Neoadjuvant chemotherapy and preoperative chemoradiotherapy in

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ORIGINALES
Neoadjuvant chemotherapy and preoperative
chemoradiotherapy in resectable carcinoma of
the rectum
Juan José Valerdi Álvareza, Martín Tejedor Gutiérreza, Juan José Albistur Toméa, Javier Arellano
Aburto b, Ruth Vera Garcíaa, Juan Ignacio Arrarás Urdaniza and Fernando Arias de la Vegaa.
aDepartment of
Oncology. bDepartment of Surgery. Hospital de Navarra.
Introduction. The effectiveness of neoadjuvant
chemotherapy (Mayo clinic schedule) and continuous oral chemotherapy (tegafur 400 mg and folinic
acid 15 mg every 12 hours) administered during
preoperative radiotherapy (4,500 cGy over 5 weeks)
were studied
Materials and methods. A total of 53 patients with
surgically-resectable rectal adenocarcinoma were
treated.
Results. Toxicities of ≤ grade II were lower with
neoadjuvant chemotherapy while the chemoradiotherapy had higher toxicity rates including grade
III diarrhoea (4%), grade III mucositis (4%), and
grade III-IV neutropenia (9%). Symptom improvement ocurred in 38% of patients after neoadjuvant
chemotherapy coparative with 55% following the
first week of chemoradiotherapy. Surgery was curative in 97% of the patients: abdominoperineal amputation in 24 patients (47%) and conservative
surgery in 28 (53%). Down-staging ocurred in 24 patients (46%), and 7 patients (14%) showed pathological complete response. Overvall survival at 5 years,
with a median follow-up of 50 months, was 70%
(cancer-specific survival was 75%) with significant
differences recorded between N+ and N0 patients
(56% and 76%, respectively; p<0.001), and between
T-0-1-2 and T3 patients (73% and 56%, respectively;
p<0.001). Only 2 patients (3%) had local relapse.
Conclusion. This treatment scheme was well tolerated and had high rate of local control and longterm times.
Key words: rectal adenocarcinoma, neoadjuvancy,
oral fluoropyrimidines, preoperative radiotherapy.
Correspondence: J.J. Valerdi.
Servicio de Oncologia.
Hospital de Navarra.
C/ Irunlarrea.
31008 Pamplona.
E-mail: jj.valerdi.alvarez @ cfnavarra.es
Received 12 February 2003; Revised 22 September 2003; Accepted 25
September 2003
00
Valerdi Álvarez JJ, Tejedor Gutiérrez M, Albistur Tomé JJ,
Arellano J, Vera García R, Arraras Urdaniz JI, Arias de la Vega F. Neoadjuvant chemotherapy and preoperative chemoradiotherapy in resectable carcinoma of the rectum. Rev Oncol
2003;5(8):
Quimioterapia neoadyuvante más
quimiorradioterapia preoperatoria en
cáncer de recto resecable
Introducción. En este estudio analizamos la utilidad de un régimen con quimioterapia neoadyuvante (esquema de la Clínica Mayo) y quimioterapia
continua oral (tegafur 400 mg y ácido folínico 15
mg cada 12 horas) asociada a radioterapia preoperatoria (4.500 cGy, en 5 semanas).
Materiales y métodos. Se trataron 53 pacientes con
cáncer de recto resecable.
Resultados. La quimioterapia neoadyuvante presentó baja toxicidad, ≤ grado II, mientras que con la
quimiorradioterapia se observaron mayores toxicidades: diarrea grado III (4%), mucositis grado III
(4%) y neutropenia grados III-IV (9%). Un 38% de
los pacientes presentaron alivio de sus síntomas
tras la quimioterapia neoadyuvante (55% tras la
primera semana de la quimiorradioterapia). Se realizó cirugía curativa en el 97% de los pacientes: amputación abdominoperineal en 24 (47%) y resección
anterior en 28 (53%). Se observó disminución del
estadio en 24 pacientes (46%), con 7 pacientes (14%)
con respuesta patológica completa. La supervivencia global a 5 años, con una mediana de seguimiento de 50 meses, fue del 70% (cáncer-específica 75%):
se encontraron diferencias significativas entre N+ y
No (56% y 76%, p<0,001), y entre pacientes con To-12 y pacientes con T3 (73% y 56%, p<0,001). Sólo dos
pacientes (3%) han presentado recaída local.
Conclusión. Este esquema de tratamiento fue bien
tolerado, consiguiendo unos altos ratios de control
local y de supervivencia a largo plazo.
Palabras clave: adenocarcinoma rectal, neoadyuvancia, fluoropirimidinas orales, radioterapia preoperatoria.
Rev Oncol 2003;5(8):465-70
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VALERDI ÁLVAREZ JJ, TEJEDOR GUTIÉRREZ M, ALBISTUR TOMÉ JJ, ET AL. NEOADJUVANT CHEMOTHERAPY AND PREOPERATIVE
CHEMORADIOTHERAPY IN RESECTABLE CARCINOMA OF THE RECTUM
TABLE 1. Patient characteristics
INTRODUCTION
Postoperative chemoradiotherapy is the standard adjuvant treatment for stage T3 and/ or N1-2 rectum carcinoma since the 1990 NCI consensus meeting1. 5-fluorouracil (5-FU) is the drug with the highest activity
against colorectal carcinoma but is also a strong radiosensitizer. The use of 5-FU was improved by its administration as continuous infusion instead of bolus
combined with postoperative radiotherapy2.
Several randomized trials were further studied in a
metaanalysis that showed the benefit of preoperative
radiotherapy against surgery alone in survival, local
control and specific cancer survival3. Moreover, the
unique randomized trial comparing preoperative and
postoperative radiotherapy showed a benefit in local
control for the preoperative arm of study4. Other
phase II trials studied preoperative chemoradiotherapy and showed rates of survival and local control
similar to those obtained with postoperative
chemoradiotherapy5,6. Some advantages found with
preoperative
chemoradiotherapy
were:
higher
sphincter preservation, decreased toxicity in small
bowel or increased resectability without higher overall toxicity. Nevertheless, some disadvantages were
found in the treatment of early stage patients; this is
now avoidable through the use of new diagnostic
technologies (i.e. transrectal CT, MNR, etc.).
The use of neoadjuvant chemotherapy offers several
biological advantages, since the tumor itself inhibits
metastasis processes and tumor removal both accelerates metastatic cellular proliferation and increases
the proliferation index during the first 7-10 days after
removal7,8. According to Goldie and Coldman9, tumor
removal would increase the number of resistant cell
clones. Thus, an early use of chemotherapy could
eradicate the subclinical disease. Experience with
neoadjuvant chemotherapy in other tumors like
breast or lung cancers have shown the benefits of
chemotherapy in resectability and survival compared
with surgery alone10,11.
Oral fluoropyrimidines modulated with leucovorin have
been tested as radiosensitizers12. Moreover, the oral administration of these drugs facilitates its use concomitantly with radiotherapy. The present prospective study
assessed the usefulness of neoadjuvant chemotherapy
and the use of oral continuous chemotherapy during
preoperative radiotherapy through evaluation of tolerance to treatment, type of surgery, tumor stage changes,
local control and survival.
PATIENTS AND M ETHODS
Patients
Between June 1996 and December 1998, 53 patients
from two hospitals with a diagnosis of surgically resectable rectum adenocarcinoma were included into
466
n = 53
Age (years)
Median
Range
Gender (male/female)
Tumor stage
N0
N+
Anus-tumor distance
< 4 cm
>4 cm
Hb < 12 g/l
CEA > 10 ng
68
44-80
37/16
33 (62%)
20 (38%)
20 (38%)
33 (62%)
11 (21%)
7 (13%)
Data shown are n (%).
TABLE 2. Eligibility criteria
Adenocarcinoma showed in biopsy
Tumor not fixed to pelvis
Localized tumor (2-14 cm)
Normal hematological and biochemical values
Abdominopelvic TAC without extension signs (to discard stage D)
Transrectal ecoendoscopy (to discard stage A)
ECOG performance status < 2
the study. Their main baseline characteristics are
shown in table 1 and the eligibility criteria are shown
in table 2. Patients with tumor stage A and D were excluded. Abdominopelvic TAC and transrectal ecography
were done in all patients in order to define accurately
the clinical stage of patients; a suitable ecography could
not be obtained for 6 patients. Thirty-three (62%) and
20 (38%) patients showed N0 and N1 tumors, respectively. The distance between anus and tumor was <4
cm in 20 patients (38%) and >4 cm in 33 patients (62%);
Hb was < 12 g/l in 11 patients (21%) and CEA ≥ 10 ng in
7 patients (13%). Time lapse between first symptom
and treatment was between 1 and 18 months.
Treatment
Neoadjuvant treatment consisted in one chemotherapy cycle according to the Mayo clinic schedule:
5-FU 425 mg/ m 2 i.v. bolus and folinic acid (FA)
20 mg/m 2 during 5 consecutive days. After 3-4 weeks,
radiotherapy was started. This was administered using
a lineal accelerator (conformed four-field technique,
including the tumoral volume with a surrounding
margin and the ganglionic groups) and a dose of 4,500
cGy during 5 weeks. Oral concomitant chemotherapy
during 25 days consisted in tegafur 400 mg and FA 15
mg administered every 12 hours. Surgery was performed after 4-6 weeks and, later, four chemotherapy
cycles (Mayo clinic schedule) were administered to 17
patients: 11 patients showed stage C tumor, 2 patients
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VALERDI ÁLVAREZ JJ, TEJEDOR GUTIÉRREZ M, ALBISTUR TOMÉ JJ, ET AL. NEOADJUVANT CHEMOTHERAPY AND PREOPERATIVE
CHEMORADIOTHERAPY IN RESECTABLE CARCINOMA OF THE RECTUM
showed affectation of mesorectum and 4 patients
showed lymphatic or vascular permeation.
The quality of life of the patients was evaluated three
times during the treatment using a general questionnaire (EORTC QLQ-C30) and a questionnaire specific
for rectal carcinoma (EORTC QLQ-38).
Statistical procedures
Survival was estimated according to the KaplanMeier method13. The Mantel method14 was used to
compare the prognostic survival variable related to the
treatment and taking into account the negativity/ positivity of neoadjuvant treatment in its clinical and
pathological evaluation.
TABLE 3. Toxicity found during chemoradiotherapy
Toxicity
Grade I
Hematological
Anemia
6 (11%)
Neutropenia
4 (8%)
Non-hematological
Diarrhea
23 (45%)
Mucositis
5 (10%)
Grade II
Grade III
Grade IV
4 (8%)
6 (11%)
1 (2%)
4 (8%)
-1 (2%)
14 (27%)
3 (6%)
6 (11%)
2 (4%)
---
Data shown are number and percentage of patients affected.
treatment but 9 out of 33 patients (27%) with tumor
located > 4 cm from anus underwent amputation.
Response
RESULTS
Toxicity
The administration of the cycle of neoadjuvant
chemotherapy showed gastrointestinal or hematological toxicities equal or lower than grade II. During
chemoradiotherapy, 6 patients (4%) showed grade III
diarrhea, 5 patients showed grade III-IV neutropenia
and 2 patients showed grade III mucositis (table 3).
Surgery
Symptomatic improvement was found in 38% of patients after neoadjuvant chemotherapy; this percentage increased to 55% after the first week of radiotherapy. Clinical and pathological stages are compared in
figure 1. Decrease of T was found in 24 (46%) out of
52 resectable patients, and in 6 out of 20 clinical N+
(35%). Seven patients (14%) showed complete pathological response. Mesorectum affectation was found
in 5 patients: 3 N+ and 2 N0.
Failures
Surgery was curative in 97% of the patients: one patient showed liver metastases during surgical procedures (when primary tumor was resected) and another patient was non-resectable locally.
Surgery was conservative in 28 patients (53%) and
abdominoperitoneal amputation was conducted in 24
patients (47%). Eight out of 20 patients (40%) with tumor close to anus (< 4 cm) received conservative
With a minimal follow-up of 36 months, two patients
(3%) out of 51 curative resectable patients showed local relapse after 9 and 25 months, respectively. Ten
patients showed distant failure, between 12 and 41
months: 7 had received adjuvant chemotherapy and 3
had not. The median time of survival free of progression for patients showing tumor relapse was 25
months.
Survival
With a median follow-up of 50 months, overall survival was 70% and specific cancer survival was 75%,
still not reaching the median of survival (fig. 2). Patients with pathological N+ and N0 showed a survival
of 56% and 76%, respectively; the difference was statistically significant (p<0.001) (fig. 3). Survival was
73% for T-0-1-2 patients and 56% for T3 patients
(p<0.001). According to the clinical stage, survival of
N0 and N+ was 78% and 58%, respectively. No significant differences were found between survival of
pathological or clinical N0 or survival of pathological
and clinical N+ patients (fig. 4).
%
100
80
60
40
20
0
T0
T1
T2
T3
Irres NO
Clinical n = 53 (100%)
Pathological n = 52 (90%)
Fig. 1. Changes in clinical and pathological stage.
00
N+
Quality of life
The health-related quality of life scores obtained were
acceptable; the most affected areas were sexual funcRev Oncol 2003;5(8):465-70
467
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Probability of survival
VALERDI ÁLVAREZ JJ, TEJEDOR GUTIÉRREZ M, ALBISTUR TOMÉ JJ, ET AL. NEOADJUVANT CHEMOTHERAPY AND PREOPERATIVE
CHEMORADIOTHERAPY IN RESECTABLE CARCINOMA OF THE RECTUM
Overall survival
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
12
24 38
48
60 72 84
Months
96 108 120 132
Fig. 2. Survival curve for treated patients with rectal adenocarcinoma.
tioning and enjoyment. Other affected areas were insomnia, concern about future, emotional functioning,
global quality of life, and those related with the specific toxicity of the treatment (micturition and defecation problems) (table 4 presents the scores in the colorectal module QLQ-CR38).
DISCUSSION
Preoperative treatment offers several well-known advantages but also some disadvantages, such as
overtreatment of patients in early disease stages. Today, the use of techniques like rectal ecoendoscopy15,
TAC, MNR16 or PET has decreased overtreatment but
also the unnecessary treatment of metastatic patients.
The comparison of survival according to clinical and
pathological stages of NO and N+ showed identical
percentages; this may confirm the reliability of the
explorations prior to treatment when defining the
clinical stage and the immediate decision to administer adjuvant treatment in patients with a decrease of
the pathological stage. Moreover, these explorations
may help to plan the increase of preoperatory
chemotherapy in this group of clinical N+ patients.
The use of neoadjuvant chemotherapy and oral continuous chemotherapy did not increase grade III-IV
hematological or gastrointestinal toxicity; this was not
in accordance with the results reported by other studies where bolus was administered during the first and
fifth week of radiotherapy16. In fact, the incidence of diarrhea was lower than that found in postoperative
treatment2. The NSABP R-03 trial17 compared a similar
schedule (neoadjuvant chemotherapy plus preoperative chemoradiotherapy) with postoperative adjuvant
treatment and showed an incidence of toxicity higher
than grade III, similar to that found in this study.
With regard to preservation of the sphincter, the surgeon is still one of the most important prognostic factors in reducing local relapses and conducting a conservative surgical procedure18,19. In the present study, 9
patients with tumor over 4 cm were amputated; only
40% of patients with tumor located at less than 4 cm
were preserved intact. These percentages were far
from those reported by other authors20,21. The percentage of sphincter preservation found (53%) does not differ from the 50% found by Hyams17 and is similar to
those shown in patients subjected to adjuvant treatment without prior treatments that could modify the
surgical indication2,22. However, this 53% was lower
than percentages shown in phase II trials of preoperative chemoradiotherapy with patients suffering from
stage II or III or T3 tumors6,23. Differences in our study
may be attributed to different training of surgeons and
not to the interval of time between chemoradiotherapy
TABLE 4. Quality of Life scores in the colorectal module. Three measurements
One measurement.
Two measurement
Three measurement
Areas.
Mean
SD
Mean
SD.
Mean
SD
1
1
2
2
2
2
97
12
32
13.7
1.7
7.1
22
17.5
12.9
6
88.9
13.2
43.7
16.8
18.1
20.1
24.1
20.7
11.3
20.3
85
8.3
35.5
15.7
12.8
23.7
23.9
16.3
13.9
17.4
34.6
0
25.6
21.3
19.2
58.3
39.4
17
0
29.4
16.4
26
30.9
32.7
32.2
0
21.2
23.3
10
70.8
30.6
19
0
33.4
25.4
19.9
23.6
38.9
23.8
9.5
62.5
58.7
26.7
66.7
35.7
0
10.4
47.8
37.6
31.7
24.2
36.2
2
2
2
2
1
1
Body image
Sexual functioning
Micturition problems
Gastrointestinal symptoms
Chemotherapy side effects
Problems in defaecation
(only in patients without stoma)
Stoma related problems
Male sexual problems
Female sexual problems
Weight loss
Worries about future
Sexual enjoyment
Quality of life scores in the colorectal module QLQ-CR38 in the three measurements. Scores range between 0 and 100.
In the areas with 1, a score of 100 represents a higher quality of life level.
In the areas with 2, a score of 100 indicates a higher level of symptoms.
468
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1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
NO pathological
N+ pathological
p < 0.01
Pac A
Pac B
Probability of survival
0
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
6
12
18
24
30 36
Months
42
48
54
Probability of survival
A
NO clinical
N+ clinical
p < 0.01
Pac A
Pac B
6
12
18
24
30 36
Months
42
48
54
60
A
NO clinic
NO pathologic
p = ns
Pac A
Pac B
0
B
0
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
60
Probability of survival
Probability of survival
VALERDI ÁLVAREZ JJ, TEJEDOR GUTIÉRREZ M, ALBISTUR TOMÉ JJ, ET AL. NEOADJUVANT CHEMOTHERAPY AND PREOPERATIVE
CHEMORADIOTHERAPY IN RESECTABLE CARCINOMA OF THE RECTUM
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
6
12
18
24
30 36
Months
42
48
54
60
B
N+ clinic
N+ pathologic
p = ns
Pac A
Pac B
0
6
12
18
24
30 36
Months
42
48
54
60
Fig. 3. Survival curve comparing N0 or N+, pathological (A)
and clinical (B).
Fig. 4. Survival curve comparing N0 clinical and N0 pathological (A), or N+ clinical and N+ pathological (B).
and surgery; this interval was always higher than 4
weeks so this allowed enough time to induce radiobiological effects and tumoral regression24.
The indication for performing mutilating or preserving
surgery was not defined in the preoperatory study; this
is the only way to evaluate the true role of the preoperative treatment in sphincter conservation. Other studies
where amputation was previously defined as a surgical
treatment and that used preoperative chemoradiotherapy (as bolus or continuous infusion) achieved rates of
conservation between 66% and 89%20,21,25.
The local control achieved in this study was 97%. This
value is similar to that found with preoperative radiotherapy and mesorectal surgery26 or to the best percentages found with preoperative treatment6,20,23, and
higher than the 86%-89% found with postoperative
adjuvant chemoradiotherapy2,22,27.
The percentage of complete pathological responses
found (14%) together with the staging decrease percentage of 46% are similar to those found in previous
studies on preoperative chemoradiotherapy6,16,17,21.
Similarly, the survival percentages after 2, 3 and 4
years (81%, 75% and 70%) fall into the mean survival
range found with preoperative chemoradiotherapy
and radiotherapy plus mesorectal surgery26, although
in this case the follow-up was 2 years. The use of oral
chemotherapy showed identical results than intra-
venous chemotherapy with the additional advantage
of an easier administration. The survival rates found,
together with the reliability given by clinical staging,
equals that found with postoperative treatment after 3
years: 75%-80%2,22,27.
In conclusion, neoadjuvancy allows a rapid control of
symptoms together with an increase of the time free
of disease without increasing overall survival; delays
in the beginning of chemoradiotherapy did not modify this profile. Surgeons still need to be specifically
trained, because their experience constitutes a prognostic factor in sphincter preservation and in the decrease in local tumor relapses. Equal survival times
between clinical and pathological stages confirm the
reliability of clinical staging techniques; this reliability avoids doubts concerning plausible infra- or
overtreatment when using preoperative treatments.
Moreover, these clinical staging techniques allow the
selection of groups of patients that may benefit from
preoperative complementary treatments. Additionally, we may offer adjuvant systemic treatment on the
basis of clinical staging (thus avoiding mistakes due
to pathological stage changes related to the treatment) or to use other drugs when no response is detected. The use of oral treatment maintains efficacy
and improves the quality of life of patients thanks to
its convenient administration.
00
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VALERDI ÁLVAREZ JJ, TEJEDOR GUTIÉRREZ M, ALBISTUR TOMÉ JJ, ET AL. NEOADJUVANT CHEMOTHERAPY AND PREOPERATIVE
CHEMORADIOTHERAPY IN RESECTABLE CARCINOMA OF THE RECTUM
Two (INT 0147 and NSABP RO-3) out of three clinical
trials started to elucidate the usefulness of preoperative treatment compared to postoperative treatment
were closed early due to poor recruiting. The remaining ongoing trial (CAO/ ARO/ AIO 94 European trial)
will provide data that may help answer this interesting question. Preliminary results after follow-up of 2
years do not show remarkable differences, although
the authors noted the excellent tolerance to treatment
and the low toxicity rates28. For the moment, it seems
logical to use the preoperative treatment in patients
candidate to amputation and in patients with clinical
stage (T3-4 No/ +). This is due to the reliability of clinical staging, the advantages in toxicity and sphincter
preservation associated with the preoperative treatment, and the equivalence in survival with postoperative treatments (apart from its indication in unresectable patients). New drugs (e.g., oxaliplatin,
CPT-11, capecitabine) may show a higher response,
but also radiosensitivity that may definitively discard
postoperative treatment.
12.
13.
14.
15.
16.
17.
18.
19.
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