In patients with resectable carcinoma of the rectum, surgery remains the best option
for cure. However, local recurrence rates of 25–40% have been reported in recent large
series of patients undergoing conventional resection (Havenga et al, 1999; Nesbakken
et al, 2002). Total mesorectal excision (TME), defined as a sharp dissection under
clear vision with the excision of the rectum and mesorectum within the mesorectal
fascia, has been adopted as the standard technique in rectal cancer by surgeons in
several European countries although there is a lack of randomised data comparing TME
with conventional surgery. Nevertheless, recurrence rates of <10% (Heald et al, 1998;
Havenga et al, 1999; Nagtegaal et al, 2002; Wibe et al, 2002) and superior survival
(Havenga et al, 1999; Kapiteijn et al, 2002) have been reported with TME. In rectal
cancer surgery, circumferential resection margin (CRM) involvement, defined as tumour
observed ⩽1 mm from the resection margin, has been shown to be an important prognostic
factor resulting in both higher rates of local recurrence (Quirke et al, 1986; Adam
et al, 1994; Birbeck et al, 2002; Nagtegaal et al, 2002; Wibe et al, 2002) and poor
survival (Adam et al, 1994; Birbeck et al, 2002; Wibe et al, 2002) even after TME
surgery (Nagtegaal et al, 2002).
Short-course preoperative radiotherapy (5 Gy daily for 5 days) has been shown to have
a survival advantage and reduction in local recurrence compared to surgery alone in
operable rectal cancer (Swedish Rectal Cancer Trial, 1997). Although only one trial
has shown a survival advantage for preoperative radiotherapy (RT), its results have
been found to be representative of that achieved in the general population (Dahlberg
et al, 1999) leading to this approach being adopted by many oncologists in Europe.
However, the value of preoperative RT in patients undergoing optimised TME surgery
has been questioned and in a large randomised Dutch study of 1805 patients, preoperative
RT has been shown to reduce local recurrence even when TME was used in all patients
(Kapiteijn et al, 2001).
Preoperative chemoradiation (CRT) has the potential advantages of eliminating distant
micrometastases at an early stage, enhancing radiosensitivity because of better oxygenated
tissue, lowering incidence of acute toxicity compared with postoperative CRT and increasing
sphincter preservation. The potential disadvantage of preoperative CRT is overtreatment
of patients either because of early pathological stage (estimated to be 18% in one
randomised study (Sauer et al, 2001)) or presence of occult metastatic disease un-detected
on pretreatment imaging. Preoperative CRT has been used by many oncologists especially
in North America for patients with clinical T3 disease based on extrapolated benefits
from postoperative CRT and a number of nonrandomised studies demonstrating significant
pathological complete response (pCR) rates and acceptable acute toxicity profile with
the use of preoperative CRT. In patients with locally advanced, primarily irresectable
cancer (i.e. a cancer where a complete gross surgical clearance is deemed unlikely
to be achieved), preoperative CRT has been used to cause tumour regression to such
an extent that the cancer can be removed radically with adequate clearance in the
resection margin (Videtic et al, 1998; Chan et al, 2000; Rodel et al, 2000).
The principles on which our study was based were severalfold: neoadjuvant combination
chemotherapy to (1) reduce the bulk of primary tumour, (2) delay the development of
or eliminate micrometastases and (3) allow immediate commencement of anti-cancer treatment
avoiding potential delay while waiting for definitive radiotherapy; preoperative synchronous
chemoradiation to further reduce the bulk of the primary carcinoma leading to a higher
R0 resection (i.e. resection with microscopic tumour clearance at resection margins)
rate and a reduction of subsequent local recurrence; surgical resection of the primary
tumour; and postoperative adjuvant chemotherapy to eliminate residual micrometa-stasis
especially in those with R1 resection (microscopic incomplete resection with tumour
present ⩽1 mm of the resection margin).
During neoadjuvant and adjuvant chemotherapy, a combination of mitomycin C (MMC) and
protracted venous infusion (PVI) 5-fluorouracil (5-FU) was used in our study based
on the in vitro synergy of these two drugs (Russello et al, 1989) and a superior response
rate, failure-free survival and quality of life for this combination compared with
PVI 5-FU alone in a previous randomised study of 200 patients with advanced colorectal
cancer (Ross et al, 1997). Preoperative MMC, infused 5-FU/leucovorin and radiotherapy
have also been shown to be an effective treatment for tethered/fixed rectal cancers
(Chan et al, 2000). The objectives of this study were to evaluate the feasibility
and benefits of delivering neoadjuvant chemotherapy prior to synchronous chemoradiation
and surgery in patients with newly diagnosed locally advanced rectal cancer.
PATIENTS AND METHODS
This study was approved by the local biomedical ethics committee. Signed, written
informed consent was obtained from each patient.
Patients selection and evaluation
The eligibility criteria were: locally advanced histologically proven adenocarcinoma
of rectum; no previous chemotherapy or radiotherapy; no evidence of metastatic disease
on clinical examination and radiological imaging; bidimensionally measurable disease;
haemoglobin >10 g dl−1, white blood count >3 × 109 l−1, neutrophil >1.5 × 109 l−1,
platelet >100 × 109 l−1, bilirubin <30 μmol l−1, creatinine <180 μmol l−1 and calculated
creatinine clearance >60 ml min−1.
Before entry into the study, all patients were assessed by our cancer network multi-disciplinary
team comprising medical, radiation and surgical oncologists, gastroenterologists and
radiologists. Patients were considered to have locally advanced disease on the basis
of digital rectal examination and imaging (computed tomography (CT) or magnetic resonance
imaging (MRI)). All patients had at least T3N0 disease on pretreatment clinical staging.
All patients were required to have chest X-ray (CXR), CT scan of chest, abdomen and
pelvis and carcinoembryonic antigen (CEA) measurement.
MRI scans of the pelvis were performed as previously described (Brown et al, 1999)
in patients who could tolerate the procedure and had no contraindications to MRI,
but were not mandated in the protocol because of inaccessibility to urgent staging
MRI from some referring clinicians at the beginning of the study. However, MRI scans
were obtained in the majority of enrolled patients. MRI criteria for locally advanced
disease were: tumour extending to within 1 mm of or beyond the mesorectal fascia (i.e.
CRM involved or threatened); T3 low-lying tumour at or below the levators, tumour
extending 5 mm or more into perirectal fat, T4 tumours and T1-4N2 tumours. Information
from both imaging and digital rectal examination was considered complimentary to give
final staging.
Treatment
Figure 1
Figure 1
Treatment schema.
shows the overall treatment schema.
Neoadjuvant chemotherapy
Twelve weeks of neoadjuvant chemo-therapy was given. Mitomycin C (7 mg m−2) was delivered
as a bolus injection repeated every 6 weeks, thus, a total of two doses were given
during this period. Screening of the peripheral blood film for red cell fragmentation,
indicating a risk of developing haemolytic uraemic syndrome with further MMC therapy,
was mandated before each course of MMC. A maximum dose of 14 mg of MMC was allowed
in each course. 5-FU (300 mg m−2 day−1) was administered as a continuous infusion
via a central venous catheter (Hickman line). No routine antiemetic medications were
given. Warfarin (1 mg day−1 orally) was administered throughout the treatment to prevent
catheter thrombosis.
Dose modifications
Toxicity was assessed according to National Cancer Institute–Common Toxicity Criteria
(NCI–CTC) version 2 (1998). Toxicity data were collected weekly during chemotherapy.
If grade 3 and 4 neutropenia occurred, subsequent doses of MMC were reduced by 25
and 50%, respectively. If stomatitis, hand–foot syndrome or diarrhoea relating to
5-FU developed, 50, 100 and 150 mg m−2 dose reductions in 5-FU were made if grade
2, 3 and 4 toxicities developed, respectively.
Synchronous chemoradiation (CRT)
On completion of 12 weeks' neoadjuvant chemotherapy, patients began chemoradiation.
This was delivered by a two-phase technique, both phases were CT planned and involved
the use of customised blocking on all fields. Phase 1 delivered a total of 45 Gy in
25 daily fractions, each of 1.8 Gy over 5 weeks and encompassed the primary tumour
and pelvic lymph nodes. The superior margin was at the level of L5/S1 while the inferior
margin varied depending on the position of the tumour within the rectum, but with
a minimum of 3 cm margin on the inferior extent. Laterally, the pelvic side walls,
plus 1 cm, were covered and the sacrum was included posteriorly. The anterior margin
depended on the position and extent of the tumour. During phase 2, the protocol aim
was to deliver 9 Gy in five fractions covering the tumour either clinically palpable
or visible on imaging with a 2 cm margin in all directions. Where CT planning indicated
that small bowel could not be adequately excluded from this volume, the dose was modified
to 5.4 Gy in three fractions. The information used to define the phase 2 target was
the pretreatment CT scan, pretreatment clinical evaluation and, where available, pretreatment
MRI.
Both the phase 1 and 2 were delivered by three field techniques, a posterior and two
laterals or two lateral obliques. Patients were treated prone with a full bladder
and received concomitant PVI 5-FU at a reduced dose of 200 mg m−2 day−1 throughout
radiotherapy. If patients already had dose reduction of 5-FU to below 200 mg m−2 day−1
during neoadjuvant chemotherapy, that same reduced dose of 5-FU would be applied during
synchronous chemoradiation.
Dose modifications
Acute toxicity was assessed according to Radiation Therapy Oncology Group–Acute Radiation
Morbidity Scoring Criteria. Toxicity data were collected weekly during radiotherapy
and then 1 month after radiotherapy. If toxicity because of 5-FU occurred during CRT,
the dose was adjusted as outlined in the neoadjuvant chemotherapy section.
Surgery
Surgery was performed 6 weeks after the completion of CRT. The choice of surgical
procedure (abdomino-perineal resection or anterior resection) was at the surgeons'
discretion.
Postoperative adjuvant chemotherapy
An identical 12 week block of postoperative chemotherapy, consisting of MMC and PVI
5-FU at the same preoperative doses, was given to all patients who had recovered within
12 weeks of surgery and had no evidence of distant disease postoperatively.
Evaluation of response
Clinical tumour response was measured using CT and MRI scans. CT scans were repeated
after the initial neoadjuvant chemotherapy at 12 weeks, after synchronous chemoradiation
at 22 weeks (i.e. 4 weeks after finishing RT) and before commencement of postoperative
adjuvant chemotherapy. The primary intention of CT scan was to exclude any development
of distant metastasis. MRI scans of pelvis were repeated once after synchronous chemoradiation
to assess primary tumour response. All available imaging was reviewed independently
by one radiologist (GB), who was blinded to the pathological findings. The local T
and N stage and tumour measurement were made according to previously published criteria
(Brown et al, 1999). No confirmatory scans for responses were performed.
Radiological tumour response was evaluated according to World Health Organisation
(WHO) Criteria (Miller et al, 1981). Complete response (CR) was defined as the complete
disappearance of all measurable lesions, without the appearance of new lesion(s).
Partial response (PR) was defined as a reduction of bidimensional lesions by ⩾50%
of the sum of the products of the largest perpendicular diameters of each measurable
lesion and no progression in other lesions or the appearance of any new lesions. Stable
disease (SD) was defined as a <50% reduction of tumour volume or a <25% increase of
the volume of one or more measurable lesions, with no new lesions. Progressive disease
(PD) was defined as an increase of ⩾25% of the size of at least one bidimensionally
measurable lesion, the appearance of new lesion(s), and/or the onset of ascites or
pleural effusion with cytological confirmation.
During neoadjuvant chemotherapy, tumour-related symptoms were assessed by research
nurses with a 15-point checklist at baseline and at each hospital visit for patients
who had these symptoms on entry into study. Particular enquiry was made regarding
symptoms of rectal bleeding, pelvic pain/tenesmus and diarrhoea/constipation. Disappearance
or attenuation of these tumour-related symptoms were recorded at each hospital visit.
Data regarding the time between commencement of treatment and resolution of symptoms
were collected weekly. This symptom checklist has been used in a number of previous
multicentre randomised studies (Ross et al, 1997,2002; Cunningham et al, 1998; Maisey
et al, 2002; Tebbutt et al, 2002).
Pathological response was assessed by examining the resected tumour specimen after
chemoradiation and compared with baseline clinical staging using imaging and digital
rectal examination. The American Joint Committee on Cancer TNM staging system (fifth
edition) was used when assessing for pathological response. Tumour downstaging was
defined as a reduction of at least one level in T or N staging (e.g. T3 to T2, N2
to N0). Tumour specimens were also examined for resection margin involvement. CRM
involvement was defined as tumour observed ⩽1 mm from the resection margin.
Follow-up
Patients were seen in the routine follow-up clinic every 3 months for the first year,
every 6 months for the second year and then annually. CEA measurement was performed
with each clinic visit. CT scans of thorax, abdomen and pelvis were performed 1 year
and 2 years after the end of treatment.
Statistical analysis
Failure-free survival and overall survival were estimated using the Kaplan–Meier method
from trial entry (Kaplan and Meier, 1958). All end points were updated in May, 2002.
Failure-free survival was calculated from the date chemotherapy commenced to the date
of either disease progression or death. Overall survival was estimated from the date
chemotherapy commenced to the date of death from any cause.
RESULTS
In all, 36 eligible patients were recruited between January 1999 and August 2001.
The median follow-up for these patients is 15 months. Table 1
Table 1
Patient characteristics
Patient characteristics
Number of patients (total n=36)
Gender
Male
26
Female
10
Median age (range)
63 years (40–85)
Performance status
0
13
1
23
shows the patient demographics. At baseline, both MRI and CT scan were carried out
in 30 patients and CT scans alone were performed in six patients. Table 2
Table 2
Baseline staging using CT±MRI scans and digital rectal examination
Baseline staging
Number of patients (%) n=36
Number of patients with CRM involved or threatened by tumour n=11
T2N0a
1 (2.8)
0
T3N0
6 (16.7)
1
T3N1
8 (22.2)
2
T3N2
6 (16.7)
6
T4N0
8 (22.2)
2
T4N1
5 (13.9)
0
T4N2
2 (5.6)
0
CRM=circumferential resection margin.
a
T3N1 on initial MRI reporting at trial entry, but subsequently reclassified after
radiology review.
shows the baseline clinical staging. One patient had T3N1 rectal cancer on initial
MRI report and was enrolled into the trial, but was subsequently reclassified as T2N0
after radiology review. This patient was included in all analyses. Eleven patients
had the potential mesorectal CRM threatened or involved by tumour on MRI at baseline.
Of those, CRM was threatened by nodal or extranodal tumour deposits rather than by
primary tumour directly in five patients.
Figure 2
Figure 2
Progress of all patients during trial.
shows the progress of all patients during the trial. No patient developed detectable
progressive disease after neoadjuvant chemotherapy. In two patients, liver metastases
were evident on CT after synchronous chemoradiation. No progression in primary tumours
was seen during the trial.
Tumour response
Radiological response
All 36 patients were evaluable for radiological response (Table 3
Table 3
Objective tumour responses by imaging
Post chemotherapy (CT only)
Post chemoradiation (CT±MRI)
Complete response
1 (2.8%)
6 (16.7%)
Partial response
9 (25%)
23 (63.9%)
Stable disease
26 (72.2%)
5 (13.9%)
Progressive disease
0 (0%)
2 (5.6%)
Objective response rates (95% confidence interval)
27.8% (14.2–45.2%)
80.6% (64–91.8%)
). CT scans were performed on all 36 patients after neoadjuvant chemotherapy and synchronous
CRT. Pelvic MRI scans were performed in 32 patients only after CRT. Four patients
did not have post-CRT MRI scans because of patient refusal (n=2), in situ coronary
stent (n=1) and unavailability of MRI (n=1).
After neoadjuvant chemotherapy, the best achieved objective response rate (ORR) of
all patients were 27.8% (95% confidence interval [CI]: 14.2–45.2%) with one CR and
nine PRs. After chemoradiation, the objective response rate was 80.6% (95% CI: 64–91.8%)
with six CRs and 23 PRs.
Resolution of symptoms
Overall 65% of patients had an improvement or resolution of symptoms. Of the patients
with symptoms, 59% had improvement in diarrhoea/constipation, 60% had reduced rectal
bleeding and 78% had diminished pelvic pain and tenesmus. All symptomatic improvement
was evident during neoadjuvant chemotherapy. The median time to improvement in diarrhoea/constipation
was 28 days (interquartile range=7–43 days) and for diminished pelvic pain and tenesmus
was 35 days (interquartile range=7.5–56 days).
Surgery and pathological response
Nineteen patients underwent an anterior resection and 15 had an abdomino-perineal
resection. Patients proceeded to surgery in a median of 6.9 weeks after finishing
RT. One patient with T4N1 tumour was found to be still inoperable at laparotomy and
no attempt of surgical resection was made. One 85-year-old patient achieved a clinical
complete response on both imaging and sigmoidoscopic evaluation and declined surgery
after CRT. He developed local recurrence 14 months later and underwent a successful
TME with complete tumour clearance. Both patients who developed liver metastases after
CRT opted to undergo resection of primary tumour before receiving further palliative
chemotherapy. One patient was found to have metastases on the serosal surface of liver
at operation undetected on preoperative CT. Thus, potentially curative surgery was
attempted on 33 patients. Another patient was found to have a rise in CEA level during
the postoperative recovery period. A positron emission tomography (PET) scan demonstrated
widespread metastatic disease without evidence of active disease on postoperative
CT.
Compared with baseline staging, 25 patients (73.5%) had downstaging of their primary
tumour on histological examination either in T (n=13) or N (n=7) or both (n=5) staging.
Pathological CR was found in one patient. Table 4
Table 4
Pathological response
Pathological staging
Baseline staging
pT0
pT1
pT2
pT3
pT4
T2
0
0
1
0
0
T3
0
3
4
11
1
T4
1
0
2
8
3
pNode negative
pNode positive
Node negative
12
2
Node positive
8
12
shows the pathological response in patients who underwent resection of their primary
tumour. The median number of lymph nodes retrieved in the surgical specimens was 5
(range 0–17). In one patient only, no lymph nodes were identified (Nx) from the surgical
specimen after CRT.
R0 resections were performed in 28 out of 34 patients (82%). Of the 11 patients with
threatened or involved CRM on baseline MRI scan, nine had tumour regression from the
resection margin after CRT. In only one patient, tumour was predicted to have regressed
from CRM on postCRT MRI, but histology showed involved resection margin.
Postoperative adjuvant chemotherapy
Twenty-two patients (61%) received adjuvant chemotherapy. Fourteen patients did not
receive adjuvant chemotherapy because of postoperative complications (n=5), progressive
disease or inoperable tumour (n=5) and physicians' or patients' decision (n=4). One
patient developed venous thrombosis secondary to Hickman line and received capecitabine
instead of PVI 5-FU during adjuvant chemotherapy.
Toxicity
Neoadjuvant chemotherapy-induced toxicity
Table 5
Table 5
Treatment induced grade 3/4 toxicity
Toxicity
Number of patients
During neoadjuvant chemotherapy
Anaemia
0 (0%)
Neutropenia
0 (0%)
Thrombocytopenia
0 (0%)
Diarrhoea
3 (8.3%)
Stomatitis
1 (2.8%)
Hand–foot syndrome
4 (11%)
Infection
2 (5.6%)
Febrile neutropenia
0 (0%)
During chemoradiation
Anaemia
0 (0%)
Neutropenia
0 (0%)
Thrombocytopenia
0 (0%)
Lower gastrointestinal
0 (0%)
Genitourinary
0 (0%)
Skin
10 (27.8%)
shows the incidences of grade 3/4 toxicities during neoadjuvant chemotherapy. There
were no deaths related to chemotherapy. No grade 3/4 haematological toxicity was seen.
Nine patients (25%) developed grade 3/4 nonhaematological toxicity although only 3%
were grade 4. The most common nonhaematological toxicity was hand–foot syndrome.
Chemoradiation-induced toxicity
Table 5 shows the incidences of grade 3/4 toxicities during chemoradiation. There
were no deaths related to chemoradiation either. The most frequent toxic effect was
treatment field erythema. In most cases, this had resolved when patients were reviewed
one month after completion of radiotherapy. No haematological, lower gastrointestinal
and genitourinary grade 3/4 toxicities were encountered during chemoradiation. No
treatment interruption was required.
Surgical complications
One patient died postoperatively from an anastamotic leak leading to multiorgan failure.
No other anastamotic leak was seen. Five other patients developed postoperative complications
including pelvic collections (n=3) and delayed wound healing (n=2).
Survival
Six out of 36 patients (16.7%) have died. Cause of death was progressive cancer in
all cases. The median survival has not yet been reached (Figure 3
Figure 3
Overall survival.
). The survival probability at 1 year was 93.5% (95% CI: 76.3–98.4%) and at 2 years
was 70.3% (95% CI: 42.3–86.6%).
Patterns of failure
The median failure-free survival was 18.6 months (Figure 4
Figure 4
Failure-free survival.
). The failure-free survival probability at 1 year was 72.1% (95% CI: 52.9–84.5%).
Two patients had local recurrences, nine developed distant metastasis (lung n=3, liver
n=4, brain n=1 and paraaortic lymphadenopathy n=1) and one had both local and distant
disease as their first sites of treatment failure.
DISCUSSION
In this study, we assessed the feasibility of delivering neoadjuvant chemotherapy
before preoperative CRT and radical resection. This treatment strategy potentially
addresses systemic micrometastases as well as reduces the frequency of locoregional
recurrence. A reduction in the size of the primary tumour with neoadjuvant chemotherapy
may have improved the effectiveness of chemo-radiotherapy and also increased R0 resection
rate. This is supported by the fact that 41% of patients included in our study had
T4 tumours and a further 33% had tumour extending to the potential mesorectal CRM
in whom resection with curative intent would not normally be attempted. Of these patients,
77% underwent a R0 resection. Moreover, neoadjuvant chemotherapy resulted in rapid
symptom resolution which would impact on patients' quality of life. Antitumour treatment
could also be started in a timely fashion without potential delay as long course radical
radiotherapy could take two months to commence in the United Kingdom.
Several strategies have been used to reduce either local recurrence or distant metastasis
for localised rectal cancer. Improved surgical technique such as total mesorectal
excision has been reported to have a lower local recurrence rate and improved survival
compared to conventional surgery (Havenga et al, 1999; Kapiteijn et al, 2002). The
value of preoperative RT in operable rectal cancer has been evaluated in two meta-analyses
(Camma et al, 2000; Colorectal Cancer Collaborative Group, 2001). Whereas the Colorectal
Cancer Collaborative Group, using individual data from 6350 patients enrolled in 13
randomised studies, found a marginal but nonsignificant survival advantage in patients
receiving preoperative RT (Colorectal Cancer Collaborative Group, 2001), a significant
reduction in mortality was found by the meta-analysis undertaken by Camma et al (2000).
Both meta-analyses demonstrated a significant reduction in local recurrence with preoperative
RT. The role of preoperative RT was further examined in the Dutch TME trial in which
the surgical technique was standardised (Kapiteijn et al, 2001). Although no significant
difference in 5-year survival was seen between the two arms, the local recurrence
rate in the preoperative RT group (5.8%) was significantly lower than in the surgery
alone group (11.6%) (Van de Velde, 2002).
At least three randomised studies of preoperative vs postoperative chemoradiation
have been conducted, but the two studies from the US (INT-0147 and NSABP R-03) closed
prematurely because of poor accrual. In the National Surgical Adjuvant Breast and
Bowel Project (NSABP) R-03 trial with only 267 patients randomised, a larger proportion
of patients receiving preoperative treatment had sphincter saving surgery (44 vs 34%)
and had no evidence of disease at 1 year compared to those receiving postoperative
treatment (Roh et al, 2001). However, increased toxicity and a slight increase in
early deaths were seen in the preoperative arm. The German CAO/ARO/AIO-94 study showed
that preoperative chemoradiation was well tolerated and carried no higher risk of
postoperative morbidity, but efficacy data are awaited (Sauer et al, 2001).
Although many studies evaluated the use of preoperative chemoradiation in patients
with newly diagnosed locally advanced rectal cancer, the definition of locally advanced
disease varies between studies (Glimelius, 2001). Many recent studies included T3
tumours staged by endoscopic ultrasound which are often less bulky than clinically
staged T3 tumours. Very few patients with T4 tumours were recruited (<5% of total
enrolled) in these studies (Janjan et al, 1999; Bosset et al, 2000; Chan et al, 2000;
Grann et al, 2001; Onaitis et al, 2001; Valentini et al, 2001). In our study, over
40% of patients had T4 tumours representing a group of patients with truly locally
advanced disease. This may account for the low pathological complete response rate
seen in our study compared with 10–30% achieved in other studies (Janjan et al, 1999;
Bosset et al, 2000; Chan et al, 2000; Grann et al, 2001; Onaitis et al, 2001; Valentini
et al, 2001). Two studies included only patients with clinically staged T4 tumours
(Videtic et al, 1998; Rodel et al, 2000). The pathological CR rate was lower (Rodel
et al, 2000) and R0 resection was less frequently achieved (Videtic et al, 1998) compared
to other published studies despite the use of higher dose radiotherapy. Toxicity was
significant in one study with 16% not completing protocol (Rodel et al, 2000). Patients
with T or N downstaging have been shown to have a significantly improved local control,
freedom from distant metastasis, disease-free survival and overall survival (Valentini
et al, 2002). Despite a low pCR rate, our pathological downstaging rate of 74% would
be clinically meaningful to this group of patients with advanced disease.
In our study, the radiological tumour response rate was 28% after neoadjuvant chemotherapy
increasing to 81% after chemo-radiation. Although the radiation component would have
contributed to the greatly improved response rate after chemoradiation, it is conceivable
that CT imaging, that was used primarily to exclude distant spread after neoadjuvant
chemo-therapy, might have underestimated the primary tumour response compared to MRI
that was used after chemoradiation. A clinical response after preoperative CRT in
rectal cancer has been shown to predict significantly better long-term clinical outcomes
(Valentini et al, 2002). This supports the use of preoperative tumour assessment by
imaging rather than simply relying on pathological downstaging as an efficacy outcome
measure. However, the accuracy of MRI in the assessment of the primary rectal cancer
after chemotherapy or chemoradiation has not been examined extensively. Continuing
evaluation of MRI, positron emission tomography and endoscopic ultrasound after neoadjuvant
treatment as a guide to surgical management may allow more conservative approach for
responding patients. However as noted in our study and other studies (Hiotis et al,
2002), many patients with clinical CR had persistent foci of tumours that were not
detectable on preoperative imaging, therefore treatment decisions should not be based
solely on the absence of clinically palpable or visible tumour after chemoradiation.
Indeed, one patient with clinical CR in our study was found to have residual tumour
and CRM involvement following resection highlighting the risk of no excision after
obtaining a clinical CR.
The ability of MRI to accurately stage rectal cancer (Brown et al, 1999; Beets-Tan
et al, 2001), define the potential mesorectal circumferential margin (Brown et al,
1999) and predict CRM involvement (Beets-Tan et al, 2001) has been demonstrated before
and supported its use in the initial staging of patients in our study. Encouragingly,
over 80% of patients in our study with CRM threatened or involved initially demonstrated
tumour regression from the CRM after treatment, thus allowing a greater proportion
of curative surgery to be performed. Reassuringly, the prediction of CRM involvement
after treatment by MRI was relatively accurate in our study and might be used to guide
surgical management after neoadjuvant treatment in the future. Other MRI features
such as tumour thickness, tumour appearances, extramural spread may give complimentary
information about tumour response in addition to TNM staging. An analysis of MRI features
at baseline and postchemoradiation and their correlation with pathological findings
and survival for patients undergoing a similar treatment programme in our institution
has been performed and will be reported separately. An ongoing study in Europe (MERCURY,
Magnetic Resonance Imaging and Rectal Cancer European Equivalence Study) is designed
to correlate MRI findings on extramural spread and potential CRM involvement with
pathological specimen and will provide valuable information on the use of MRI for
rectal cancer.
Direct comparison of our efficacy results with other studies would be problematic
because of differences in the patient population (e.g. proportion of patients with
T4 or node-positive tumours), and in the doses and schedules of drugs used in the
preoperative CRT. The follow-up in our study is also relatively short to assess the
impact of our treatment programme on survival. Rather, we have demonstrated the feasibility
of using neoadjuvant chemotherapy prior to synchronous CRT, and the immediate benefits
associated with its use such as tumour response, resolution of symptoms, low risk
of disease progression and R0 resectability in many patients.
Neoadjuvant chemotherapy with MM C and PVI 5-FU was well tolerated with no unexpected
toxicity, the incidence of side effects was similar to that reported in randomised
studies (Ross et al, 1997; Maisey et al, 2002; Tebbutt et al, 2002) and it also did
not increase the frequency of severe adverse events during CRT. The low incidence
of grade 3/4 lower gastrointestinal and genitourinary toxicity during CRT might be
related to the fact that patients underwent 12 weeks of neoadjuvant chemotherapy prior
to CRT, therefore patients who were susceptible to fluorouracil-related toxicity would
have had appropriate dose reductions already.
However, our strategy will require further refinement. A more effective approach would
be incorporation of newer chemotherapy agents as distant metastasis is the most frequent
cause of our treatment failures. Oxaliplatin and infused 5-FU/leucovorin (LV) has
shown considerable antitumour activity in randomised phase III studies (de Gramont
et al, 2000; Giacchetti et al, 2000) and has recently been found to be superior to
irinotecan/bolus 5-FU/LV in terms of efficacy and toxicity profile in metastatic colorectal
cancer (Goldberg et al, 2002). Concomitant oxaliplatin, infused 5-FU/ LV and radiotherapy
have been reported in locally advanced rectal cancer with a pathological complete
response rates of 14–29% (Freyer et al, 2001; Aschele et al, 2002; Gerard et al, 2002;
Sebag-Montefiore et al, 2002). Capecitabine has also been combined with oxaliplatin
(Borner et al, 2002; Taberno et al, 2002) or radiotherapy (Dunst et al, 2002; Kim
et al, 2002) and yielded promising activity in colorectal cancer. In our current active
protocol, we have elected to substitute MMC and PVI 5-FU with oxaliplatin and capecitabine
during the neoadjuvant chemotherapy and use capecitabine as the radiosensitising agent
during chemoradiation.
In conclusion, neoadjuvant systemic chemotherapy prior to synchronous chemoradiation
can be administered with negligible risk of local disease progression and low risk
of systemic spread. It produced considerable symptomatic response with associated
tumour regression. This treatment programme allowed sufficient tumour shrinkage for
R0 resection in the majority of our patients with locally advanced rectal cancer including
those with initial circumferential resection margin involvement.