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					REVIEW Scandinavian Journal of Surgery 92: 65–73, 2003


P. Hatfield, D. Sebag-Montefiore
Leeds Cancer Centre, Cookridge Hospital, Leeds, United Kingdom
Key words: Rectal cancer; local recurrence; adjuvant radiotherapy; chemoradiotherapy; palliative care;
radiotherapy toxicity

INTRODUCTION                                               REDUCING LOCAL RECURRENCE IN
                                                           RESECTABLE DISEASE
There has been considerable effort over the last three
decades to investigate the role of radiation in rectal     There is a considerable evidence base from ran-
cancer. Until the mid 1990’s randomised controlled         domised controlled trials that include a surgery alone
trials included a standard arm of surgery alone. To-       arm. Two recent overviews have been published
day, however, there is unequivocal evidence that ad-       (1, 2) with similar conclusions. One of these (1), pub-
juvant radiation reduces the risk of local recurrence      lished in 2001, examined trials started before 1987
in resectable rectal cancer. Current controversy re-       and has the advantage of access to individual patient
lates to the sequencing with respect to surgery, the       data in 22 of the 28 identified trials. Over 8000 pa-
choice of radiation schedule and the benefits of con-      tients were included in these trials (6350 in preoper-
current chemotherapy. At the same time there have          ative and 2157 patients in postoperative radiation tri-
also been important improvements in pelvic pre-            als). A highly statistically significant reduction in
operative imaging, surgical technique, and his-            local recurrence and cancer-related mortality was
topathological analysis of the resected specimen that      demonstrated, but not in overall mortality. There was
will require further randomised trials in order to re-     also clear evidence of a dose response, with a greater
fine the role of radiation in this new “era.”              reduction in local recurrence risk with the use of
                                                           higher doses of pre-operative radiation (biologically
                                                           effective dose (BED) > 30). These strategies seemed
INDICATIONS                                                more effective than post-operative radiotherapy re-
                                                           gimes of equivalent or higher BED.
There are four main indications for radiation in rec-         The earlier study (2) only examined pre-operative
tal cancer. The greatest interest has focussed on re-      radiotherapy trials. Fourteen studies were identified
ducing the risk of local recurrence in patients with       that had published by December 1999. Individual
resectable rectal cancer. The second indication is to      patient data were not analysed but crude rates of
shrink locally advanced rectal cancer to facilitate suc-   mortality, cancer related death and recurrence were
cessful resection although this is confused by a lack      combined for the meta-analysis. Similar conclusions
of agreement in how to define the local extent of dis-     were reached although the reduction in overall mor-
ease. Thirdly there is an increasing interest in the use   tality with radiotherapy just reached significance.
of radiation to shrink or “downsize” resectable dis-       This result was heavily influenced by the large size
ease to achieve sphincter-preserving surgery. Final-       of the Swedish Rectal Cancer Trial (SRCT) (3).
ly there is an important role for radiation in the pal-
liation of inoperable primary and locally recurrent
disease.                                                   PRE-OPERATIVE RADIOTHERAPY

                                                           The advantage of pre-operative radiotherapy is that
                                                           the pelvic anatomy is undisturbed. Consequently
                                                           there is usually less small bowel in the radiation field
                                                           and this results in less gastrointestinal acute toxicity
Correspondence:                                            and high compliance. The tissues are likely to be well
  D. Sebag-Montefiore, M.D.
  Leeds Cancer Centre
                                                           oxygenated and tumour radio-sensitivity may be in-
  Cookridge Hospital                                       creased. Disadvantages include over-treatment when
  Leeds                                                    a routine policy of pre-operative radiotherapy is used
  LS16 6QB                                                 exposing some patients to the risks of late radiation
  United Kingdom                                           damage without benefit. Table 1 outlines some of the
  Email:             main trials using preoperative radiotherapy.
66                                                 P. Hatfield, D. Sebag-Montefiore

                                                              TABLE 1
                                Randomised Trials of Pre-Operative Radiotherapy against Surgery alone.

Trial                       No. of patients (n) Total dose (Gy) No. of fractions          BED            LR (p value)   Survival

MRC I (4)                          564                05                01                07.5               n.s.          n.s.
MRC I                              557                20                10                20.4               n.s.          n.s.
VASOG I (5)                        700              20/25               10             21.0/28.3             n.s.          n.s.
St Marks RCG (6)                   475                15                03                22.5             < 0.050         n.s.
Essen (7)                          142                25                13                24.5               n.s.          n.s.
Bergen (8)                         309              .531.5              18                26.8               n.s.          n.s.
VASOG II (9)                       359              .531.5              18                26.8                –            n.s.
NWRCG (10)                         284                20                04                30.0             < 0.001         n.s.
SGSTCIRC Japan (11)                166                30                15                30.6               n.s.          n.s.
EORTC 76–81 (12 )                  466              .534.5              15                34.6             0 0.003         n.s.
MRC II (13)                        279                40                20                36.0               0.04          n.s.
Stockholm I/II (14, 15)           10190               25                05                37.5             < 0.010         n.s.
Swedish RCT (3)                   11650               25                05                37.5             < 0.001      p = 0.004
Dutch TME trial (16)              18610               25                05                37.5             < 0.001         n.s.

(n = number of patients considered evaluable in recent overview (1) where applicable, VASOG = Veterans Association Surgical Oncol-
ogy Group, NWRCG = North Western Rectal Cancer Group, Swedish RCT = Swedish Rectal Cancer Trial, MRC = Medical Research
Council, EORTC = European Organisation for the Research and Treatment of Cancer, TME = Total Mesorectal Excision,
BED = Biologically effective dose, LR = Local recurrence, n.s. = not significant)

THE DEVELOPMENT OF THE 25 GY                                         of five Swedish counties who met the inclusion cri-
IN 5 FRACTION SCHEDULE.                                              teria of the SRCT during the trial recruitment period
                                                                     (17). It demonstrates that 52 % of all eligible patients
The potential use of pre-operative radiation was ap-                 agreed to randomisation in the SRCT. The important
proached cautiously. One key requirement was the                     finding is that the local recurrence rate for eligible
development of a short, accelerated schedule that                    patients who did not enter the trial and who received
minimised any delay in definitive (surgical) treat-                  surgery only was identical to the local recurrence rate
ment. This led to a number of trials that used 5 Gy                  for surgery alone within the SRCT. Secondly, propo-
per fraction including two in the United Kingdom                     nents of this approach in Sweden have reported their
and three in Sweden.                                                 subsequent non-trial experience with this approach
   Both the Stockholm I (14) and the St. Marks RCG                   and demonstrated local recurrence rates less than
Study (6) used parallel-opposed fields. Furthermore,                 10 % (18).
the Stockholm I trial used very large fields with the                   There is clear evidence from the Stockholm I and
superior field border at L1/2. A subsequent trial, the               St. Mark’s RCG Study to suggest that post-opera-
SRCT (3), randomised patients between 25 Gy in                       tive mortality is increased with the use of parallel-
5 fractions using a planned 3 or 4 field approach fol-               opposed fields. This problem was rectified in the
lowed by surgery and surgery alone. Impressively,                    SRCT trial protocol by mandating the use of a
1168 patients were randomised between 1987 and                       planned 3 or 4 field arrangement with the superior
1990. After a minimum follow up of 5 years, there                    border at the L4/5 junction. Interestingly, in the 8 %
was a statistically significant and clinically meaning-              (48 of 573) of patients with protocol deviations in
ful reduction in local recurrence (from 27 % to 11 %)                the SRCT where only two fields were used, in-
and improvement in overall survival (from 48 % to                    creased mortality was seen. It is therefore essential
58 %) when pre-operative radiation preceded sur-                     that when the 25 Gy in 5 fraction schedule is em-
gery. The results from this trial were very influential              ployed that a planned three or four field technique
because of the consistent findings of improved local                 is used.
control in the previous ICRF, Stockholm I and II tri-
als and the improvement in survival that was seen
for the first time in the largest trial. Adjuvant chem-              “LONG COURSE” PRE-OPERATIVE RADIATION
otherapy was not used in any of the patients in the                  SCHEDULES
   There is therefore considerable supporting evi-                   The alternative approach is to use a longer course of
dence from individual randomised controlled trials                   radiation with a lower dose per fraction. Most cur-
using a 5 Gy accelerated radiation schedule. This is                 rent long course schedules use 45–50.4 Gy over 5–
confirmed within the recent overview where the                       5.5 weeks using 1.8–2.0 Gy per fraction. Despite evi-
above trials represent over 70 % of the patients with-               dence for improved local control there is no trial ev-
in the subset of > 30 Gy BED. One important further                  idence for improved survival using this strategy. The
question is whether this approach can produce a sim-                 main reason for the use of such schedules relates to
ilar level of benefit when applied to the general pop-               the trials of post-operative radiation and chemoradi-
ulation. There is indirect evidence that supports this               ation and the translation of radiation schedules de-
view. Firstly a study has identified through Swedish                 veloped in unresectable disease to patients with re-
Cancer registries all patients within the population                 sectable disease. The concurrent chemoradiotherapy
                                                The use of radiotherapy in rectal cancer                                            67

                                                               TABLE 2
                        Randomised trials comparing post-operative radiotherapy to surgery without radiotherapy.

Trial                          No. of patients (n)           Dose                 Fractions        LR significance (p)   Survival

GITSG (20)                             227                  40–48                   20–28                  n.s.            n.s.
ECOG (21)                              208                    45                      25                    –              n.s.
NSABP R-01 (22)                        381                  46/47                   26/27                 0.060            n.s.
Odense (23)                            495                    50                      25                   n.s.            n.s.
EORTC 81–86 (24)                       172                    46                      23                   n.s.            n.s.
Rotterdam (25)                         172                    50                      25                   n.s.            n.s.
ANZ Study (26)                         033                    45                      25                   n.s             n.s.
MRC3 (27)                              469                    40                      20                  0.001            n.s.

(n = number of patients considered evaluable in recent overview (1), MRC = Medical Research Council, GITSG = Gastrointestinal Tu-
mour Study Group, NSABP = National Surgical Adjuvant Breast and Bowel Project, EORTC = European Organisation for Research and
Treatment of Cancer, LR = Local recurrence rate, n.s. = not significant).

(cCRT) schedules are discussed in the section on lo-                  as a control arm (see Table 2). The MRC3 trial is the
cally advanced disease.                                               only trial that demonstrated a statistically significant
   The use of cCRT pre-operatively in resectable dis-                 reduction in local recurrence, with no impact in over-
ease has dramatically increased despite a very small                  all survival. The systematic overview, however, dem-
evidence base of randomised controlled trials. The                    onstrates that there is a significant improvement in
current EORTC 22921 trial in resectable disease com-                  local recurrence and cancer specific survival although
pares pre-operative RT with cCRT and also tests the                   the proportional reduction of these events is smaller
benefit of post-operative adjuvant chemotherapy                       than that found for pre-operative radiation. Most of
(aCT) against control. The German CAO/ARO/                            the post-operative trials are small and therefore un-
AI094 trial compares pre and post-operative cCRT.                     derpowered to detect small improvements.
A recent Polish trial has completed recruitment com-
paring short-course pre-operative radiotherapy
(SCPRT) with cCRT (19).                                               THE DEVELOPMENT OF POST-OPERATIVE
   Pre-operative long course cCRT, is used particu-                   CHEMORADIATION.
larly in mainland Europe. However the indications
may include macroscopic tumour shrinkage to facil-                    The relatively disappointing results of the trials of
itate successful resection, reduction of local recur-                 post-operative radiation alone, and the aim of im-
rence risk and to increase the probability of sphinc-                 proving overall survival, led to trials that integrated
ter preservation.                                                     chemotherapy. Interpretation is difficult mainly due
                                                                      to trial design. It is important to distinguish between
                                                                      concurrent chemoradiation (cCRT) when chemother-
POST OPERATIVE RADIATION                                              apy is delivered during the radiation phase of treat-
                                                                      ment and adjuvant chemotherapy (aCT) when chem-
The main advantage of post-operative radiation is the                 otherapy alone at systemically effective doses is de-
ability to select patients considered to be at increased              livered either prior to or after the radiation phase of
risk of local recurrence based on histopathological                   treatment.
examination of the resected specimen. This avoids
the inevitable over-treatment that comes with a poli-
cy of routine SCPRT. Disadvantages are that a high-                   RANDOMISED TRIALS TESTING POST-
er dose of radiation is required (which may relate in                 OPERATIVE CHEMORADIATION
part to hypoxia within the field of surgery) and small
bowel acute toxicity is increased. This is due to the                 There are at least 7 randomised trials that have test-
presence of larger volumes of bowel within the radi-                  ed the role of post-operative chemoradiation (see Ta-
ation field and adhesions that may reduce its mobil-                  ble 3). Of these, only 3 trials have included a surgery
ity. There is also the problem of compliance (ability                 alone arm and 3 a chemotherapy alone arm. There is
to receive the planned total dose of radiation) either                therefore considerable heterogeneity within the trials.
due to inadequate recovery from surgery prior to re-                     In North America, the current standard of care
ceiving radiation or acute toxicity curtailing treat-                 consists of post-operative chemoradiation (aCT +
ment before the planned total dose has been reached.                  cCRT) for patients with pT3/4 or N+ disease (TNM
                                                                      stage II and III). This view was defined by the Na-
                                                                      tional Institute of Health in a consensus statement in
RANDOMISED CONTROLLED TRIALS USING                                    1990 (35), based on the results of three trials conduct-
POST-OPERATIVE RADIATION.                                             ed in the United States. These were the Gastrointes-
                                                                      tinal Tumour Study Group (GITSG) 71–75 (28), the
Eight evaluable randomised trials have been identi-                   North Central Cancer Treatment Group (NCCTG)
fied in the overview (Lancet) that assess post-opera-                 794751 (29) and the National Surgical Adjuvant
tive radiation (BED 36–44) and include surgery alone                  Breast and Bowel Project (NSABP) R-01 (22) studies.
68                                              P. Hatfield, D. Sebag-Montefiore

                                                           TABLE 3
                             Important randomised trials involving post-operative chemoradiotherapy.

Trial                                No.             Treatment arms                       Results

GITSG 7175 (28)                       227            Surgery alone                        5YS: RT + MF 59 %, Control 43 %
                                                     MF                                   (p < 0.01)
                                                     RT + MF
Mayo/NCCTG 79-47-51 (29)              204            MF + 5FU/RT + MF                     7YS: Combined arm 63 %, RT alone
                                                     RT                                   48 % (p = 0.04)
GITSG 7189 (30)                       210            5FU/RT + 5FU                         3yr DFS: 45 % MF vs 69 % 5FU
                                                     MF/RT + MF
Mayo/NCCTG 86-47-51 (31)              453            MF + RT/5FU + MF                     MF not better than 5FU alone
                                                     (bolus vs infusional 5FU)            Infusional superior to bolus 5FU
                                                     5FU + RT/5FU + 5FU
                                                     (bolus vs infusional 5FU)
Norway (32)                           144            Surgery                              Local recurrence: 32 % vs 11 % (p < 0.05)
                                                     Surgery + 5FU/RT                     Survival: 49 % vs 63 % (p < 0.05)

NSABP R-02 (33)                       694            Chemotherapy vs Chemo/RT             Radiotherapy did not improve overall
                                                     (Men-MOF or 5FU/LV,                  survival but did reduce local recurrence
                                                     women 5FU/LV)
INT 0114 (34)                       17920            5FU + RT/5FU + 5FU                   No significant difference between arms
                                                     + LEV or LV or both

(INT = Intergroup, NCCTG = North Central Cancer Treatment Group, 5FU = 5-Fluorouracil, MF = methyl CCNU + 5FU, MOF =
MF + vincristine (Oncovin), LV = leucovorin, LEV = levamisole, RT = pelvic radiotherapy)

   The NCCTG trial was perhaps the more influen-                  PRE-OPERATIVE VERSUS POST-OPERATIVE
tial and randomised only 204 patients. There was a                RADIATION.
statistically significant reduction in local recurrence
and improvement in overall survival. It is important              The Uppsala trial (37) randomised 471 patients be-
to note that one arm of the study consisted of radia-             tween routine SCPRT and “selective” post-operative
tion alone and the other aCT both before and after                radiation alone to patients with T3 or N+ disease
cCRT. It is therefore impossible to assess the relative           (stage II and III). The postoperative radiation consist-
contributions of the aCT and cCRT components. The                 ed of 60 Gy in 30 fractions given as a split course.
subsequent NCCTG 864751 trial (31) demonstrated                   There is little doubt that a maximal dose of radiation
an improvement in overall survival but no difference              was delivered post-operatively although there may
in local recurrence for continuous infusion 5FU com-              be criticism of the radiobiological disadvantages of
pared with bolus 5FU during cCRT (with aCT given                  a split course treatment. This trial demonstrated a
before and after cCRT). The one small trial that di-              local recurrence rate of 13 % following routine
rectly compared post-operative cCRT with surgery                  SCPRT compared with 22 % using “selective” post-
alone did show a significant reduction in local recur-            operative radiotherapy. There was no difference in
rence and improvement in overall survival (32). In                overall survival.
contrast, the NSABP R02 trial (33) demonstrated that                 The recent overview demonstrates clear evidence
the addition of cCRT to aCT compared to aCT alone                 that adjuvant radiation significantly reduces the risk
did not show any impact on overall survival al-                   of local recurrence and is effective when used pre-
though there was a significant reduction in local re-             operatively or post-operatively. The randomised con-
currence as the first component of failure to 8 %                 trolled trials have significantly influenced clinical
(cCRT + aCT) from 13 % (aCT).                                     practice. In Sweden, a policy of SCPRT is the pre-
   The current North American standard of care,                   ferred approach, whereas in North America the
which was defined 12 years ago has some disadvan-                 standard of care has been widely adopted using “se-
tages. Firstly, although considered “selective” only              lective” post-operative chemoradiation for stage II
stage I (T1-2N0) patients avoid post-operative aCT                and III patients.
and cCRT. Secondly, the acute toxicity of post-op-
erative cCRT is significantly greater than a pre-op-
erative approach. Thirdly, there is recent evidence               A NEW ERA OF CLINICAL TRIALS OF
that a policy of post-operative aCT and cCRT is not               ADJUVANT THERAPY IN RECTAL CANCER
necessarily translatable to the general population
particularly when the older patient is considered                 There is now considerable evidence to demonstrate
(36).                                                             improved outcome following careful sharp surgical
                                          The use of radiotherapy in rectal cancer                                    69

dissection of the mesorectal tissue. There appears to              A number of publications have already reported
be general agreement as to the importance of sharp              certain aspects of the trial in more detail. Histopatho-
circumferential dissection. There is still debate relat-        logical stage and the incidence of CRM involvement
ing to the longitudinal extent of the mesorectal exci-          are not altered when surgery takes place within 10
sion. The evidence comes directly from individual               days of the initial fraction of SCPRT (43). A simple
surgical series (38), population based studies (39, 40)         grading system applied to the gross surgical speci-
and indirectly from a recently published randomised             men in a small subset from the trial appears to cor-
controlled trial (16). This development alone is suffi-         relate with local outcome (44).
cient to draw a distinction between the randomised                 It is inevitable that subset analysis will be per-
trial evidence discussed above where the local recur-           formed to try and identify patients who will and will
rence rates following surgery alone were commonly               not benefit from SCPRT. There are numerous intrigu-
greater than 20 % and the proponents of sharp mes-              ing subset analyses from this trial including the tim-
orectal dissection who report local recurrence rates            ing of surgery and operative mortality (45), the im-
of 10 % or less.                                                pact of SCPRT on an involved CRM (46) and differ-
   A further improvement relates to the examination             ences in local recurrence rates with respect to tumour
of the histopathological specimen. There is strong              position (16). We must be very cautious in regarding
evidence to support the hypothesis that local recur-            such subset analyses as anything more than hypoth-
rence of rectal cancer is predicted by the presence of          esis generating. They require further randomised ev-
microscopic cancer cells within 1mm of the circum-              idence to confirm or refute them (47).
ferential resection margin (CRM). This has been dem-               In the United Kingdom, the Medical Research
onstrated by the initial and subsequent reports from            Council (MCR) CR07 trial has a very similar trial de-
Professor Quirke’s group in Leeds (41, 42) and a pop-           sign to the Dutch trial. One important difference is
ulation-based audit in Norway (40).                             the use of cCRT for patients with an involved CRM
   There was therefore a need to test the policy of             after initial surgery. Over 800 patients have been ran-
routine SCPRT when this is added to surgical exci-              domised (October 2002) and it continues to recruit.
sion based on sharp mesorectal excision. An alterna-
tive approach would consist of initial surgery and the
use of a “selective approach” to post-operative radi-           LOCALLY ADVANCED DISEASE
ation based on involvement of the CRM (rather than
patients with stage II and III disease).                        A major problem is the lack of an agreed definition
                                                                of “locally advanced” disease. The development of
                                                                pre-operative imaging assessment has focussed on
                                                                prediction of T and N stage, with trans-rectal ultra-
                                                                sound accepted as the reference investigation. The
                                                                recognition of the importance of CRM has led to in-
Two trials were planned using the above approach.               creased interest in cross-sectional imaging (particu-
The Dutch Colorectal Cancer Study Group trial (16)              larly MRI) to demonstrate the relationship of the tu-
randomised 1861 patients between 1996 and 1999. It              mour to the mesorectal fascia, the intended “CRM”
attempted to standardise surgery by including a                 for a mesorectal excision. Digital rectal examination
training programme for the use of total mesorectal              performed by experienced coloproctologists can also
excision (TME) and histopathological assessment in-             identify patients with a poor outcome with surgery
volved determination of the CRM. The trial com-                 alone (48).
pared a policy of routine SCPRT with initial TME and               Therefore, locally advanced disease may apply to
post-operative radiation (50 Gy in 25 fractions) for            a spectrum of disease that ranges (for some clini-
involvement of the CRM. Patients with resectable                cians) from resectable T3N1 disease on TRUS to a
disease whose margins were considered likely to be              fixed tumour invading the prostate and sacrum. This
tumour free were considered eligible.                           leads to great difficulty in interpreting individual
   The initial early outcome of this trial reported lo-         studies of chemoradiation.
cal recurrence at two years of 2 % with the use of
SCPRT and 8 % with initial TME with no significant
difference in overall survival. Acute complications             DEVELOPMENT OF PELVIC MRI
attributable to the addition of SCPRT included a
slight increase in blood loss and delayed perineal              A number of small single centre studies (49–53) re-
wound healing. We will have to wait for mature fol-             port the value of high resolution pelvic MRI using
low up for 5 year local recurrence rates and data on            phased array surface coils in the pre-operative stag-
late functional outcome.                                        ing of rectal cancer. There is early promise that this
   This trial also describes a new benchmark for the            approach can identify patients whose local disease
use of TME in a multicentre trial setting. Curative             extent invades beyond the mesorectal fascia (com-
resection was achieved in 90 %. Seventy percent of              monly described as T4 disease) and where the pri-
patients underwent sphincter-preserving resections              mary tumour extends close to the mesorectal fascia.
with an anastomotic leak rate of 12 %. The overall              Prospective studies are in progress to try and con-
rate of involvement of the CRM was 17 % and was                 firm these findings. Pelvic MRI may be a future
lower for anterior resections when compared with                method of defining the local disease extent and fa-
abdomino-perineal resection.                                    cilitate future randomised controlled trials.
70                                            P. Hatfield, D. Sebag-Montefiore

RANDOMISED CONTROLLED TRIALS                                   END POINTS

Two trials from the United Kingdom have evaluated              Most CRT phase II studies report early outcome, in-
the addition of pre-operative radiation to surgery             cluding measures of histopathological “downstag-
alone. The definition of locally advanced disease was          ing.” There is an important need to define the bene-
based on the clinical finding of tethering or fixity. The      fits of the degree of histopatholgical impact of CRT
North West Rectal Cancer trial (10) used 20 Gy in 4            in relation to the CRM and local recurrence. His-
fractions to a planned volume and the MRC CR02 tri-            topathological complete response (pCR) is common-
al (13) used 40 Gy in 20 fractions using parallel op-          ly regarded as the most important measure. Howev-
posed fields. Both trials demonstrated a significant           er the pCR rate is likely to be lower in patients with
reduction in local recurrence but no difference in             a larger volume of disease, a significant variable in
overall survival. After completion of pre-operative            studies of locally advanced disease when selection
radiation in the MRC trial there was a gap of a mini-          is not defined by MRI.
mum of four weeks prior to surgery, although this                 A lack of histopatholgical evidence of response to
did not result in any statistical improvement in the           cCRT appears to be a predictor of poor outcome (60).
curative resection rate.                                       Other studies have attempted to grade the extent of
   A small trial from Uppsala (54) randomised 70 pa-           cCRT treatment effect seen in the resected specimen
tients with fixed, unresectable disease between 46 Gy          (61, 62).
radiation alone and a complex CRT schedule using                  Failure of pre-operative cCRT in locally advanced
40 Gy and methotrexate, leucovorin and 5 fluorour-             disease is due to a number of factors and these are
acil over 8 weeks. There was a statistically significant       not always fully described in individual reports.
reduction in local recurrence with CRT but no dif-             cCRT may be considered to have failed because of
ference in overall survival.                                   acute toxicity precluding surgical resection, when
                                                               local disease remains unresectable by clinical assess-
                                                               ment or failed trial dissection and in those patients
                                                               that undergo palliative (R2) resection. There is a
It is outside the scope of this article to review the very     need for further studies to confirm whether micro-
large number of phase II studies that describe early           scopic involvement of the irradiated CRM (R1 re-
outcome following pre-operative radiation with or              section) is a further measure of failure, but this
without concurrent chemotherapy. A small number                seems likely.
of individual studies will be described to illustrate             Future studies are also required to determine
the development of chemoradiation regimens that                whether any histopathological measures of response
are in current use and the direction of future re-             to CRT will be useful surrogate predictors of local
search.                                                        recurrence and survival.
    The commonly used cCRT shedules are based on
45–50.4 Gy of pelvic radiation with either continuous
infusion 5FU or bolus 5FU and leucovorin (5FULV).              PALLIATIVE RADIOTHERAPY
Rich et al. (55) demonstrated that 300 mg/m2/day
5 days per week could be combined with 45 Gy. Al-              In patients with recurrent disease in the pelvis, or for
ternatively 5FU doses of 200–225 mg/m2/day may be              whom surgery is not an option as primary treatment
used continuously. Minsky et al have performed dose            due to co-morbidity, then radiotherapy or chemora-
escalation studies using both high dose and low dose           diotherapy can be given with palliative intent. Ob-
leucovorin combined with bolus 5FU and radiation               jective tumour regression can be produced and
(56, 57). Bosset et al. performed three consecutive            symptoms can be alleviated. Radiotherapy is partic-
phase II studies (58) that led to the recommended              ularly effective for pain, bleeding and discharge but
cCRT regimen for phase III evaluation of 45 Gy pel-            often less effective for altered bowel habit.
vic radiation with a short infusion of 5FU (350 mg/               What is not clear in the palliative setting is the
m2) and leucovorin (20 mg/m2) D1-5 and 29–33. This             optimum dose and fractionation, since there have
regimen is under evaluation in the EORTC 22921 tri-            been no significant randomised comparisons of dif-
al of resectable rectal cancer. There has not been a           ferent regimes. In very frail patients with advanced
direct comparison of 5FULV with continuous infu-               disease it can often be appropriate to give a single
sion 5FU CRT regimens and considerable uncertain-              fraction of 8–10 Gy to the pelvis, which can prove
ty remains surrounding the radiation and chemother-            extremely effective for pain and bleeding. This
apy interaction. There is a significant risk of acute          avoids the inconvenience and stress of repeated
toxicity with the use of non-validated CRT regimens            journeys to the treatment centre for more protract-
as well as uncertainty over the effect of the CRT in-          ed regimes. In fitter patients many clinicians would
teraction on late complications.                               consider 20 Gy in 5 fractions or 30 Gy in 10 fractions
    Currently there is considerable interest in the in-        but there is little evidence that these produce better
tegration of other drugs such as capecitabine, oxali-          results. In rare instances it may be justified to give
platin and irinotecan into chemoradiation schedules.           more intensive chemoradiotherapy regimes to pa-
The majority of these studies are dose finding com-            tients with better prognoses. It should be acknowl-
bination chemotherapy regimens added to radiation.             edged however that treatment intent is palliative
However, there remains considerable uncertainty as             and the side effects should be justifiable to both doc-
to how to derive the optimum regime (59).                      tor and patient.
                                          The use of radiotherapy in rectal cancer                                             71

TOXICITY OF RADIOTHERAPY                                        (66) regimes have been shown to increase bowel fre-
                                                                quency, urgency and rates of incontinence over sur-
Pelvic radiotherapy is associated with several well-            gery alone.
recognised acute and long-term toxicities. The likeli-             Sexual dysfunction is another potential late com-
hood of side effects is related to the treatment vol-           plication. It is often poorly assessed and can clearly
ume, total dose, fraction size, treatment time, beam            be multi-factorial. Surgery, radiotherapy and the psy-
energy and technique. It can also be increased by oth-          chological effects of the diagnosis and treatment are
er factors such as co-morbid conditions (e.g. diabe-            all important. Thus reliable answers will only come
tes mellitus, hypertension, connective tissue diseas-           from randomised trials
es or inflammatory bowel disease), prior surgery or                Many trials of radiotherapy and chemo-radiother-
the use of concurrent chemotherapy.                             apy are published with inadequate details on long-
   Acute complications include effects on small bow-            term toxicity and quality of life. To some extent this
el (diarrhoea, abdominal discomfort), large bowel               is related to the difficulty in collecting the data and
(proctitis, tenesmus, blood or mucus discharge),                untangling the potential causes. Nevertheless, with
bladder (dysuria, frequency and bleeding) and skin              ever more aggressive regimes being used it will be-
(erythema and necrosis). Furthermore, patients often            come increasingly important to assess so that patients
experience fatigue, which is probably multifactorial            can make informed choices.
in most cases (ie anxiety, travelling and direct toxici-
ty). Occasionally bone marrow suppression can be
significant, particularly when non-validated concur-            CONCLUSIONS
rent chemotherapy regimens are used. As a general
rule concurrent chemotherapy will produce some                  Radiotherapy has a well-established role in the ad-
acute toxicities that are not seen with radiation alone         juvant and palliative treatment of rectal cancer. The
such as mucositis and myelosuppression. When pre-               next few years are likely to see increased refinement
operative radiation is considered there is less evi-            of our current techniques. For instance, we may be
dence to demonstrate whether toxicities are signifi-            able to achieve better patient selection through the
cantly increased by CRT, when compared with radi-               use of imaging or even molecular markers. More ef-
ation alone, for normal tissues within the radiation            fective regimes of chemoradiotherapy are likely to be
fields.                                                         developed and trials designed to show when they
   When post-operative radiation is used there is a             should be used. More targeted use of short course
greater incidence of acute toxicity attributable to the         pre-operative radiotherapy in the TME era may also
normal tissues within the radiation fields and cCRT             be possible with maturing evidence from the Dutch
increases the incidence of diarrhoea significantly.             trial and the results of CR07. It will also be interest-
Acute effects are usually self-limiting and recover             ing to see if these trials show any survival benefit for
over the course of weeks.                                       short course pre-operative radiotherapy in this set-
   An unusual acute toxicity of short course pre-op-            ting.
erative radiation is neurological toxicity that express-
es itself during the course of irradiation. A very small
series of patients from Sweden has been reported
who experienced severe subacute neuropathy (63). In             REFERENCES
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