Is the therapeutic index better with gemcitabine-based chemoradiation
than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer?
Crane CH, Int J Radiat Oncol Biol Phys 2002 Apr 1;52(5):1293-302
Pancreatic Tumor Study Group, Department of Radiation Oncology, The
University of Texas M. D. Anderson Cancer Center,
Between September 1996 and May 2000, 114 patients with localized unresectable
adenocarcinoma of the pancreas were treated with concurrent chemoradiation. Locally
advanced unresectable disease was defined as low-density tumor in contact with the
superior mesenteric artery (SMA) or celiac artery, or occlusion of the superior
mesenteric-portal venous confluence. Fifty-three patients were selected to receive
gemcitabine in 7 weekly cycles (250-500 mg/m(2)) with concurrent radiotherapy (median dose
30 Gy, range 30-33 Gy in 10-11 fractions). The remaining 61 patients received
continuous-infusion 5-FU (200-300 mg/m(2)) with concurrent radiotherapy (30 Gy in 10
fractions). Radiotherapy was delivered to the primary tumor and regional lymphatics.Severe
acute toxicity (ST) was defined as toxicity requiring a hospital stay of more than 5 days,
mucosal ulceration with bleeding, more than 3 dose deletions of gemcitabine or
discontinuation of 5-FU, or toxicity resulting in surgical intervention or death.
Kaplan-Meier analysis was used to calculate the actuarial rate of local progression on
imaging (LP), the rate of distant metastasis (DM), and the overall survival (OS) rate. The
imaging was reviewed in resected patients. RESULTS: Patients receiving gemcitabine developed significantly more ST during treatment (23% vs.
2% than did those receiving 5-FU. Patients treated
with gemcitabine had a similar 10-month LP rate (62% vs. 61%), 10-month DM rate (55% vs.
47%), 1-year OS rate (42% vs. 28%), and median OS duration (11 months vs. 9 months) to
patients treated with 5 FU (all p = NS). Despite the selection of healthier
patients to receive gemcitabine, there was a significantly higher severe toxicity rate
than with 5-FU. The median and 1-year survivals were not significantly different with the
use of concurrent gemcitabine; however, the tumors treated were significantly larger.
Additionally, a small number of patients with minimal arterial involvement whose disease
met our radiographic definition of unresectable disease had margin-negative resections
after treatment with gemcitabine-based chemoradiation. These possible benefits and the
high rate of severe toxicity define a very narrow therapeutic index for concurrent
gemcitabine-based chemoradiation given by this schedule of administration.
Phase I trial of twice-weekly gemcitabine and concurrent radiation
in patients with advanced pancreatic cancer.
Blackstock AW, B
J Clin Oncol 1999 Jul;17(7):2208-12
Department of Radiation Oncology, Wake Forest University
PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicities, and potential
antitumor activity of twice-weekly gemcitabine and concurrent
radiation in patients with locally advanced pancreatic cancer. The initial dose of
gemcitabine was 20 mg/m(2) by 30-minute intravenous infusion each Monday and Thursday for
5 weeks concurrent with 50.4 Gy of radiation to the pancreas.
Gemcitabine doses were escalated in 20-mg/m(2) increments in successive cohorts of three
to six additional patients until dose-limiting toxicity was observed. RESULTS: The
dose-limiting toxicities at 60 mg/m(2) given twice-weekly were nausea/vomiting,
neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a
40-mg/m(2) dose was well tolerated. Of the eight patients eligible for a minimum
follow-up of 12 months, three remain alive, one of whom has no evidence of disease
progression. CONCLUSION: A dose of twice-weekly gemcitabine at 40 mg/m(2) produced mild
thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent
radiation to the upper abdomen in patients with advanced pancreatic cancer. These data
suggest this regimen is well tolerated and may possess
significant activity.
Eastern Cooperative Oncology Group Phase I trial of protracted
venous infusion fluorouracil plus weekly gemcitabine with concurrent radiation therapy in
patients with locally advanced pancreas cancer: a regimen with unexpected early toxicity.
Talamonti MS, J Clin Oncol 2000 Oct 1;18(19):3384-9
Northwestern University Medical School, Chicago, IL
PURPOSE: We performed a phase I trial of protracted venous infusion (PVI) fluorouracil
(5-FU) plus weekly gemcitabine with concurrent radiation therapy in patients with locally
advanced pancreas cancer to determine the maximum-tolerated dose of gemcitabine that could
be safely administered. We also sought to identify the toxicities associated with this
treatment protocol. PATIENTS AND METHODS: Seven patients with locally advanced pancreas
cancer were treated with planned doses of radiation (59.4 Gy) and
PVI of 5-FU (200 mg/m(2)/d) with gemcitabine doses of 50 to 100 mg/m(2)/wk.
RESULTS: Two of three patients at the 100-mg/m(2)/wk dose level experienced dose-limiting
toxicity (DLT), as did three of four at the 50-mg/m(2)/wk dose level. One patient
experienced a mucocutaneous reaction described as a Stevens-Johnson syndrome that was
attributed to chemotherapy. Three patients developed gastric or duodenal ulcers with
severe bleeding requiring transfusion. One patient developed severe thrombocytopenia
lasting longer than 4 weeks. Three of the five episodes of DLT
developed at radiation doses < or = 36 Gy. CONCLUSION: Based on this
experience, we cannot recommend further investigation of regimens incorporating
gemcitabine into regimens of radiation with PVI 5-FU. The mechanism of this synergistic
toxicity remains to be determined.
Phase I trial of radiation dose escalation with concurrent weekly
full-dose gemcitabine in patients with advanced pancreatic cancer.
McGinn CJ J Clin Oncol 2001 Nov 15;19(22):4202-8
Department of Radiation Oncology, University of Michigan, 1
Thirty seven patients with unresectable (n = 34) or incompletely resected pancreatic
cancer (n = 3) were treated. Gemcitabine was administered as a 30-minute intravenous
infusion at a dose of 1,000 mg/m(2) on days 1, 8, and
15 of a 28-day cycle. Radiation therapy was initiated on day 1 and directed at the primary
tumor alone, without prophylactic nodal coverage. The starting radiation dose was 24 Gy in 1.6-Gy fractions. Escalation
was achieved by increasing the fraction size in increments of 0.2 Gy, keeping the duration
of radiation constant at 3 weeks. A second cycle of gemcitabine alone was
intended after a 1-week rest. RESULTS: Two of six assessable patients experienced
dose-limiting toxicity at the final planned dose level of the trial (42 Gy in 2.8-Gy
fractions), one with grade 4 vomiting and one with gastric/duodenal ulceration. Two
additional patients at this dose level experienced late gastrointestinal toxicity that
required surgical management. CONCLUSION: The final dose investigated (42 Gy) is not
recommended for further study considering the occurrence of both acute and late toxicity.
However, a phase II trial of this novel gemcitabine-based chemoradiotherapy approach, at a
radiation dose of 36 Gy in 2.4-Gy fractions, is recommended
on the basis of tolerance, patterns of failure, and survival data.
Protracted 5-fluorouracil infusion with concurrent radiotherapy as a
treatment for locally advanced pancreatic carcinoma.
Ishii H, Okada S, Tokuuye K, Nose H, Okusaka T, Yoshimori M, Nagahama H, Sumi M, Kagami
Y, Ikeda H
Cancer 1997 Apr 15;79(8):1516-20
Department of Internal Medicine, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
BACKGROUND: Radiotherapy plus bolus 5-fluorouracil (5-FU) is
generally accepted as the standard treatment for locally advanced pancreatic carcinoma. To
intensify the antitumor effect of chemotherapy, the authors administered protracted 5-FU
infusion with concurrent radiotherapy. The aim of this study was to determine the
feasibility and effectiveness of this combined therapy. Twenty patients, all of whom had
histologically confirmed exocrine pancreatic carcinoma that was nonresectable but confined
to the pancreatic region, were enrolled in a Phase II trial of protracted 5-fluorouracil
infusion (200 mg/m2/day) with concurrent radiotherapy (50.4 gray in
28 fractions over 5.5 weeks). Chemotherapy began on the first day of radiation and
continued through the entire radiation course. Thereafter, weekly infusions (500 mg/m2)
were administered until disease progression. RESULTS: Of the 20 patients, 17 (85%)
completed the scheduled course of chemoradiotherapy. Grade 3 or worse toxicity, graded
according to World Health Organization criteria, was observed in 4 patients (20%). Two
patients (10%) achieved partial response, and disease remained stable in 16 patients
(80%). After the completion of combined therapy, serum CA 19-9 levels were reduced by more
than 50% in 10 of 12 patients (83%) who had pretreatment CA 19-9 levels of 100 U/mL or
greater. The median progression free survival and 1-year progression free survival rate
were 4.9 months and 29.5%, respectively. The median overall survival
and 1-year overall survival rate were 10.3 months and 41.8%, respectively.
CONCLUSIONS: This treatment showed moderate activity against locally advanced pancreatic
carcinoma and was accompanied by an acceptable toxicity level.
High-dose local irradiation plus prophylactic hepatic irradiation and
chemotherapy for inoperable adenocarcinoma of the pancreas. A preliminary report of a
multi-institutional trial (Radiation Therapy Oncology Group Protocol 8801).
Komaki R, Wadler S, Peters T, Byhardt RW, Order S, Gallagher MJ, Herskovic A, Pederson
J
Cancer 1992 Jun 1;69(11):2807-12
Department of Clinical Radiotherapy, University of Texas M. D. Anderson Cancer Center,
Houston 77030.
Adenocarcinoma of the pancreas is an extremely malignant neoplasm with a particular
propensity to spread to the liver. In an effort to combine chemotherapy with high-dose
local irradiation plus a modest dose of irradiation to suspected (subclinical) hepatic
metastasis, patients with unresectable pancreatic carcinomas with no known distant
metastasis were treated on a prospective multi-institutional Radiation Therapy Oncology
Group (RTOG) Phase I/II trial. High total dose continuous radiation therapy to the
pancreas (6120 cGy in 34 fractions over 7 weeks) and
simultaneous prophylactic hepatic irradiation (PHI, 2340 cGy in 13 fractions for the last
2.5 weeks) were combined with administration of 5-fluorouracil
1000 mg/m2/day (maximum, 1500 mg) by intravenous continuous infusion for 5 days starting
on day 1 and repeated on day 30 for 5 days, followed by a dose of 600 mg/m2 as a weekly
bolus injection starting during week 9 for 6 months. The patients ranged in age from
32 to 75 years (median, 64 years). Karnofsky performance status was 80 to 100 in 74% of
patients. The tumor was confined to the head of the pancreas in 72% of patients. The
planned radiation therapy for the pancreas was completed in 87% of patients, 80% received
the planned PHI, and 85% completed the first two cycles of chemotherapy.During all cycles
of chemotherapy and radiation therapy, 2 patients died of complications (Grade 5, 1
hepatic and 1 infection), 9 had life-threatening reactions (Grade 4, 7 hematologic, 1
neurologic, and 1 mucositis), and 31 patients had severe effects (Grade 3) according to
the RTOG toxicity scale. Overall hepatic metastasis was documented in 32% (13% as the
first site of failure), persistent or progressive pancreatic tumor was evident in 73%, and
abdominal and extra-abdominal spread were reported in 27% and 8% of patients,
respectively. Eighty percent (63 patients) died (median survival,
8.4 months). Although this study suggests that PHI may reduce the frequency of
hepatic metastasis, failure to control the primary tumor and intraabdominal spread remain
overwhelming.
Treatment of unresectable, locally advanced pancreatic
adenocarcinoma with combined radiochemotherapy with 5-fluorouracil, leucovorin and
cisplatin.
Kornek GV, Schratter-Sehn A, Marczell A, Depisch D, Karner J, Krauss G, Haider K,
Kwasny W, Locker G, Scheithauer W
Br J Cancer 2000 Jan;82(1):98-103
Department of Internal Medicine I, Vienna University Medical School, Austria.
The aim of the study was to evaluate the effectiveness and safety of a combined treatment
modality including systemic chemotherapy with 5-fluorouracil (FU), leucovorin, cisplatin
and external beam radiotherapy in patients with locally advanced pancreatic cancer.
Systemic chemotherapy consisted of FU 400 mg m(-2) and leucovorin 20 mg m(-2) both given as intravenous bolus injection on
days 1-4, plus cisplatin 20 mg m(-2) administered as 90-min
infusion on days 1-4. Treatment courses were repeated every 4 weeks x 6 unless prior
evidence of progressive disease. Radiation therapy using megavolt irradiation of > or =
6 MV photons with a 3- or 4-field technique was delivered during the second and third
chemotherapy course, that was reduced in dose by 25%. Between October 1994 and July 1996,
a total of 38 patients were entered onto this trial, all of whom were assessable for
toxicity and survival. Eighteen of these (47%) had objective remissions to combined
radiochemotherapy, including four CR (11%), 13 (34%) had stable disease and seven patients
(18%) showed tumour progression during treatment. The median progression-free interval of
the entire study population was 10 months (range 3-32), and median
overall survival was 14.0 months (range 3-45+ months); 53% of all patients were
alive at 12 months, and 18% of patients were alive at 24 months respectively. Severe
haematological side-effects comprised neutropenia in 18%, thrombocytopenia in 8% and
anaemia in 11%. The most frequent non-haematological side-effects were nausea/vomiting
(WHO grade 3: 18%), and diarrhoea (grade 3: 13%). This combined radiochemotherapy regimen
was tolerable and effective in patients with locally advanced pancreatic cancer. Since
therapeutic results, in fact, compare favourably with other series, including surgical
treatment of potentially resectable tumours, further evaluation of combined treatment
modalities in the neoadjuvant setting seems warranted.
Combined chemoradiotherapy for unresectable pancreatic cancer.
Martin JL, Harvey HA, Lipton A, Martin R
Am J Clin Oncol 1999 Jun;22(3):309-14
Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania State University,
Hershey, USA.
This study was undertaken to evaluate the efficacy of a regimen of combined
chemoradiotherapy in patients with unresectable adenocarcinoma of the pancreas. An
analysis was undertaken on 27 patients from January 1992 to May 1996. Patients had a
median age of 70 years (range, 40-78) and Eastern Cooperative Oncology Group Performance
Status of 0-2. Eighteen patients had locoregional disease (T2-T3, N0-N1, M0), and nine had
metastatic disease. Chemotherapy consisted of four cycles of 5-fluorouracil
1 gm/m2/day as a continuous infusion over 110 hours, streptozotocin
300 mg/m2/day over 30 minutes on days 2-4, and cisplatin 100
mg/m2 over 2 hours on day 4 only, followed by a maintenance regimen of 5-fluorouracil and
leucovorin every 2 weeks. The radiotherapy was administered as a split course concurrently
with chemotherapy to a total dose of 6000 cGy. Toxicity was
frequent, but there were no treatment-related deaths. Grade III and IV toxicity was
primarily limited to myelosuppression, stomatitis, and gastrointestinal side effects.
Fifteen patients (56%) were able to complete either three or four cycles of
chemoradiotherapy. All patients were evaluable for toxicity, response, and survival. Nine
patients (33%) had an objective response (four complete response 5 partial response), two
remained stable, and 16 (59%) had disease progression. Median
survival for the entire group was 19 weeks (2-139), and the median survival for
overall responders was 56 weeks (15-139). No patient with localized disease underwent
subsequent surgical resection. The authors conclude that those patients who are able to
tolerate the entire treatment regimen may achieve a useful prolongation of time to tumor
progression.
Combined modality treatment with accelerated radiotherapy and
chemotherapy in patients with locally advanced inoperable carcinoma of the pancreas:
results of a feasibility study.
Prott FJ, Schonekaes K, Preusser P, Ostkamp K, Wagner W, Micke O, Potter R, Sulkowski
U, Rube C, Berns T, Willich N
Br J Cancer 1997;75(4):597-601
Department of Radiotherapy, University of Munster, Medical School, Germany.
Between July 1990 and September 1993, 32 patients with locally advanced irresectable
adenocarcinoma of the pancreas, histologically proven by laparotomy, were involved in our
study. Patients were treated with hyperfractionated,
accelerated radiotherapy and simultaneous application of 5-fluorouracil and folinic acid.
Chemotherapy was given on days 1,2 and 3. Determination of the target volume for
radiotherapy was carried out by computerized axial tomography. The total tumour dose of 44.8 Gy was applied relative to the 90% isodose in two daily fractions of
1.6 Gy, resulting in ten fractions per week. On the first three days of
radiotherapy, 600 mg m-3 of 5-fluorouracil and 300 mg m-3 of
folinic acid were given i.v. According to response, chemotherapy was repeated in 4-week
intervals. The median survival time for all patients was 12.7
months, compared with 3-7 months after palliative surgery (historical control).
The median progression-free interval was 6.6 months. Toxicity and therapy-induced
morbidity were recorded according to WHO criteria. Nausea and vomiting of WHO grade I and
II occurred in 72.1% and of grade III and IV in 27.9% of the patients. WHO grade I and II
diarrhoea was seen in 11 patients. The overall incidence of leucopenia and
thrombocytopenia was 37.4%; severe side-effects (WHO III-IV) occurred in 9.3% of all
patients. One patient experienced a severe mucositis (WHO III). This combined modality
treatment consisting of accelerated hyperfractionated radiotherapy and chemotherapy turned
out to be feasible for patients with locally advanced, irresectable pancreatic cancer. The
therapy could be applied in a short period of time, approximately half the time used in
conventional therapy schemes.
Paclitaxel and concurrent radiation for locally advanced pancreatic
and gastric cancer: a phase I study.
Safran H, KJ Clin Oncol 1997 Mar;15(3):901-7
Brown University
PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and
potential antitumor activity of weekly paclitaxel with concurrent radiation (RT) for
locally advanced pancreatic and gastric cancer. PATIENTS AND METHODS: Thirty-four patients
with locally advanced adenocarcinoma of the pancreas or stomach were studied. The initial
dose of paclitaxel was 30 mg/m2 by 3-hour intravenous (I.V.)
infusion repeated every week for 6 weeks with 50 Gy RT. Doses
were escalated at 10-mg/m2 increments in successive cohorts of three new patients until
dose-limiting toxicity was observed. RESULTS: The dose-limiting toxicities at 60 mg/m2/wk
were abdominal pain within the RT field, nausea, and anorexia. Of 23 patients with
assessable disease, 11 (seven with gastric, four with pancreatic cancer) had objective
responses for an overall response rate of 48%. CONCLUSION: Concurrent paclitaxel with
upper abdominal RT is well tolerated at dosages that have substantial activity. A phase II
trial of neoadjuvant paclitaxel and RT at the MTD of 50 mg/m2/wk is underway.
Protracted intravenous fluorouracil infusion with radiation therapy in
the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative
Oncology Group Trial.
Whittington R,
J Clin Oncol 1995 Jan;13(1):227-32
School of Medicine, University of Pennsylvania, Philadelphia.
PURPOSE: The purpose of this study was to determine the maximum-tolerated dose (MTD) of
fluorouracil (5-FU) administered as a protracted intravenous (IV) infusion with concurrent
radiation in patients with pancreaticobiliary carcinoma. METHODS: Twenty-five patients
with recurrent, residual, or unresectable carcinoma of the pancreas or biliary tract were
treated on a phase I trial of protracted IV infusions of 5-FU,
beginning at 200 mg/m2/d, concurrent with radiation therapy (59.4 Gy
in 33 fractions over 6 to 7 weeks). Chemotherapy began on the first day of
radiation and continued through the entire course of treatment. After each cohort of five
patients had been treated and observed, the daily dose was escalated in 25-mg/m2
increments until dose-limiting toxicity was encountered. An additional cohort of five
patients was treated at the MTD. Clinical examination and computed tomography (CT) were
used to evaluate response and patterns of progression. RESULTS: The MTD of 5-FU was 250
mg/m2/d. The dose-limiting toxicity was oral mucositis. The
median survival duration of all patients treated was 11.9 months and the 2-year survival
rate was 19%. Eleven of 25 patients remain free of local progression and four
patients are without evidence of progression at 18+, 18+, 34+, and 44+ months following
treatment. CONCLUSION: Concurrent radiation with protracted 5-FU infusion at 250 mg/m2/d
is well tolerated and shows evidence of activity against tumors of the pancreas and
biliary system.
Eastern cooperative oncology group phase I trial of protracted
venous infusion fluorouracil plus weekly gemcitabine with concurrent radiation therapy in
patients with locally advanced pancreas cancer: A regimen with unexpected early toxicity.
Talamonti MS,
Northwestern University Medical School, Chicago, IL.
J Clin Oncol 2000 Oct 19;18(19):3384-9
PURPOSE: We performed a phase I trial of protracted venous infusion (PVI) fluorouracil (5-FU) plus weekly gemcitabine
with concurrent radiation therapy in patients with locally advanced pancreas cancer to
determine the maximum-tolerated dose of gemcitabine that could be safely administered. We
also sought to identify the toxicities associated with this treatment protocol. PATIENTS
AND METHODS: Seven patients with locally advanced pancreas cancer were treated with
planned doses of radiation (59.4 Gy) and PVI of 5-FU (200
mg/m(2)/d) with gemcitabine doses of 50 to 100 mg/m(2)/wk. RESULTS: Two of three patients
at the 100-mg/m(2)/wk dose level experienced dose-limiting toxicity (DLT), as did three of
four at the 50-mg/m(2)/wk dose level. One patient experienced a mucocutaneous reaction
described as a Stevens-Johnson syndrome that was attributed to chemotherapy. Three
patients developed gastric or duodenal ulcers with severe bleeding requiring transfusion.
One patient developed severe thrombocytopenia lasting longer than 4 weeks. Three of the
five episodes of DLT developed at radiation doses </= 36 Gy. CONCLUSION: Based on this
experience, we cannot recommend further investigation
of regimens incorporating gemcitabine into regimens of radiation with PVI 5-FU. The
mechanism of this synergistic toxicity remains to be determined.
Hyperfractionated radiation and chemotherapy for unresectable
localized adenocarcinoma of the pancreas. The Gastrointestinal Tumor Study Group
experience.
Seydel HG,
Cancer 1990 Apr 1;65(7):1478-82
Wayne State University, Detroit, Michigan.
Eighteen patients with unresectable localized adenocarcinoma of the pancreas were treated
by a combination of chemotherapy plus hyperfractionated radiation therapy to the pancreas
for 4080 cGy with an additional 960 cGy to the pancreatic tumor
and a surrounding margin. One hundred and twenty cGy were given twice daily 4 to 6 hours
apart. High-energy photon or electron beams were used with treatment planning based on
computed tomographic (CT) scans. Patients were given chemotherapy in the form of 5-fluorouracil (5-FU) at 350 mg/m2 on the first 3 and last 3 days of
radiation therapy. On day 53, chemotherapy was given that included 600 mg/m2 IV of 5-FU, 1
gm/m2 of streptozotocin, and 10 mg/m2 IV of mitomycin C. The 5-FU and streptozotocin were repeated on days 60,
81, and 88, and the stretozotocin and mitomycin (SMF) cycles were repeated every 8 weeks
until progression. Radiation toxicity was generally tolerable with one of 18 evaluable
patients having severe nausea and vomiting and two of 18 patients having severe diarrhea.
One patient had total liver failure and died 3 months after initiation of therapy. Six
patients had severe hematopoietic toxicity during chemotherapy. Overall, the severe
toxicity rate was higher (67%) than in previous studies. Median
survival was 35 weeks, the 1-year survival rate was 39%, and the patient who
survived the longest died at 68 months. Although this schedule of hyperfractionated
radiation and chemotherapy was disappointing, combined experimental radiation approaches
plus chemotherapy for localized unresectable adenocarcinoma of the pancreas deserve
additional research.
OLD STUDIES BELOW
Ann Surg 1979 Feb;189(2):205-8
A multi-institutional comparative trial of radiation therapy alone and in combination
with 5-fluorouracil for locally unresectable pancreatic carcinoma. The Gastrointestinal
Tumor Study Group.
One hundred six patients with histologically confirmed pancreatic carcinoma were
randomized to one of three radiation treatment programs: 1) radiation therapy alone to
6000 rads; 2) 6000 rads plus 6-FU; or, 3) 4000 rads plus 5-FU. Patient survival was the
primary study parameter. Both 4000 rads plus 5-FU (p less than .02) and 6000 rads plus
5-FU (p less than .01) were associated with a significantly longer patient survival than
6000 rads alone. Respective median survivals were 36 weeks, 40
weeks, and 20 weeks. The survival difference between 4000 rads plus 5-FU and 6000
rads plus 5-FU was not statistically significant at the time point selected.
Cancer 1985 Dec 1;56(11):2563-8
Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of
locally unresectable pancreatic carcinoma. Gastrointestinal Tumor Study Group.
One hundred fifty-seven patients with locally unresectable pancreatic carcinoma were
randomly allocated to therapy with radiation and 5-fluorouracil or radiation and
Adriamycin (doxorubicin). A total of 138 of 143 analyzable patients have died, and no differences in the relative survival impact of the treatments have been
observed (P greater than 0.8). Toxicity on the Adriamycin arm was more substantial
(P less than 0.05) and primarily attributable to Adriamycin chemotherapy after the
completion of radiotherapy.
J Natl Cancer Inst 1988 Jul 20;80(10):751-5
Treatment of locally unresectable carcinoma of the pancreas: comparison of
combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone.
Gastrointestinal Tumor Study Group.
Randomized trials of the Gastrointestinal Tumor Study Group have previously
demonstrated enhanced survival of patients with locally unresectable pancreatic cancer
treated with 5-fluorouracil in combination with radiation therapy compared with that of
patients treated with radiation therapy alone. The present study compared the survival of
patients treated with multidrug chemotherapy [streptozocin, mitomycin, and 5-fluorouracil
(SMF)] versus radiation combined with 5-fluorouracil followed by the same three-drug SMF
combination. In 43 patients randomly allocated between these two arms, an improved median survival for the combined-modality therapy (42 weeks) compared with
chemotherapy alone (32 weeks) was demonstrated. Overall survival following this
combined-modality treatment program (41% at 1 year) was significantly superior to that
following SMF chemotherapy alone (19% at 1 year), by a two-tailed log rank test (P less
than .02). Serial studies of the Gastrointestinal Tumor Study Group with patients with
locally unresectable pancreatic adenocarcinoma have shown that combined-modality therapy
is superior to either optimal radiotherapy or chemotherapy alone.
Br J Surg 1991 Nov;78(11):1332-4
Treatment perspectives in locally advanced unresectable pancreatic cancer.
Jeekel J, Treurniet-Donker AD
Department of Surgery, University Hospital Dijkzigt, The Netherlands.
Locally advanced unresectable pancreatic cancer is sometimes encountered without
manifest distant metastases. Twenty patients with histologically proven unresectable
pancreatic cancer without distant metastases were treated with
radiotherapy and 5-fluorouracil (5-FU). Radiotherapy consisted of 50 Gy external
upper abdomen radiation in two courses, concomitant with intravenous 5-FU 375 mg/m2 given
as a bolus injection 4-6h before radiation on the first 4 days of each treatment course.
The treatment protocol was completed in 18 patients without complications. The median survival time was 10 months which compares favourably with a
3-5 months median survival time when treatment is withheld. Nine patients (45 per
cent) were alive at 1 year, two patients at 2, 3 and 4 years. A second-look operation was
performed in four patients 6, 11, 12 and 22 months after completion of radiotherapy. In
two patients the tumour could be resected. It appears that treatment with radiotherapy and
5-FU may benefit patients with locally advanced unresectable pancreatic cancer.
J Clin Oncol 1985 Mar;3(3):373-8
Treatment of locally unresectable cancer of the stomach and pancreas: a randomized
comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance
5-fluorouracil--an Eastern Cooperative Oncology Group study.
Klaassen DJ, MacIntyre JM, Catton GE, Engstrom PF, Moertel CG
One hundred ninety-one patients with pathologically confirmed, locally unresectable
adenocarcinoma of the stomach (57 patients) and pancreas (91 patients), were randomly
allocated to therapy with 5-fluorouracil (5-FU) alone, 600 mg/m2 intravenously (IV) once
weekly, or radiation therapy, 4,000 rad, plus adjuvant 5-FU, 600 mg/m2 IV, the first three
days of radiotherapy, then follow-up maintenance 5-FU, 600 mg/m2, weekly. Forty-three
patients (22%) could not be analyzed because of ineligibility or cancellation, thus 148
patients were evaluable. The median survival time was similar for both treatment programs
and for both types of primary carcinoma, and was as follows: gastric primary carcinoma,
5-FU, 9.3 months; 5-FU plus radiotherapy, 8.2 months; pancreatic
primary carcinoma, 5-FU, 8.2 months; 5-FU plus radiotherapy, 8.3 months.
Substantially more toxicity was experienced by patients treated with the combined modality
arm than by those patients receiving 5-FU alone. Severe or worse toxicity experienced by
patients with gastric primary carcinoma treated by 5-FU was 19%, and the combined modality
arm was 31%. The toxicity experienced by patients with pancreatic primary carcinoma
treated with 5-FU was 27%, and the combined modality arm was 51%. Significant prognostic
variables included: weight loss in stomach-cancer patients; and performance status, degree
of anaplasia, and reduced appetite in pancreas-cancer patients.
Cancer 1981 Oct 15;48(8):1705-10
Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high
dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil),
and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group.
Moertel CG, Frytak S, Hahn RG, O'Connell MJ, Reitemeier RJ, Rubin J, Schutt AJ,
Weiland LH, Childs DS, Holbrook MA, Lavin PT, Livstone E, Spiro H, Knowlton A, Kalser M,
Barkin J, Lessner H, Mann-Kaplan R, Ramming K, Douglas HO Jr, Thomas P, Nave H, Bateman J,
Lokich J, Brooks J, Chaffey J, Corson JM, Zamcheck N, Novak JW
One-hundred-ninety-four eligible and evaluable patients with histologically confirmed
locally unresectable adenocarcinoma of the pancreas were randomly assigned to therapy with
high-dose (6000 rads) radiation therapy alone, to moderate-dose (4000 rads) radiation +
5-fluorouracil (5-FU), and to high-dose radiation plus 5-FU. Median
survival with radiation alone was only 51/2 months from date of diagnosis. Both
5-FU-containing treatment regimens produced a highly significant survival improvement when
compared with radiation alone. Forty percent of patients treated with the combined
regimens were still living at one year compared with 10% of patients treated with
radiation only. Survival differences between 4000 rads plus 5-FU and
6000 rads plus 5-FU were not significant with an overall median survival of ten months.
Significant prognostic variables, in addition to treatment, were pretreatment performance
status and pretreatment CEA level. |
