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improved outcomes in colon and rectal surgery
Table 30.3 Preoperative neoadjuvant radiation studies.
Study Open/Closed
Stockholm I (1)
1980 to 1987
Stockholm II (17)
3/87 to 5/93
Swedish Rectal (18)
3/87 to 2/90
Dutch TME (19)
1/96 to12/99
Manchester (20)
1981 to 1989
MRC II (21) 289 S
Polish (22)
1999 to 2002
EORTC (23)
4/93 to 5/03
FFCD 9203 (24)
1993
Number
of Pts
849 S
557 S
1168 S
1861 S
284 S
312 25Gy–S
1011 45Gy–S
762 45Gy–S–C
Therapy
Arms
25Gy–S
25Gy–S
25Gy–S
25Gy–S
20Gy–S
40Gy–S
50.4Gy+C–S
45Gy+C–S
45Gy-S–C
45Gy+C–S–C
45Gy+C–S–C
Local (Pelvic)
Recurrence % at 5 years
28
14 (p < 0.001)
25
12 (p < 0.001)
27
11 (p < 0.001)
10.4
5.6 (p < 0.001)
36
13 (p < 0.001)
48
32 (p = 0.04)
9
14 (p = 0.17)
17.1
9.6
8.7
7.6
16.5
8.1 (p = 0.004)
Overall Survival
% at 5 years
36
36
39
46 (p = 0.03)
(Pts having
curative surg)
48
58 (p < 0.001)
64
64
39
46 (p = 0.03)
19
26 (p = 0.09)
67.2
66.2
63.2 no post op C
vs. 67.2 with post
op C (p = 0.12)
67.2
66.2
Comments
to L2 level no lateral
beam
Patients older than 80
excluded
Patients older than 80
excluded
Patients older than 80
included
5Gy x 4, survival for
those having curative
resection:
20x2Gy; S four weeks
after xrt
Mostly TME
T3/T4. Patients older than
75 excluded
Stage I and age over 80
excluded
Stage I and age over 75
excluded
Symbols as in Table 30.2.
Table 30.4 Pre versus postoperative and chemotherapy studies.
Study Open/
Closed
Upsala (25)
10/80 to 12/85
German (26)
2/95 to 9/02
Symbols as in Table 30.2.
Number of
Pts random Therapy Arms
471 25.5Gy–S
S–60Gy
823 50.4Gy+C–S–C
S–50.4G+C–C
Recurrence % at 5 years
significant improvement in overall survival and the incidence
of local recurrence compared to surgery alone. Based on
Gastrointestinal Tumor Study Group and North Central Cancer
Treatment Group studies a U.S. National Institutes of Health
Consensus Development Conference in 1990 recommended
that postoperative radiation and chemotherapy be standard
treatment for stage II and III rectal cancer.(9, 10, 27) An advantage of postoperative treatment is that selection for adjuvant
treatment can be based on pathologic staging whereas with preoperative treatment selection is based on necessarily imperfect
clinical staging.
The use of preoperative radiation has been extensively evalu-
ated in Europe. From inspection of the randomized trials in Table
30.3 it is evident that preoperative radiation treatment reliably
produces a clinically and statistically significant reduction in the
incidence of local recurrence by about 50 to 60%. This remains
true even in the Dutch Colorectal Cancer Group trial which was
Local (Pelvic)
12
21 (p = 0.02)
6
13 (p = 0.006)
Overall Survival
at % 5 years
44
39 (p = 0.43)
74
76 (p = 0.80)
Comments
5.1x5Gy and 30x2Gy.
TME, exclude stage I
and age over 75
designed to minimize the need for pelvic irradiation by mandating surgery to be total mesorectal excision (TME).(19) As indicated in the entries in Table 30.2 and 30.3 for the surgery only
arms, TME is apparently more rigorously extirpative than the
surgery of historical practice. Its use reduced the local recurrence
at five years after surgery alone to 10.4% compared to the 25 to
28% found in comparable Stockholm I and II and Swedish rectal
trials, that did not require TME.(1, 17, 18)
About 35% of the patients in the Dutch study had disease
found in pelvic nodes making them stage III. Among this subgroup, 20.6% of those who did not have radiation treatment and
10.6% of those who did suffered a local recurrence (p < 0.001).
About 28% had stage II disease. Among these the local recurrence rate without radiation was 7.2% and with radiation 5.3%
(p = 0.331). About 28% had stage I disease. Among these the
local recurrence rate was 1.7% without radiation and 0.4% with
(p = 0.091). Among 7% of patients with distant metastasis found
radiation therapy: acute and late toxicity
at surgery (stage IV) there was local recurrence in 26.9% without radiation and 15.9 with (p = 0.207). Thus, for all four stages
there was less local recurrence in patients who had radiation, but
the differential only reached statistical significance for the node
positive (stage III) subgroup and the entire randomized population. Similarly it was found that the difference reached statistical
significance in the subgroup that had LAR but not in subgroups
that had APR or Hartman pouch surgery and in the subgroup for
which the distal tumor edge was between 5 and 10 cm from the
anal verge but not those more proximal or distal.
The Swedish Rectal study differs from the Dutch study in that
TME was not required.(18) The proportion of patients in each
stage was similar but the differential in rate of local recurrence
between arms of the trial was greater and statistically significant
for all stages. In the stage III subgroup of the Swedish study the
local recurrence was 40% without preoperative radiation and
20% with (p < 0.001). For stage II it was 23% without and 10%
with radiation (p = 0.002). For stage I it was 4% without and
2% with radiation (p = 0.02).
Comparison of these two studies suggests that benefit from
preoperative radiation in preventing local recurrence is maximal
if given to patients likely to have node positive (stage III) disease,
expected to have LAR as opposed to APR and with lowest tumor
extent in the mid to distal rectum. However, some reduction in
risk of local recurrence may be expected for all patients.
As shown in Table 30.3, overall survival rate was not affected
by the short course preoperative radiation treatment in the Dutch
TME trial and in the earlier Stockholm I trial. On the other
hand, in the Swedish Rectal trial the short course preoperative
radiation treatment produced a statistically significant gain in
overall survival. Two other short course preoperative radiation
trials, Stockholm II and Manchester showed statistically significant improvement in overall survival among the subgroup that
actually underwent curative resection but not in all randomized
patients.(17, 20)
Failure to improve overall survival even though local recurrence rate is significantly reduced can occur in two important
ways. First, the dominant cause of death may be from development of distant metastatic disease to such an extent that a small
incidence of local recurrence in the surgery only arm and its
reduction by radiation treatment has no statistically significant,
or even discernible, impact on survival. This may be the principle
explanation in the TME trial.
The other way the impact on survival of a local recurrence
advantage may be reduced, or lost, is if excess non rectal cancer deaths are produced in the radiation treatment arm. This is
likely the explanation for limitation of statistically significant
survival benefit to the subgroup that had curative surgery in the
Stockholm II trial.(17) At median follow-up of 8.8 years for this
trial 19% of the radiation arm patients and 12% of the surgery
only arm had died of non cancer causes (p = 0.1). There was cardiovascular death in 13% in the radiation arm and 7% in the surgery only arm (p = 0.07). This differential was established within
the first 6 months after surgery, during which 5% of irradiated
patients and 1% of the surgery only patients died from cardiovascular causes (p = 0.02). The excess cardiovascular deaths were
predominantly in patients older than 68 years. It is suggested this
is due to change in the coagulation properties of blood during the
several months of recovery from pelvic surgery and radiation that
leads to increased thrombotic events in the irradiated patients.
The only randomized study of preoperative radiation with a
surgery only control arm that used a radiation treatment regimen resembling the long course described above is the MRC II
trial.(21) Patients were eligible if they had a partially or totally
fixed rectal tumor on physical exam. The population likely consisted mostly of T3 and T4 tumors, that is, there were likely more
locally advanced cancers than in the short course trials. As shown
in Table 30.2, there was a significant decrease in local recurrence
in the radiation arm and a tendency to increased survival, though
not statistically significant, similar to the findings in several short
course trials.
The Polish trial compares short-course preoperative radiation
with long-course preoperative radiation plus concurrent chemotherapy.(22) Most of the surgery was with TME. Patients were
clinically staged with physical exam, transrectal ultrasound and/
or MRI. Only those with evidence of T3 or T4 tumors that were
palpable on digital exam and had no anal sphincter involvement
were included. Patients found to have involved nodes at surgery usually received postoperative chemotherapy. More in the
short course arm were node positive suggesting down staging by
the long course treatment. There was no difference in survival
between the two arms. There is a suggestive difference in local
recurrence favoring the short course but it did not reach statistical significance. There was no statistically significant difference in
the fraction that received a permanent stoma but with a tendency
to favor the long course arm for sphincter preservation.
The EORTC trial examined the effect of adding chemotherapy to long course preoperative radiation with the finding that if
chemotherapy is given concurrently with preoperative radiation,
post operatively, or both, the rate of local recurrence is reduced
significantly relative to preoperative long course radiation with
no chemotherapy.(23) This suggests concurrent radiochemotherapy does not contribute much if postoperative chemotherapy
is given. On the other hand, the FFCD trial in which both arms
got postoperative chemotherapy reports a significant decrease in
local recurrence if concurrent chemotherapy is given with preoperative radiation.(24) There was no survival difference.
Two randomized trials listed in Table 30.4 have directly compared pre and postoperative radiation treatment arms. In the
earlier Upsala trial the preoperative arm had the short course of
radiation.(25) Those randomized to the postoperative arm and
found to have stage II or III disease were treated with long course
to a higher dose of 60 Gy in 2 Gy fractions. In the recent German
trial the surgery was mandated to be with TME and clinical staging was intended to exclude stage I patients from the study.(26)
Those randomized to the preoperative arm and the subset of
those randomized to the postoperative arm who were proved to
have stage II or III disease at surgery received the similar regimens
of chemotherapy and radiochemotherapy though in different
sequence. The chemoradiotherapy consisted of 50.4 Gy in fractions of 1.8 Gy each except that an additional 5.4 Gy to a reduced
volume was included in the postoperative treatment. Both these
trials showed a statistically significant difference in local recurrence
rate favoring the preoperative arm and no significant difference in
improved outcomes in colon and rectal surgery
survival when grouped by intention to treat at randomization.
It is of note that 28% of the postoperative arm of the German
trial received no radiation treatment. Of these, in 18% the cause
was finding pathologic stage I disease and in 10% the cause was
postoperative death or complications or finding of stage IV disease at surgery. Patient selection and the treatment regimen of the
preoperative arm of the German trial is now standard treatment
in many institutions.
In all the above trials surgery consisted of LAR or APR. For
patients with evidence of a stage T1 or T2 rectal cancer distal to
the peritoneal reflection i.e., usually within 10 cm from the anal
verge, smaller than about 4 cm and occupying a limited fraction
of the circumference of the rectal wall, local excision via trans
anal, trans sphincteric (York-Mason) or posterior proctotomy
(Kraske) procedure may be able to achieve en bloc full thickness
excision of the tumor with negative margins. This limited surgery
may be elected in lieu of APR or LAR to preserve sphincter function or to avoid major surgery in those not fit or not willing to
undergo it. Comparison of local excision (LE) with APR or LAR
as to the ability to remove all the carcinoma has not been established by any randomized trial. Nevertheless, it is expected that
limited local excision will not as reliably prevent local recurrence
as the more radical surgery, particularly TME. This is confirmed
by the local recurrence rates reported in the retrospective series
shown in Table 30.2, particularly for T2 disease. The decrease in
local recurrence with adjuvant radiation, with or without concurrent chemotherapy, suggests that the local excision with adjuvant
treatment is efficacious enough to be considered as an option
under some circumstances. Bias in the retrospective series would
be to select for radiation treatment those patients with unfavorable features in their pathology such as positive or close margins,
lymphovascular invasion or high histologic grade. Thus, the benefit from adjuvant treatment may be more than indicated by the
results shown.
The RTOG protocol 89–02 study enrolled patients with tumors
judged by their surgeon to be distal enough to not allow clearance
by LAR and who underwent local excision via trans-anal, transsacral or trans-coccygial approach.(16) To be eligible the tumor
had to be mobile, <4 cm in size and occupy <40% of the rectal
circumference. Those patients with cancer found to be pathologic
stage T1, with histologic grade 1 or 2, excised with at least 3 mm
margins in all directions, absent any lymphatic or vascular invasion and with normal CEA received no post operative treatment.
Patients lacking any one of these favorable features were treated
with radiation to the pelvis with boost to the tumor site to a total
dose of 50 to 56 Gy in 1.8 to 2 Gy fractions with concurrent 5Fu
chemotherapy. If the margin was microscopically positive or
closer than 3 mm the dose to the tumor bed was increased to
give a total dose of 59.4 to 65 Gy. The local recurrence rate for
T2 tumors, all of which received adjuvant treatment was 4 of 25
(16%) that for T3 tumors was 3 of 13 (23%). It is not clear what
the chance of salvage for local failure with APR is, but it may be
as much as 50%.(28) The results for local excision shown in Table
30.2 support the view that local excision with postoperative adjuvant treatment with radiation and chemotherapy, although not
as likely to be curative as radical surgery, is an acceptable option
for tumors of a size and position which permit it, when there is
sufficient reason to avoid radical surgery. The treatment of early
rectal cancers has recently been reviewed.(29)
ACUTE ADVERSE EFFECTS
The most common and limiting adverse effect that occurs during
and/or shortly after a course of pelvic irradiation (acute effect) is
diarrhea. A scale adopted by the RTOG and EORTC for reporting
acute effects of irradiation of the lower GI tract is representative
and in use in current trials.(30) Grade 1 is given for increased
frequency or change in bowel habits not requiring medication
or rectal discomfort not requiring analgesics. A score of grade 2
implies diarrhea requiring Immodium or Lomotil medication, or
mucous or bloody discharge not requiring sanitary pads or rectal or abdominal pain requiring analgesic medication. A score of
grade 3 is given for diarrhea requiring parenteral support, mucous
or bloody discharge requiring sanitary pads or abdominal distention with distended bowel loops on radiograph. Grade 4 implies
acute or subacute bowel obstruction, or fistula or perforation, or
GI bleeding requiring transfusion or abdominal pain or tenesmus
requiring tube decompression or bowel diversion. Grade 3 and 4
are often combined and reported as severe adverse effects.
In the EORTC trial, 1011 patients were treated with preoperative irradiation to a dose of 45 Gy in 25 fractions over 5 weeks.
(23) Half were randomly assigned to also have concurrent preoperative chemotherapy and half had none. Acute grade 2 toxicity was reported in 38.4% of those who received the concurrent
preoperative chemotherapy and 29.7% of those who did not (p <
0.001). Grade 3 or 4 acute adverse effects are reported in 13.9% of
those whose treatment included preoperative chemotherapy and
7.4% of those who had only preoperative radiation (p < 0.001).
The rate of local recurrence as a first event was approximately 9%
at five years in those who received chemotherapy preoperatively,
postoperatively or both and 17% in those who had no chemotherapy at all (p < 0.002). There was no statistically significant
difference in overall survival. This suggests the additional acute
toxicity of preoperative concurrent radiation and chemotherapy
over that of preoperative radiation alone may not be necessary if
post operative chemotherapy is to be given. This is contradicted
by the FFCF trial.(24)
The incidence of severe diarrhea during postoperative radiation treatment following LAR or APR depends on the specific
concurrent chemotherapy regimen. For 656 patients treated on
a phase III NCCTG trial it was found to be 13% for bolus infusion of 5FU at a dose of 500 mg/m2 on each of three days of the
first and fifth week. It was 23% for infusion of 5FU at the rate of
225 mg/m2 per day given continuously for the entire length of the
course of radiation.(31) Improvement in survival at four years of
70% with the continuous regimen compared to 60% with bolus
infusion was felt to justify the definite, though modest, increase
in toxicity.
The type of surgery was also a significant determinant of the
risk of severe diarrhea. In those who had undergone LAR there
was a 31% rate of severe diarrhea compared to 13% in those who
had an APR (p < 0.001). This differential is not unexpected as
there is a significant rate of diarrhea after LAR in the absence of
radiation. In this regard, it is of note that the frequency of bowel
movements at the time of discharge after LAR via total mesorectal
radiation therapy: acute and late toxicity
excision in 81 patients who were not treated with radiation averaged about 8 per day.(32)
In the trial that randomized patients to pre versus post operative
long course chemoradiotheapy conducted by the German Rectal
Cancer Study Group the incidence of sever diarrhea among 399
patients randomized to preoperative treatment was 12%. Among
the 237 patients actually treated with postoperative radiation the
rate of severe diarrhea was 18% (p = 0.04).(26) The post operative arm included some 23% who had APR. Thus among those
who had an LAR, and are most comparable to patients in the pre
operative arm with respect to bowel and anal function, the rate
of severe diarrhea must have been >18% and the differential in
favor of pre operative treatment even greater. On the other hand
if the 110 patients in the post operative arm who, for one reason
or another, had no radiation treatment are included in the toxicity score, there was no difference in rate of severe acute grade 3
or 4 toxicity.
Other grade 3 or 4 acute side effects reported in the German
study were hematologic and dermatologic. The percent grade 3
and 4 hematologic toxicity was 6% in the pre and 8% in the post
operative arms (p = 0.27). Dermatologic toxicity refers to radiation dermatitis in the perineal skin or perineal crease suture line
(Figure 30.1). Grade 3 or 4 radiation dermatitis is reported for
11% of pre and 15% of the post operative patients who had radiation (p = 0.09). The rate of grade 3 or 4 level acute toxicity of any
kind was 27% in the pre and 40% in the post operative patients
who had radiation (p = 0.001).
These results from two randomized studies support the conclusion that pre operative standard fractionated 5 to 6 week radiation treatment with chemotherapy produces less diarrhea and
other acute adverse effect than in comparable patients who have
the same treatment after surgery. The differential is definitely
present. However it is a modest difference so that, in itself, it does
not provide a compelling reason for preferring preoperative neoadjuvant treatment over postoperative treatment. Further more,
28% of patients in the post operative arm of the German study
were spared radiation treatment because of the finding of stage
I disease (18%) or distant metastasis (10%) at surgery, and thus
had zero adverse radiation effects.
The short preoperative radiation treatment course of 5 fractions of 5 Gy each in one week rarely produces significant adverse
effects in the 2 to 3 weeks during radiation treatment and before
surgical resection. In the Dutch TME trial, grade 1 acute gastrointestinal side effects were reported in 12%, grade 2 in 2.3%
and grade 3 in 1 of 605 patients.(19) Acute neurologic effects of
radiation were reported as grade 1 (requiring no intervention) in
7.5%, as grade 2 (requiring narcotic pain medicine or adjustment
of treatment) in 1% and grade 3 (intractable severe pain or causing treatment interruption) in 2.8%. This has been attributed to
radiation induced lumbosacral plexopathy. It was first reported in
patients treated with the short course in Upsala and in the Swedish
Rectal trial.(33) It consists of pain in the lower extremities and
gluteal area and in a minority of the patients it was associated
with other lower extremity neurologic signs. In a few patients the
effect persisted or recurred for months to years. Acute neurologic
effects have not been reported with the lower fractional doses of
the long course preoperative radiation treatment. Acute effects on
Figure 30.1 Radiation dermatitis.
the genitourinary and other systems were less frequent than those
manifest in the GI and neurologic systems.
SURGICAL COMPLICATIONS AFTER
PREOPERATIVE IRRADIATION
Patients treated preoperatively with short course radiotherapy in
the Stockholm I trial had surgical mortality of 8% compared with
2% in the surgery only arm (p < 0.01).(1) Among patients over 75
years in age the mortality in the preop arm was 16% and again only
2% in the surgery only arm. The dominant cause of the increase in
post operative death was cardiovascular. The radiation treatment in
Stockholm I was specified to be with AP and PA directed beams only
and encompassed, in addition to the pelvis, the para-aortic nodes
cephalad to the L2 vertebral level. With the inclusion of laterally
directed beams and restriction of the radiated volume to the pelvis as
well as exclusion of the elderly patients in the subsequent Stockholm
II, Swedish Rectal and Dutch TME trials the surgical mortality was
not statistically different between preop radiation and surgery only
arms.(17–19) For instance, in the Dutch TME trial the surgical mortality was 3.5% in the preoperative radiation arm and 2.6% in the
surgery only arm (p = 0.38).(34) The in-hospital death rate was 4%
in the preop radiation arm and 3.3% in the surgery only arm (p =
0.49) and very strongly correlated with age in both arms. There was
no exclusion for age in this trial with the oldest patient being 92.
In the Dutch TME trial there was no significant difference
between the two arms in operating time (median 180 minutes), or
improved outcomes in colon and rectal surgery
length of hospital stay (15 or 14 days median).(34) Median blood
loss in the preop radiation arm was 1,100 ml. In the surgery only
arm it was 1,000 ml (p < 0.001). The percent of LAR patients with a
diverting stoma increased from 60 to 67% in the 60 days following
surgery. In the surgery only arm it increased from 54 to 63% (p =
0.17). A statistically significant difference in postoperative complications between the arms was found for cardiac events; 5% with
preop radiation and 3% surgery only (p < 0.05), psychologic disor-
ders; 4% with preop radiation and 1% surgery only (p < 0.01), and
for any complication; 48% in preop radiation arm and 41% surgery only (p < 0.01). Complications in the APR patients occurred
in 29% of irradiated patients and 18% of surgery only patients
(p < 0.01). There was no significant difference in complication rate
among LAR patients, 11 and 12% in respectively the radiation and
surgery only arms. These results indicate that there is the potential
for short course preoperative radiation to complicate the ensuing
surgery and recovery particularly manifest in patients over the age
of 70 and even more so in those over the age of 80. This is minimized but not eliminated by adherence to the now standard radiation treatment planning specifications noted in the introduction.
The German trial required TME surgery but excluded patients
over the age of 75. The radiation treatment was the long course
(50.4 Gy in 28 fractions of 1.8 Gy each) with concurrent chemotherapy and was given either pre- or postoperatively.(26, 35) There
was 0.8% surgical mortality in the preop arm and 1% in the post
op arm indicating no increase attributable to the preop radiochemotherapy. The incidence of any postoperative complication was
34.5% in the preop arm and 34% in the postop arm. Anastomotic
leak occurred in 13 and 12%, delayed wound healing in 5 and
6% of, respectively, pre and postop arms. All other complications
occurred in <3% of each arm with no significant difference.
The Polish trial randomized patients between preoperative short
course radiation and long course radiation with chemotherapy.(22,
36) Surgery was by TME for the more distal tumors and patients
over age 75 were excluded. The overall rate of complication events
was 31% in the short course arm and 22% in the long course arm
(p = 0.06) showing a near significant trend. The overall number
of patients suffering a complication was 27% in the short and
21% in the long arm (p = 0.27). Post operative death occurred in
0.7% of the long course and 1.3% of the short course arm (p =
1.0). Re-operation was needed in 8.2% of the short and 9.5% of the
long course patients (p = 0.85). No statistically significant difference, and no suggestive trend, was found to favor one or the other
arm with respect to other less severe complications.
In conclusion, it appears that if patients over age 75 are
excluded there is little or no significant increase in the risk of surgical mortality and other complications with either the short or
long preoperative courses of radiation treatment. The risk of surgical mortality and complications is likely increased by the short
course of preoperative radiation in the more elderly patients. It
has not been shown whether or not a similar increase in surgical risk is incurred in older patients with the long preoperative
radiochemotherapy course.
CHRONIC LATE ADVERSE EFFECTS OF RADIATION
Patients enrolled in the Dutch TME preoperative short course
radiation trial who were alive with no evident disease were sent a
questionnaire by mail to assess bowel, stoma and urinary function.
(37) A response was obtained from 597 (84% of those mailed).
Among these the median time since surgery was 5.09 years. The
mean number of bowel movements during the day among the 362
patients who had no stoma was 3.69 in the irradiated patients and
3.02 in the surgery only patients (p = 0.011). The mean number of
nocturnal movements was 0.48 in the irradiated patients and 0.35
in the surgery only (p = 0.207). Daytime fecal incontinence was
reported in 62% of those irradiated and 38% of the surgery only
patients (p < 0.001) and nocturnal incontinence in, respectively,
32 and 17% (p = 0.001). The incontinence also occurred more
often and was more troublesome in the irradiated compared to
surgery only patients. Pads were in use for incontinence and anal
mucous and blood loss in 56% of irradiated and 33% of surgery
only patients (p < 0.001). Among the 235 responding patients
with a stoma there was no significant difference between irradiated and surgery only patients with respect to stoma function.
A review of the patients treated on the Dutch TME trial was
conducted to determine risk factors for development of fecal
incontinence.(38) Potential risk factors examined included age,
gender, childbirth, body mass index, cancer stage, tumor distance
from anal verge, anastomosis distance from anal verge, duration
of surgery, blood loss at surgery, presence of a pouch, temporary
stoma and anastomotic leak. No risk factors emerged as statistically significant among the surgery only patients. Among the
preoperative radiation patients only blood loss at surgery and
distal tumor margin distance from the anal verge were statistically significant risk factors. Blood loss at surgery >1,400 ml had
relative risk (RR) of incontinence of 3.24 (p = 0.005) compared
to those with less blood loss. Relative to distance of distal tumor
margin <5 cm from the anal verge, distance between 5 and 10
cm had RR of 0.21 (p = 0.016), and >10 cm had RR of 0.13 (p =
0.003). The location of the distal tumor extent determines the
inferior extent of the radiation treatment port. Among those few
respondents who had the perineum, and consequently the entire
anal sphincter, included in the radiation field compared to those
who did not, the RR for fecal incontinence at 2 years after surgery was 2.64 (p = 0.085) and at 5 years after surgery the RR was
7.45 (p = 0.059). It was also noted that the fraction of patients
reporting fecal incontinence increased after reaching a minimum
at 2 years postsurgery whereas that in surgery only patients it
increased only slightly. This time course is consistent with a late
effect of radiation on pelvic nerves and fibrosis.
Urinary function was not significantly different in irradiated
and surgery only patients. About 39% of patients in each group
reported incontinence of urine. Back and buttock pain, hip stiffness and difficulty walking were not significantly different in the
two groups suggesting absence of chronic radiation induced lumbosacral plexopathy in this trial.
The rate of hospital admission was significantly increased in
the irradiated patients compared with surgery only patients in
the first 6 months after surgery. Admissions were for infection,
endocrine, cardiovascular and gastrointestinal diagnoses. Of
note, among gastrointestinal admissions, those for constipation
and abdominal pain were significantly increased in irradiated
patients but those for bowel obstruction were not. The rate of
hospital admission more than six months after surgery was not
radiation therapy: acute and late toxicity
significantly different for patients in the two groups including for
myocardial infarction or stroke.
A comparative study by phone interview of patients two or
more years after they had undergone LAR for rectal cancer at
Mayo clinic reports significantly more bowel symptoms in the
41 who had also had postoperative long course pelvic irradiation
and chemotherapy than in the 59 who had only surgery.(39) The
fraction having more than 5 bowel movements a day was 37%
in the irradiated group and 14% in the surgery only group (p <
0.001). The fraction of patients who reported incontinence was
66% in the irradiated group and 7% in the surgery only group
(p < 0.001). In the irradiated group 41% wore a pad and in the
surgery only group 10% (p < 0.001). Urgency with inability to
defer defecation for 15 minutes was reported in 78% of the irradiated and 19% of the surgery only patients (p < 0.001).
A retrospective study of 192 patients who had LAR with coloanal anastomosis at the Mayo clinic and had preopertative (long
course) radiation, postoperative radiation or no radiation reports
anastomotic stricture was the most common late effect requiring surgical intervention.(40) This occurred with nearly the
same frequency in all three groups; 16% no radiation, 14% preop
radiation and 15% post op radiation. It was usually managed
with dilation and was not a significant cause of permanent fecal
diversion. Permanent fecal diversion resulted from recurrence,
bowel obstruction, incontinence, fistula, stricture, abscess/leak
and patient preference. The five year survival without colostomy
was 92% in patients who had no radiation treatment and 72% in
those did (p < 0.001). There was no significant difference between
the rate in pre and post operatively irradiated patients.
A scale adopted by the RTOG and EROTC for reporting late
chronic effects of radiation on the bowel is as follows.(30) Grade
1 implies mild diarrhea, mild cramping, 5 movements per day,
slight rectal discharge or bleeding. Grade 2 implies moderate
diarrhea and colic, more than 5 movements per day, excessive
mucous or intermittent bleeding. Grade 3 implies obstruction or
bleeding requiring surgery. Grade 4 implies necrosis, perforation
or fistula. Fecal incontinence was not explicitly included in the
grading criteria.
The German trial reports grade 3 and 4 long-term gastrointestinal effects, for example, diarrhea and small bowel obstruction, in
9% of the preop arm and 15% of the postop arm (p = 0.07); anastomotic stricture in 4% of the preop and 12% of the post op arms
(p = 0.003).(26) Bladder dysfunction of grade 3 or 4 occurred in
2% of the preop and 4% of the postop arms (p = 0.21). Any grade
3 or 4 effect occurred in 14% of the preop and 24% of the postop
patients (p = 0.01). With the long course fractionation of pelvic
chemoradiotherapy for adjunctive treatment of rectal cancer, the
preoperative irradiation appears significantly less likely to produce
severe chronic long-term sequelae than postoperative irradiation.
The Polish trial comparing short course preoperative radiation
with long course preoperative radiochemotherapy at median follow up of 48 months reports the overall incidence of late toxicity as 28.3% in the short and 27% in the long course arms (p =
0.81).(22) The incidence of severe late toxicity, presumably grade
3 or 4, was 10.1% in the short and 7.1% in the long course arms
(p = 0.36). Severe gastrointestinal toxicity occurred in 5.1% of
the short and 1.4% of the long course patients, no p value given.
A quality of life questionnaire on anorectal function including
questions on bowel function, continence and urgency reports no
significant difference between the short and long course arms.
(40) For instance, 39% and 41% of, respectively, the short course
and long course patients reported use of pads. In answering the
question, “did your health status and/or treatment cause your
sexual life to decline” there also was no significant difference in
the two arms. This direct comparison of long and short course
preoperative treatment shows no statistically significant difference in late toxicity.
The evidence from the several trials summarized here indicates
that both preoperative and postoperative radiation treatment are
associated with increased chance of chronic adverse effect on bowel
function. The direct comparison of pre- and postoperative long
course radiochemotherapy in the German trial indicates there is
less likelihood of this with the preoperative treatment. The Polish
trial comparing long and short course preoperative irradiation
finds no clear difference and does not resolve the issue of which of
these has the least chance of producing chronic adverse effects.
CHRONIC RECTAL EFFECTS
In contrast to acute radiation injury, chronic injury is an indolent process that can present three months after therapy completion or up to 30 years later.(41) In addition to the acute cellular
toxicity, radiation causes a progressive, obliterative arteritis, and
submucosal fibrosis. Transmural injury of the bowel wall can lead
to a progressive vasculitis, thrombosis and ultimately, to varying
degrees of ischemia and necrosis. This process may lead to narrowing of the bowel lumen and eventual obstruction. The effects
of chronic radiation are primarily related to the total dose of radiation received as well as the total volume of tissue irradiated.(42)
There is some evidence to suggest that chronic radiation proctitis
is more likely to occur in those initially experiencing severe acute
proctitis and this has been termed the consequential late effect.
(43) However, the absence of acute complications does not protect against the development of chronic radiation induced injury.
Several other factors have also been identified that may increase
the likelihood of developing chronic radiation injury. This
includes a history of prior abdominal or pelvic surgery, presumably secondary to adhesion formation resulting in entrapment of
the bowel, and a history of vascular occlusive disease (including
hypertension and diabetes).(41, 44)
Of all the gastrointestinal organs, the rectum is most commonly affected by pelvic radiotherapy.(45) It has been estimated
that 75% of subjects receiving pelvic radiotherapy will experience
rectal symptoms during treatment and almost 20% will continue
with chronic proctitis.(46) In addition, 5% may develop perirectal fistulas, strictures or incontinence. Symptoms include loose
stools, urgency, bleeding, pain, and tenesmus. Endoscopy reveals
friability and granularity, pallor, erythema or prominent submucosal telangiectasias (Figure 30.2).(47) Histologic findings in the
chronic phase include severe vascular changes such as telangiectasia of capillaries, platelet thrombi formation and narrowing of
arterioles always accompanied by lamina propria fibrosis and
crypt distortion.(48)
Though rectal bleeding is most often the presenting symptom
of chronic proctitis in the setting of prior radiation, it should
improved outcomes in colon and rectal surgery
Figure 30.2 Radiation Proctitis.
not be assumed that this is the sole cause. As up to one-third of
patients were found to have a diagnosis unrelated to the previous
radiotherapy and 12% had a significant neoplasia, endoscopic
evaluation is mandatory. with new onset of hematochezia after
prior radiation therapy.(49)
Treatment
Numerous therapeutic agents have been evaluated and/or are
currently utilized against radiation-induced proctitis. In many
cases, patients presenting initially with symptoms suggestive of
radiation proctitis will first be offered treatment with antiin-
flammatory medications. This most commonly involves either
oral or enema delivered steroids or various 5-Aminosalicylic
acid (5-ASA) preparations. Though often utilized in both the
acute and chronic settings, evidence is lacking for the use of
steroid preparations in the treatment of radiation proctitis.
A prospective, randomized trial compared oral sulfasalzine plus
rectal steroids to rectal sucralfate and oral placebo. The sulfasalzine regimen did demonstrate a significant improvement
in both clinical symptoms and endoscopic findings, however, by
comparison clinically this was less effective than sucralfate.(50)
Sucralfate provides a protective barrier and promote epithelial
healing has allowed its use in the treatment of radiation proctitis. One randomized, controlled trial found that oral sucralfate
decreased diarrhea symptoms in both the acute and chronic
phases.(51) Short-Chain Fatty Acids (SCFA) act as a major fuel
source for colorectal mucosa. Two small randomized, placebo
controlled trials using SCFA enemas noted improvement in
symptoms and endoscopic findings.(41, 52)
Various endoscopic ablation therapies have been applied to
the treatment of chronic proctitis related bleeding due to local
telangiectasias. The two most commonly utilized approaches are
the laser and the argon plasma coagulator. There are no prospective, randomized trials assessing either of these approaches,
only several retrospective case series. The largest series reporting
on the use of Nd:YAG laser found excellent response rates and
a significant decrease in rectal bleeding.(53) Rare complications
included mucous discharge, ulcers or stricture. Similar results
were obtained using an argon plasma coagulator in three treatment sessions.(54) However, over 70% required maintenance
treatment over the long term.(55)
Four and ten percent formalin have been utilized for the treatment of bleeding related to chronic proctitis. Two approaches are
commonly utilized, that of a rectal formalin irrigation and a dab
technique utilizing topical application of formalin with swabs
or soaked gauze. De Parades et al. reported a prospective case
series using the formalin gauze application and noted a beneficial
result in 70%.(56) However, significant rates of stricturing and
incontinence were reported. Numerous other retrospective series
have reported good success with formalin. Of those using a gauze
or pledget mediated application, at least a 75% success rate for
cessation or improvement in bleeding was reported.(57) Many
required multiple treatments though complications were minimal. Due to the small volume used, 10% formalin is often used.
Of those reporting use of formalin rectal irrigations, 50 cc aliquots of 4% formalin were utilized up to a total volume of 400–500
cc. Again a >75% success rate was noted with this approach, with
the most common reported complication being anal or pelvic
pain occurring in 25% of those treated.(58)
There is low level evidence supporting the use of hyperbaric
oxygen treatments for chronic radiation proctitis and a single
prospective series which reported significant improvement of
bleeding, diarrhea and urgency, but no change in rectal pain with
oral vitamins E and C.(59, 60) Metronidazole along with antiinflammatory agents (oral mesalazine and betamethasone enema)
produced a significantly lower incidence of rectal bleeding and
diarrhea in chronic radiation proctitis.(61)
Despite the numerous medical approaches available for the
treatment of radiation proctitis, surgical therapy remains an
option for refractory cases The indications for surgery are most
commonly rectum or rectosigmoid stenoses and rectovaginal fistulae, while the most common presenting symptoms are rectal
bleeding, diarrhea, or tenesmus.(61) The majority of patients
undergo diversionary procedures (proctectomy with colostomy,
with or without a Hartmann rectal stump) with resection performed less commonly. When continuity is restored, a coloanal
anastomosis (with or without colonic J-pouch) with proximal covering stoma is the procedure of choice in select cases.
Successful outcomes with diversion alone are reported in the
range of 72–73%.(62) In refractory rectal bleeding this option
has less morbidity. Overall, morbidity with surgical intervention
is extremely high, ranging from 30% to 65% with mortality rates
in the postoperative period reported at 6.7–25%.(62, 63)
CONCLUSION
Chemotherapy and radiation treatment to the pelvis as an adjuvant to surgical resection, either individually or when both are
administered, reduces the chance of pelvic recurrence and can
increase the chance of a patient’s surviving the disease. This has
been demonstrated in several randomized trials for both the preand postoperative treatment sequences, as noted in the tables and
in meta analyses.(2, 3, 64) However, the adjunctive treatment
has the potential for significant adverse effects. It is important
to select the form of adjuvant treatment likely to be most beneficial. It is also important to select for adjuvant treatment those
radiation therapy: acute and late toxicity
patients most likely to benefit and exclude those most likely to
suffer severe or life threatening adverse effects.
That preoperative treatment with radiation can complicate the
ensuing surgery and postoperative recovery is illustrated in the
occurrence of additional non cancer, mostly cardiovascular, deaths
among the irradiated patients in the immediate postoperative period
and the first six months post surgery in the Stockholm trials. Similar
adverse effect was not evident in the later Swedish and Dutch TME
trials that also used the short course radiation regimen nor was it
evident in the studies that used the long course preoperative treatment regimens. These later trials were with better radiation therapy
technique and all but the Dutch TME trial excluded the most elderly
patients. Nevertheless, the potential for serious adverse effect on the
surgery is still a consideration. It is clear that this is minimized by
restricting the irradiated volume to those parts of the pelvis at risk
for harboring disease and that elderly patients are most at risk from
adding preoperative adjunctive treatment to the surgery.
Reduction in local recurrence by preoperative treatment is
present even when surgery is by TME. In the Dutch TME trial
the benefit was most significant in the node positive (stage III)
patients. It was present but rather small and did not reach statistical significance in the other stage subgroups. This suggests that
patients, particularly those older than about 75, may be better
served by proceeding directly to surgery unless there is clinical
evidence or reason to suspect nodal disease. Postoperative radiation and chemotherapy, if indicated by pathologic stage, is an
acceptable treatment option.
The German trial has provided evidence that preoperative
long course chemoradiation is in balance preferable to the similar
treatment postoperatively. The selection criteria and preoperative
treatment arm of the German trial are standard in many treatment
centers. However, given the inconclusive results of the Polish trial
comparing similar preoperative chemoradiotherapy with short
course preoperative radiation, another larger trial, with specification of post surgery chemotherapy, comparing these two forms
of preoperative treatment may be helpful as both regimens have
features to recommend them. The short course has better compliance, is more economical and has the theoretical advantage of
more timely removal of all evident disease than the long course.
The long course may facilitate complete surgical removal by more
down staging, provide earlier exposure of the patient to systemic
chemotherapy treatment and have less surgical and long-term
adverse effects than the large fractional doses of the short course.
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