Radiotherapy and Oncology, 24 (1992) 191-194 0 1992 Elsevier Science Publishers B.V. All rights reserved. 0167-8140/92/$05.00
191
RADION 01009
Short Communication
Conventional
external irradiation alone as adjuvant treatment in resectable pancreatic cancer: results of a prospective study
J. F. Bosseta, J. J. Pavy”, M. Gilletb, G. Mantionb,
E. Pelissierb and S. Schraub”
Departments of “Radiotherapy and b Surgery, CHU BesanGon, Besaqon,
France
(Received 27 August 1991, revision received 10 March 1992, accepted 23 March 1992)
Key words: Pancreatic
5-fluorouracil(5-FU) increases survival if compared to surgery alone [20]. The aim of this paper is to report on the toxicities and the treatment results of a prospective non-randomised study conducted by a single institution, using a conventional post-operative EBRT only after resection of ductal carcinoma of the pancreas.
cancer; Adjuvant radiotherapy
Summary Between l/85 prospective
and l/90,
14 consecutive patients were entered into a
study of conventional
beam radiotherapy
adjuvant
post-operative
after complete resection for a pancreatic
adeno-
carcinoma. The surgical procedure was a Whipple resection in nine patients, a distal pancreatectomy createctomy
in four patients and a total pan-
in one patient. There were three Tlb, eight T, and three
T, tumours (UICC 1987); nodal involvement was present in five cases. The radiotherapy a 23
x
was delivered using a four-field box technique with
MV photon beam. All patients received a total dose of 54 Gy
to the tumour bed. The mean treated volume was 900 cm3. Acute toxicities consisted mainly of weight loss (mean: 2 kg). Two patients had a grade 2 diarrhoea and two patients a grade 2 gastritis. Late effects were minimal and only observed in two patients. The overall locoregional recurrence (LR) rate was 50 % . The median disease-free survival was 12 months, and the median survival was 23 months. This post-operative
conventional radiotherapy
treatment gives results that
are comparable to the results of the GITSG-adjuvant study using a combination of split-course radiotherapy and 5-fluorouracil (5-FU).
Introduction
Ductal adenocarcinoma of the pancreatic gland is a common tumour and its incidence is steadily increasing [ 11. It now ranks tenth among cancer in Europe [ 251. It is also a highly malignant disease, being the fourth cause of cancer deaths in the United States [ 131. The median survival after the diagnosis is 4 months on average [ 161. Surgery is the reference treatment for operable non-metastatic patients and is considered as the only possibility for cure [5,23,24,28,38,41,43,45]. However, long-term survival remains poor [ 17,291. Locoregional failure, as first site, rates as high as 50% after apparent complete tumour removal [22,37]; this is in good agreement with the fact that 49% of the patients have locoregional disease only, at the time of diagnosis [ 181. The efficacy of irradiation to control pain or to prevent local progression [ 71 indicates that the tumour is accessible to such treatment. In the adjuvant setting, the role of radiotherapy needs to be clearly defined. Today, only one randomised trial with a limited amount of patients and a short follow-up period has indicated that a split course external beam radiotherapy (EBRT) combined with Address for correspondence:
Materials
and methods
external
J. F. Bosset, Service de Radiothkrapie,
Between January 1985 and January 1990, 14 consecutive patients were enroled in the study. All patients had a ductal adenocarcinoma of the pancreas and in all patients a macroscopically complete surgery was performed. Cancer of the ampulla, the duodenum and the distal common bile duct were excluded as well as cystadenocarcinoma and islet cell type carcinoma of the pancreas. No patient referred for adjuvant treatment was excluded. Seven males and seven females were treated, whose ages ranged from 33 years to 69 years (average = 60 years). At the time of study entry, the ECOG status was 0 for two patients 1 for 10 and 2 for two. The tumour was located in the head of the gland in 10 patients, in the body in three patients and in the tail in one. Only three patients had tumour grossly confined to the gland, while the other patients had an invasion of the capsula (4 patients), a direct attachment to the portal vein (2 patients), to the mesenteric vessels (2 patients), to the vena cava (one patient), to the colon, left kidney and spleen (one patient), or to the stomach and ileum (one patient). A Whipple resection was performed in nine patients, a distal pancreatectomy in four patients and a total pancreatectomy in one. The surgical removal was extended to the left kidney and colon in one patient, and to the stomach, adrenal gland and ileal loops in another patient, because of tumour extension. No patient was left with visible or palpable gross tumour after removal. The mean macroscopical diameter of the tumours was 4 cm (1.5-8 cm). In 13 patients the tumour was a ductal invasive adenocarcinoma and in one a mucoid adenocarcinoma type. Five patients had nodal invasion. Four patients had a microscopically positive posterior margin while one patient had a microscopically positive margin at the level of the distal pancreatic section. In one case, the margin was not clearly stated and therefore considered as unknown. According to the TNM classification (UICC 1987), 3 patients had a T,, tumour, 8 patients a T, tumour and 3 patients a T, tumour. This correspond to stage I in 7 patients, stage II in 2 and stage III in 5 patients. Surgical procedure and tumour characteristics are summarised in Table I. Post-operative EBRT was delivered using a linear accelerator and 23 MV photon beam. The mean delay between surgery and radiotherapy was 2 months (1.5-5 months). All patients were similarly CHU Jean Minjoz, 25030 Besanqon Cedex, France
192 TABLE
I
Surgical
procedure and turnour characteristics.
Patient
1 2
CPjCI
T
N
Stage
Margin free
Site of 1st recurrence
CI
TZ T,
_
II
Yes
LR
II
Tlb
DFS (months)
Status/delay (months)
19
DOC 21 NED 60
3
CI CP
III
4
CI
T2
+ _
Yes Yes
I
No
5
CI
T3
_
II
Yes
6
T2
_
I
Yes
LR + M (liver)
34
DOC 35
7
CI CI
T3
_
II
No
M (liver)
23
DOC 36
8
CP
T,b
I
No
M (liver)
12
DOC 23
9
CP
+
III
Yes
LR
12
DOC 19
10
CI
T,b T2
+
III
No
LR
19
DOC 34
11 12
Cl
T,
+
III
LR
10
DOC 12
T,
M (peritoneum)
14
CI
+ _ _
111
13
CI CI
No NA
I I
Yes Yes
M (liver) LR
20 12 12
DOC 22 DOC 19 DOC 13
T2 T,
M (liver) LR + M (peritoneum)
CP = confined within the pancreas; CI = contiguous invasion; LR = locoregional NED = no evident of disease; DOC = dead of cancer; NA = not available.
treated. The limits of the tumour volume were defined on the basis of the preoperative CT scan and according to the surgical clips left at the edge of the tumour bed. This tumour volume included the tumour bed, the posterior peripancreatic soft tissues, the distal section of the pancreatic gland, the upper mesenteric and coeliac nodes. The target volume had to encompass the tumour volume by a minimum margin of 2 cm in all dimensions. IVP and upper gastrojejunal imaging were performed in the simulation room. The initial target volume was treated by a four-field technique up to a dose of 45 Gy (1.8 Gy/F, 5 F per week), all fields being treated every day. The average measured volume was 900 cm3. Then, a 9 Gy boost dose was delivered to the tumour bed in 5 fractions using only AP-PA fields (average field size: 9 x 9 cm). All the patients received a total dose of 54 Gy and the mean duration of the treatment was 44 days. The dose was prescribed using the ICRU 29 recommendations. The internal half of the right kidney, the upper half of the left kidney and an undetermined portion of the Roux-en-Y loop had to be irradiated. The mean delivered dose to the spinal cord was 27 Gy. In general, the gastrojejunal anastomosis was out of the treated volume. Follow-up During treatment, the patients were clinically examined every week. After treatment, the patients were examined every 3 months, and in addition biochemical tests (Ca 19.9) and the required radiological investigations were performed (chest X-Ray, abdominal ultra-sound (US) and/or CT scan). Acute and late toxicities were scored using the WHO scoring system. Failures were detected clinically and confirmed radiologically as a tumour regrowth on CT scan and/or US imaging. They were classified as locoregional recurrences (LR) if they were localised within the treated area; any other localisation was considered as metastasis (M). Only two patients had an histological confirmation of the recurrence, one patient by a second-look operation and the second by a US guided function of the liver. No further specific treatment was offered at the time of the relapse. The survival was calculated from the date of surgery. Survival curves were obtained using the Kaplan-Meier method. No patient was lost to follow up.
60+ 11
recurrence;
M = metastasis;
DOC 33
1
DOC 11
46+
NED 46
DFS = disease-free
survival;
Results There were no treatment interruptions and no toxic death occurred due to acute toxic side-effects. The mean weight loss was 2 kg ( + l6 kg). Acute toxicities occurred in five patients: grade 1 gastritis in one patient, grade 2 gastritis in two patients, grade 2 diarrhoea in one patient and one patient had a grade 2 diarrhoea plus a grade 1 gastritis. After 6 months, late sequela developed in two patients: one who ultimately died of cancer (LR) presented a grade 2 ileitis and one who is alive without disease at 46 months with a grade 1 ileitis and a grade 1 gastritis. The mean follow-up period is 28 months (ll60 months). Twelve patients died from cancer between 11 and 36 months after surgery and two patients are alive free of cancer 46 and 60 months after treatment, respectively. The median disease-free survival is 12 months and the median overall survival is 23 months (Fig. 1). The site of first failure was locoregional in 5 patients, locoregional and hepatic in one patient, locoregional and peritoneal in one patient, hepatic alone in 4 patients and peritoneal alone in one patient. The overall locoregional recurrence rate was 50 %. The small number of patients did not allow to assess statistically the quality of the margin, the nodal involvement nor the stage as potential pronostic
LT L,
&403
8 20-
3 &
0
.
0
12
24 36 Tie in months (-
) and overall survival
of surgery calculated
using the Kaplan-Meier
Fig. 1. Disease-free
survival
48
60
(- - -) from the date method.
193 factors. The sites of recurrence and status of patients are summarised in Table I. Discussion
Surgical resection is the standard treatment for pancreatic cancer. Theresectabilityrateislow: lo-15% [2,16,28,29]. Thepost-operative mortality is now less than 10% [42,45] and even 5% in recent series of trained teams [ 14,28,38]. In spite of this, the 5-year survival remains low (5%), with a median survival varying from 10 to 17 months [ 17,20,23,41,46]. For tumours located in the head of the gland, that occur most frequently, a Whipple resection is the standard surgical procedure [41]. The extension of the surgery does not seem to influence the survival [ 3,281. Admitted favourable pronostic factors are the size (below 2 cm), the absence of capsular disruption, and the absence of nodal involvement [27]; 4-20% of the resected pancreatic tumours fit these criteria [21,28] (corresponding to the T,, N, UICC 1987). The median survival of these patients ranges from 13 to 24 months [4,21]. No patient had these favourable criteria in our series. After macroscopically complete resection, the LR rate is high, from 30 to 70% [ 10,15,37]. The high LR rate can be explained by the difficulties to obtain free margins due to the tumour extension into the retropancreatic fat, and to the vicinity of the large vessels, portal vein and superior mesenteric artery [ 19,21,42]. Furthermore, after a Whipple resection, there is a microscopic residual disease left in 5-38% of the patients [21,28,42] and 30% of the patients have had an incomplete node dissection [ 6,421. Hepatic metastases are present in 50% of the failures, usually associated with LR, and peritoneal spread is present in 31% [ 10,15,37]. Historically, pancreatic cancer has been thought to be radioresistant, however, experimental studies demonstrate that this is not explained by intrinsic radioresistance [35]. For locally advanced tumour, EBRT is able to control the pain in 30-50% of the treated patients who have a S-12-month survival [7,26,39]. The addition of 5-FU to a split-course irradiation significantly improves the overall survival in comparison with a split-course irradiation only [ 261, and does as well as the addition of doxorubicin but with less toxic side effects [9]. The combination of 5-FU streptozotocin, mitomycin-C (SMF) did not generate any survival benefit relative to 5-FU plus conventional EBRT followed by SMF [ 111. Different radiotherapy schedules (split course versus conventional) have never been tested prospectively.
No benefit
demonstrated
for doses of more than 40 Gy using split-course
in local control
from dose increment
ules. [ 261. The dose increment gained by brachytherapy
was sched-
[30,36,44]
or more recently by intraoperative radiotherapy (IORT) increases the local control rate but does not influence the overall survival [ 8,3 1,32,40]. This was confirmed by a controlled study conducted by the NC1 with a small number of patients [ 341. In resected cancers, data on post-operative radiotherapy background are limited. Kopelson [22] reported on seven patients with pancreatic or ampullary tumours receiving adjuvant post-operative radiotherapy. Only one patient received more than 45 Gy and was alive NED at 2 years. Gerard et al. published the largest series from a single institution: 34 patients with resected pancreatic adenocarcinoma were treated to 44-50 Gy post-operative EBRT. Surgery was considered to be macroscopically complete in 19 patients and macroscopically incomplete in 15 patients. The 3 year overall survival was 19% in the first group and 0% in the second. The median overall survivals were the same in both groups, 10 months. Sites of failure were not analysed [ 121. The NC1 conducted a controlled trial in 32 patients with resected pancreatic cancer testing IORT. Patients with Stage II or III disease were randomly allocated to either an IORT dose of 20 Gy with a 9-12 MeV electron beam or a postoperative EBRT of 50 Gy. IORT increased the local control from 0% for the EBRT group up to more than 80% for the IORT group, however, the overall survival was not significantly prolonged [33]. The GITSG [20] reported on the only controlled study in which 43 patients with resected pancreatic cancers were randomly allocated to surgery alone (22 patients) or surgery plus post-operative EBRT (40 Gy, split course over 6 weeks) combined with 5-FU (21 patients). Chemotherapy was maintained every 2 weeks for 2 years. There was a trend for a survival benefit for the EBRT group (21 months versus 11 months, p = 0.05). Nevertheless, the median disease-free survival was not different (11 months versus 9 months). After the study completion, 30 more patients were treated according to the same regime corroborating the initial results. The analysis of the sites of failure indicated that the adjuvant treatment did not reduce the local failure rate nor the liver metastasis frequency but appeared to increase the overall survival without any influence on the time of onset nor the site of metastases [lo]. Our results are in good agreement with those of the GITSG, the median disease free and the overall survival being 12 and 23 months, respectively, versus 11 and 21 months for the GITSG. Thus, EBRT alone delivered in a conventional course with a dose of 54 Gy seems as effective as the split-course radiotherapy combined with 5-FU. Nevertheless, we observed a very high rate of local failure (7/14 ~50%). Therefore, the adjunction of 5-FU or IORT to our regime, allowed by the observed good tolerance, may be able to improve the results.
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29 Nakase, A., Matsumoto, Y., Uchida, K. and Honjo, I. Surgical treatment of cancer of the pancreas and the periampullary region: cumulative results in 57 institutions in Japan. Ann. Surg. 185: 52-57, 1977. 30 Peretz, T., Nori, D., Hilaris, B., Manolatos, S., Linares, L., Harrison, L., Anderson, L. L., Fuks, Z. and Brennan, M. F. Treatment of primary unresectable carcinoma of the pancreas with I-125 implantation. Int. J. Radiat. Oncol. Biol. Phys. 17: 931-935, 1989. 31 Roldan, G. E., Gunderson, L. L., Nagomey, D. M., Martin, J. K., Ilstrup, D. M., Holbrook, M. A., Kvols, L. K. and McIlrath, D. C. External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer 61: 1110-l 116, 1988. 32 Shipley, W. U., Wood, W. C., Tepper, J. E., Warshaw, A. L., Orlow, E. L., Kaufman, S. D., Battit, G. E. and Nardi, G. L. Intraoperative electron beam irradiation for patients with unresectable pancreatic carcinoma. Ann. Surg. 200: 289-296, 1984. 33 Sindelar, W. F. and Kinsella, T. J. Randomized trial of intraoperative radiotherapy in resected carcinoma of the pancreas. Int. J. Radiat. Oncol. Biol. Phys. 12 (Supp. I): 110, 1986. 34 Sindelar, W. F. and Kinsella, T. J. Randomized trial of intraoperative radiotherapy in unresectable carcinoma of the pancreas. Int. J. Radiat. Oncol. Biol. Phys. 12 (Supp. I): 111, 1986. 35 Smith, I. E., Courtenay, V. D., Mills, J. and Peckham, M. J. In vitro radiation response of cells from four human tumours propagated in immune-suppressed mice. Cancer Res. 38: 390-395, 1978. 36 Syed, A. M. N., Puthawala, A. A. and Neblett, D. L. Interstitial iodine125 implant in the management ofunresectable pancreatic carcinoma. Cancer 52: 808-813, 1983. 37 Tepper, J., Nardi, G. and Suit, H. Carcinoma of the pancreas: review of MGH experience from 1963 to 1973. Analysis of surgical failure and implications for radiation therapy. Cancer 37: 1519-1524, 1976. 38 Trede, M., Schwa& G. and Saeger, H. D. Survival after pancreatoduodenectomy. 118 consecutive resections without an operative morality. Ann. Surg. 211: 447-458, 1990. 39 Treumiet-Donker, A. D., Van Mierlo, M. J. M. and Van Putten, W. L. J. Localized unresectable pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 18: 59-62, 1990. 40 Tuckson, W. B., Goldson, A. L., Ashayeri, E., Halyard-Richardson, M., Dewitty, R. L. and Leffall, L. D. Intraoperative radiotherapy for patients with carcinoma of the pancreas. The Howard University Hospital experience, 1978-1986. Ann. Surg. 207: 648-653, 1988. 41 Van Heerden, J. A. Pancreatic resection for carcinoma of the pancreas: Whipple versus total pancreatectomy - an institutional perspective. World J. Surg. 8: 880-888, 1984. 42 Warren, K. W., Choe, D. S., Plaza, J. and Relihan, M. Results of radical resection for periampullary cancer. Ann. Surg. 181: 534-540, 1975. 43 Warshaw, A. L. and Swanson, R. S. Pancreatic cancer in 1988. Possibilities and probabilities. Ann. Surg. 208: 541-553, 1988. 44 Whittington, R., Dobelbower, R. R., Mohiuddin, M., Rosato, F. E. and Weiss, S. M. Radiotherapy of unresectable pancreatic carcinoma: a six year experience with 104patients. Int. J. Radiat. Oncol. Biol. Phys. 7: 1639-1644, 1981. 45 Williams, J. A., Cubilla, A., Maclean, B. J. and Fortner, J. G. Twentytwo year experience with periampullary carcinoma at Memorial SloanKettering Cancer Center. Am. J. Surg. 138: 662-665, 1979. 46 Wilson, S. M. and Block, G. E. Periampullary carcinoma. Arch. Surg. 108: 539-544, 1974.
191
RADION 01009
Short Communication
Conventional
external irradiation alone as adjuvant treatment in resectable pancreatic cancer: results of a prospective study
J. F. Bosseta, J. J. Pavy”, M. Gilletb, G. Mantionb,
E. Pelissierb and S. Schraub”
Departments of “Radiotherapy and b Surgery, CHU BesanGon, Besaqon,
France
(Received 27 August 1991, revision received 10 March 1992, accepted 23 March 1992)
Key words: Pancreatic
5-fluorouracil(5-FU) increases survival if compared to surgery alone [20]. The aim of this paper is to report on the toxicities and the treatment results of a prospective non-randomised study conducted by a single institution, using a conventional post-operative EBRT only after resection of ductal carcinoma of the pancreas.
cancer; Adjuvant radiotherapy
Summary Between l/85 prospective
and l/90,
14 consecutive patients were entered into a
study of conventional
beam radiotherapy
adjuvant
post-operative
after complete resection for a pancreatic
adeno-
carcinoma. The surgical procedure was a Whipple resection in nine patients, a distal pancreatectomy createctomy
in four patients and a total pan-
in one patient. There were three Tlb, eight T, and three
T, tumours (UICC 1987); nodal involvement was present in five cases. The radiotherapy a 23
x
was delivered using a four-field box technique with
MV photon beam. All patients received a total dose of 54 Gy
to the tumour bed. The mean treated volume was 900 cm3. Acute toxicities consisted mainly of weight loss (mean: 2 kg). Two patients had a grade 2 diarrhoea and two patients a grade 2 gastritis. Late effects were minimal and only observed in two patients. The overall locoregional recurrence (LR) rate was 50 % . The median disease-free survival was 12 months, and the median survival was 23 months. This post-operative
conventional radiotherapy
treatment gives results that
are comparable to the results of the GITSG-adjuvant study using a combination of split-course radiotherapy and 5-fluorouracil (5-FU).
Introduction
Ductal adenocarcinoma of the pancreatic gland is a common tumour and its incidence is steadily increasing [ 11. It now ranks tenth among cancer in Europe [ 251. It is also a highly malignant disease, being the fourth cause of cancer deaths in the United States [ 131. The median survival after the diagnosis is 4 months on average [ 161. Surgery is the reference treatment for operable non-metastatic patients and is considered as the only possibility for cure [5,23,24,28,38,41,43,45]. However, long-term survival remains poor [ 17,291. Locoregional failure, as first site, rates as high as 50% after apparent complete tumour removal [22,37]; this is in good agreement with the fact that 49% of the patients have locoregional disease only, at the time of diagnosis [ 181. The efficacy of irradiation to control pain or to prevent local progression [ 71 indicates that the tumour is accessible to such treatment. In the adjuvant setting, the role of radiotherapy needs to be clearly defined. Today, only one randomised trial with a limited amount of patients and a short follow-up period has indicated that a split course external beam radiotherapy (EBRT) combined with Address for correspondence:
Materials
and methods
external
J. F. Bosset, Service de Radiothkrapie,
Between January 1985 and January 1990, 14 consecutive patients were enroled in the study. All patients had a ductal adenocarcinoma of the pancreas and in all patients a macroscopically complete surgery was performed. Cancer of the ampulla, the duodenum and the distal common bile duct were excluded as well as cystadenocarcinoma and islet cell type carcinoma of the pancreas. No patient referred for adjuvant treatment was excluded. Seven males and seven females were treated, whose ages ranged from 33 years to 69 years (average = 60 years). At the time of study entry, the ECOG status was 0 for two patients 1 for 10 and 2 for two. The tumour was located in the head of the gland in 10 patients, in the body in three patients and in the tail in one. Only three patients had tumour grossly confined to the gland, while the other patients had an invasion of the capsula (4 patients), a direct attachment to the portal vein (2 patients), to the mesenteric vessels (2 patients), to the vena cava (one patient), to the colon, left kidney and spleen (one patient), or to the stomach and ileum (one patient). A Whipple resection was performed in nine patients, a distal pancreatectomy in four patients and a total pancreatectomy in one. The surgical removal was extended to the left kidney and colon in one patient, and to the stomach, adrenal gland and ileal loops in another patient, because of tumour extension. No patient was left with visible or palpable gross tumour after removal. The mean macroscopical diameter of the tumours was 4 cm (1.5-8 cm). In 13 patients the tumour was a ductal invasive adenocarcinoma and in one a mucoid adenocarcinoma type. Five patients had nodal invasion. Four patients had a microscopically positive posterior margin while one patient had a microscopically positive margin at the level of the distal pancreatic section. In one case, the margin was not clearly stated and therefore considered as unknown. According to the TNM classification (UICC 1987), 3 patients had a T,, tumour, 8 patients a T, tumour and 3 patients a T, tumour. This correspond to stage I in 7 patients, stage II in 2 and stage III in 5 patients. Surgical procedure and tumour characteristics are summarised in Table I. Post-operative EBRT was delivered using a linear accelerator and 23 MV photon beam. The mean delay between surgery and radiotherapy was 2 months (1.5-5 months). All patients were similarly CHU Jean Minjoz, 25030 Besanqon Cedex, France
192 TABLE
I
Surgical
procedure and turnour characteristics.
Patient
1 2
CPjCI
T
N
Stage
Margin free
Site of 1st recurrence
CI
TZ T,
_
II
Yes
LR
II
Tlb
DFS (months)
Status/delay (months)
19
DOC 21 NED 60
3
CI CP
III
4
CI
T2
+ _
Yes Yes
I
No
5
CI
T3
_
II
Yes
6
T2
_
I
Yes
LR + M (liver)
34
DOC 35
7
CI CI
T3
_
II
No
M (liver)
23
DOC 36
8
CP
T,b
I
No
M (liver)
12
DOC 23
9
CP
+
III
Yes
LR
12
DOC 19
10
CI
T,b T2
+
III
No
LR
19
DOC 34
11 12
Cl
T,
+
III
LR
10
DOC 12
T,
M (peritoneum)
14
CI
+ _ _
111
13
CI CI
No NA
I I
Yes Yes
M (liver) LR
20 12 12
DOC 22 DOC 19 DOC 13
T2 T,
M (liver) LR + M (peritoneum)
CP = confined within the pancreas; CI = contiguous invasion; LR = locoregional NED = no evident of disease; DOC = dead of cancer; NA = not available.
treated. The limits of the tumour volume were defined on the basis of the preoperative CT scan and according to the surgical clips left at the edge of the tumour bed. This tumour volume included the tumour bed, the posterior peripancreatic soft tissues, the distal section of the pancreatic gland, the upper mesenteric and coeliac nodes. The target volume had to encompass the tumour volume by a minimum margin of 2 cm in all dimensions. IVP and upper gastrojejunal imaging were performed in the simulation room. The initial target volume was treated by a four-field technique up to a dose of 45 Gy (1.8 Gy/F, 5 F per week), all fields being treated every day. The average measured volume was 900 cm3. Then, a 9 Gy boost dose was delivered to the tumour bed in 5 fractions using only AP-PA fields (average field size: 9 x 9 cm). All the patients received a total dose of 54 Gy and the mean duration of the treatment was 44 days. The dose was prescribed using the ICRU 29 recommendations. The internal half of the right kidney, the upper half of the left kidney and an undetermined portion of the Roux-en-Y loop had to be irradiated. The mean delivered dose to the spinal cord was 27 Gy. In general, the gastrojejunal anastomosis was out of the treated volume. Follow-up During treatment, the patients were clinically examined every week. After treatment, the patients were examined every 3 months, and in addition biochemical tests (Ca 19.9) and the required radiological investigations were performed (chest X-Ray, abdominal ultra-sound (US) and/or CT scan). Acute and late toxicities were scored using the WHO scoring system. Failures were detected clinically and confirmed radiologically as a tumour regrowth on CT scan and/or US imaging. They were classified as locoregional recurrences (LR) if they were localised within the treated area; any other localisation was considered as metastasis (M). Only two patients had an histological confirmation of the recurrence, one patient by a second-look operation and the second by a US guided function of the liver. No further specific treatment was offered at the time of the relapse. The survival was calculated from the date of surgery. Survival curves were obtained using the Kaplan-Meier method. No patient was lost to follow up.
60+ 11
recurrence;
M = metastasis;
DOC 33
1
DOC 11
46+
NED 46
DFS = disease-free
survival;
Results There were no treatment interruptions and no toxic death occurred due to acute toxic side-effects. The mean weight loss was 2 kg ( + l6 kg). Acute toxicities occurred in five patients: grade 1 gastritis in one patient, grade 2 gastritis in two patients, grade 2 diarrhoea in one patient and one patient had a grade 2 diarrhoea plus a grade 1 gastritis. After 6 months, late sequela developed in two patients: one who ultimately died of cancer (LR) presented a grade 2 ileitis and one who is alive without disease at 46 months with a grade 1 ileitis and a grade 1 gastritis. The mean follow-up period is 28 months (ll60 months). Twelve patients died from cancer between 11 and 36 months after surgery and two patients are alive free of cancer 46 and 60 months after treatment, respectively. The median disease-free survival is 12 months and the median overall survival is 23 months (Fig. 1). The site of first failure was locoregional in 5 patients, locoregional and hepatic in one patient, locoregional and peritoneal in one patient, hepatic alone in 4 patients and peritoneal alone in one patient. The overall locoregional recurrence rate was 50 %. The small number of patients did not allow to assess statistically the quality of the margin, the nodal involvement nor the stage as potential pronostic
LT L,
&403
8 20-
3 &
0
.
0
12
24 36 Tie in months (-
) and overall survival
of surgery calculated
using the Kaplan-Meier
Fig. 1. Disease-free
survival
48
60
(- - -) from the date method.
193 factors. The sites of recurrence and status of patients are summarised in Table I. Discussion
Surgical resection is the standard treatment for pancreatic cancer. Theresectabilityrateislow: lo-15% [2,16,28,29]. Thepost-operative mortality is now less than 10% [42,45] and even 5% in recent series of trained teams [ 14,28,38]. In spite of this, the 5-year survival remains low (5%), with a median survival varying from 10 to 17 months [ 17,20,23,41,46]. For tumours located in the head of the gland, that occur most frequently, a Whipple resection is the standard surgical procedure [41]. The extension of the surgery does not seem to influence the survival [ 3,281. Admitted favourable pronostic factors are the size (below 2 cm), the absence of capsular disruption, and the absence of nodal involvement [27]; 4-20% of the resected pancreatic tumours fit these criteria [21,28] (corresponding to the T,, N, UICC 1987). The median survival of these patients ranges from 13 to 24 months [4,21]. No patient had these favourable criteria in our series. After macroscopically complete resection, the LR rate is high, from 30 to 70% [ 10,15,37]. The high LR rate can be explained by the difficulties to obtain free margins due to the tumour extension into the retropancreatic fat, and to the vicinity of the large vessels, portal vein and superior mesenteric artery [ 19,21,42]. Furthermore, after a Whipple resection, there is a microscopic residual disease left in 5-38% of the patients [21,28,42] and 30% of the patients have had an incomplete node dissection [ 6,421. Hepatic metastases are present in 50% of the failures, usually associated with LR, and peritoneal spread is present in 31% [ 10,15,37]. Historically, pancreatic cancer has been thought to be radioresistant, however, experimental studies demonstrate that this is not explained by intrinsic radioresistance [35]. For locally advanced tumour, EBRT is able to control the pain in 30-50% of the treated patients who have a S-12-month survival [7,26,39]. The addition of 5-FU to a split-course irradiation significantly improves the overall survival in comparison with a split-course irradiation only [ 261, and does as well as the addition of doxorubicin but with less toxic side effects [9]. The combination of 5-FU streptozotocin, mitomycin-C (SMF) did not generate any survival benefit relative to 5-FU plus conventional EBRT followed by SMF [ 111. Different radiotherapy schedules (split course versus conventional) have never been tested prospectively.
No benefit
demonstrated
for doses of more than 40 Gy using split-course
in local control
from dose increment
ules. [ 261. The dose increment gained by brachytherapy
was sched-
[30,36,44]
or more recently by intraoperative radiotherapy (IORT) increases the local control rate but does not influence the overall survival [ 8,3 1,32,40]. This was confirmed by a controlled study conducted by the NC1 with a small number of patients [ 341. In resected cancers, data on post-operative radiotherapy background are limited. Kopelson [22] reported on seven patients with pancreatic or ampullary tumours receiving adjuvant post-operative radiotherapy. Only one patient received more than 45 Gy and was alive NED at 2 years. Gerard et al. published the largest series from a single institution: 34 patients with resected pancreatic adenocarcinoma were treated to 44-50 Gy post-operative EBRT. Surgery was considered to be macroscopically complete in 19 patients and macroscopically incomplete in 15 patients. The 3 year overall survival was 19% in the first group and 0% in the second. The median overall survivals were the same in both groups, 10 months. Sites of failure were not analysed [ 121. The NC1 conducted a controlled trial in 32 patients with resected pancreatic cancer testing IORT. Patients with Stage II or III disease were randomly allocated to either an IORT dose of 20 Gy with a 9-12 MeV electron beam or a postoperative EBRT of 50 Gy. IORT increased the local control from 0% for the EBRT group up to more than 80% for the IORT group, however, the overall survival was not significantly prolonged [33]. The GITSG [20] reported on the only controlled study in which 43 patients with resected pancreatic cancers were randomly allocated to surgery alone (22 patients) or surgery plus post-operative EBRT (40 Gy, split course over 6 weeks) combined with 5-FU (21 patients). Chemotherapy was maintained every 2 weeks for 2 years. There was a trend for a survival benefit for the EBRT group (21 months versus 11 months, p = 0.05). Nevertheless, the median disease-free survival was not different (11 months versus 9 months). After the study completion, 30 more patients were treated according to the same regime corroborating the initial results. The analysis of the sites of failure indicated that the adjuvant treatment did not reduce the local failure rate nor the liver metastasis frequency but appeared to increase the overall survival without any influence on the time of onset nor the site of metastases [lo]. Our results are in good agreement with those of the GITSG, the median disease free and the overall survival being 12 and 23 months, respectively, versus 11 and 21 months for the GITSG. Thus, EBRT alone delivered in a conventional course with a dose of 54 Gy seems as effective as the split-course radiotherapy combined with 5-FU. Nevertheless, we observed a very high rate of local failure (7/14 ~50%). Therefore, the adjunction of 5-FU or IORT to our regime, allowed by the observed good tolerance, may be able to improve the results.
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