-11). [ref: 171] These results must be
interpreted with caution because they are not from a randomized
clinical trial. Prognostic factors that were related significantly to
survival included the amount of residual tumor after surgical
resection, the use of IORT, the symptomatic status of the patient, the
degree of fixation of tumor to surrounding structures, and the
performance status of the patient (Table 54-5). Results from patients
with a history of pelvic irradiation before local recurrence are less
satisfactory. In a Mayo Clinic series, survival at 5 years was only
13%, and local control at 4 years was 34%. [ref: 69]

Thirty-nine patients with locally recurrent rectal or rectosigmoid
cancer were treated at Massachusetts General Hospital with
preoperative external-beam irradiation followed by IORT. [ref: 187]
Nine patients did not receive IORT because it was not technically
feasible, the tumor was unresectable or metastatic, or the tumor was
completely resected with negative margins. For all 39 patients, the
5-year survival rate was 29%, and the disease-free survival rate was
21%. Five-year local control and disease-free survival rates in the 30
patients who received IORT were 26% and 19%, respectively. Local
control was related to the degree of surgical resection performed
before IORT. Local control was 62% and 18% in patients who had
complete and partial resections, respectively. Four patients received
no or minimal preoperative irradiation because of a history of prior
pelvic irradiation. Of these 4 patients, 3 had local failure; 3 died
of cancer and 1 of intercurrent disease. Currently, patients with
locally recurrent rectal cancer who have a history of pelvic
irradiation are not considered candidates for IORT at the
Massachusetts General Hospital. [ref: 187]

Twenty-six patients received external-beam radiation therapy and IORT
for localized pelvic recurrence of large bowel cancer at
Rush-Presbyterian Hospital. [ref: 97] The 3-year relapse-free and
overall survival rates were 15% and 25%, respectively. Local failure
occurred in 11 of 18 patients with gross disease after surgery and in
4 of 8 patients with microscopic disease. The local failure rate was
higher in patients who received external-beam radiation therapy doses
of less than 40 Gy (11 of 15 patients, 73%) than in those who received
more than 40 Gy (4 of 11 patients, 36%). Like the group at the
Massachusetts General Hospital, these investigators no longer use IORT
when a full course of external-beam pelvic radiation therapy is not
possible.

External-beam radiation therapy with IORT has also been used in the
treatment of primary locally advanced rectal cancer. [ref: 65,66,186]
At the Massachusetts General Hospital, the actuarial overall
disease-free survival rate at 5 years was 32% for patients with
incompletely resected tumors and 53% for patients treated with
adjuvant IORT (i.e., patients with completely resected tumors). Local
control at 5 years was 60% for patients who underwent partial surgical
resection and 88% for patients who received adjuvant IORT. At the Mayo
Clinic, local control and survival rates at 5 years for 56 patients
with primary locally advanced disease were 82% and 42%, respectively.
[ref: 66]

Although the addition of IORT to external-beam radiation therapy and
surgical resection may result in improved local control and possibly
improved survival, long-term follow-up demonstrates an overall
survival rate of less than 20%. Methods for achieving better local
control and preventing distant metastasis are needed. Modulation of
5-FU activity by levamisole [ref: 113,123] or leucovorin [ref:
40,99,116, 132,139,143] or by specialized delivery methods such as
continuous infusion [ref: 133] may provide improved systemic and local
disease control. Investigation of these and other innovative treatment
methods within the context of prospective clinical trials provides the
best hope for improving outcomes in the future. A randomized clinical
trial is planned in Europe to compare external-beam radiation therapy
with and without IORT in patients with locally recurrent and primary
locally advanced disease. Results from this study should provide a
definitive assessment as to whether IORT should have a continuing role
in the treatment of selected patients with colorectal cancer.

Colon Cancer

No randomized prospective trials have examined the value of
postoperative adjuvant radiation therapy for colon cancer. However,
several retrospective studies suggest that this would be a fruitful
avenue for research. [ref: 18,38,95,96,165,185,189] In view of the
positive results with adjuvant systemic therapy in high-risk colon
cancer patients, [ref: 100,121,123] a randomized trial comparing
radiation therapy, 5-FU, and levamisole versus 5-FU and levamisole
alone after resection in patients with high-risk colon cancer has been
undertaken. Currently, adjuvant radiation therapy for colon cancer
should not be used except in the context of a prospective clinical
trial.

Chemotherapy

Until recently, the results of most studies of chemotherapy for
advanced disease or adjuvant therapy have been disappointing. [ref:
64,125] However, several recent clinical trials have demonstrated a
clear role for chemotherapy in well-defined settings. A Mayo
Clinic/NCCTG study suggested improved outcome in patients with Dukes
stage C disease in overall and disease-free survival with adjuvant
levamisole therapy with or without 5-FU. [ref: 100] A subsequent
intergroup confirmatory trial verified the value of 5-FU and
levamisole for node-positive patients. [ref: 121,123] For patients
with metastatic colorectal cancer, trials of 5-FU and leucovorin have
demonstrated improved response rates and, in some cases, improved
quality of life and better survival when compared with single-agent
5-FU therapy. [ref: 40,99,132, 139,143] In a small study at the
Roswell Memorial Park Institute, [ref: 103] patients with metastatic
disease were randomly assigned to receive either 5-FU alone,
methotrexate plus 5-FU, or leucovorin plus 5-FU. [ref: 139] Response
rates were 11%, 5%, and 48%, respectively. Survival was not altered
significantly. However, a larger Mayo Clinic/NCCTG study showed
improved survival for patients receiving regimens containing 5-FU plus
leucovorin. [ref: 132]

Sequelae of Therapy

The most common form of acute toxicity during adjuvant pelvic
radiation therapy for rectal cancer is diarrhea. Approximately 24% of
patients develop severe or life-threatening diarrhea (according to the
National Cancer Institute Common Toxicity Criteria) when pelvic
radiation therapy is used in combination with protracted infusion of
5-FU. [ref: 133] The maximal frequency of other severe or worse
toxicities is 3% when pelvic radiation therapy is used with concurrent
protracted venous infusion of 5-FU.

The risk of functionally significant long-term toxicity after pelvic
radiation therapy and chemotherapy appears to be higher than
previously appreciated. This was suggested by a study in which
assessment of bowel function was undertaken in a group of patients who
either had or had not received postoperative radiation therapy and
chemotherapy after anterior resection for rectal cancer. The two
groups of patients were well balanced for factors that had a potential
impact on bowel function, such as level and type of anastomosis.
Consistently worse bowel function, by multiple measures, was found
among the patients who had received radiation therapy and
chemotherapy. For example, 56% reported at least occasional fecal
incontinence, compared with only 7% of those who did not receive
adjuvant treatment (P < 0.001). [ref: 94]

A large retrospective analysis of patients who received radiation
therapy for high-risk, completely resected colon cancer or for
incompletely resected colon cancer found that acute enteritis
resulting in hospitalization or a break from treatment occurred in 16
(8%) of 203 patients. Long-term toxicity requiring surgery was
observed in 9 patients (4.4%). Nonsurgical complications, such as
chronic abdominal pain, were not assessed. [ref: 185] The paucity of
data with regard to serious nonsurgical complications and the
potential for significant toxicity requiring surgical intervention
underscore the importance of avoiding adjuvant therapy for large bowel
cancer outside the setting of a clinical trial.

Endocavitary radiation therapy for rectal cancer generally is well
tolerated. Approximately 35% of patients have minor rectal bleeding
after treatment. Rectal urgency occurs in about 20% of patients. These
symptoms usually resolve. Ulcers develop in about 75% of patients
after endocavitary radiation therapy, but this condition is usually
asymptomatic and resolves in most patients. [ref: 101]

Severe treatment-related toxicity can occur in patients with locally
advanced disease who undergo IORT. Immediate complications include
pelvic abscess and delayed perineal wound healing. [ref: 171] Common
long-term sequelae of IORT include neurotoxicity in approximately 32%
of patients, hydronephrosis in about 63% of patients when a ureter is
included in the radiation therapy field, and small bowel obstruction
in about 12% of patients. [ref: 164,171] Neurotoxicity appears to
depend on the site irradiated. If the pelvic sidewall is included
within the field, the incidence of neuropathy approaches 50%, but if
the field is limited to the presacrum, the incidence is less than 10%.
[ref: 164] In one series, the risk of severe complications in a group
of patients with locally recurrent rectal cancer was 30% with surgery
alone; 14% with external-beam radiation therapy; 45% with surgery,
external-beam radiation therapy, and IORT; and 60% with surgery and
brachytherapy. [ref: 171] The significant risk of complications
associated with aggressive treatment underscores the need for
prospective clinical trials to assess definitively the value of IORT.

No form of treatment has clearly been demonstrated to be of value in
the management of the complications of radiation therapy. Therefore,
prevention of complications is of critical importance. Methods for
minimizing the volume of normal tissue within the radiation therapy
field should be used (see Radiation Therapy Techniques). Randomized
trials testing two pharmacologic agents, olsalazine and
cholestyramine, for prevention of treatment-related diarrhea showed
that these agents are associated with unacceptable toxicity. [ref:
26,111,112] Sucralfate is a more promising drug. A European clinical
trial has suggested that this agent may decrease both acute and
long-term toxicity after pelvic irradiation. [ref: 72] A confirmatory
randomized trial is in progress.