Gemcitabine/cisplatin versus 5-fluorouracil/mitomycin C chemoradiotherapy in locally advanced pancreatic cancer: a retrospective analysis of 93 patients

Brunner, Sauer Rolf, Fietkau, Fietkau Rainer

Description

Despite of a growing number of gemcitabine based chemoradiotherapy studies in locally advanced pancreatic cancer (LAPC), 5-fluorouracil based regimens are still regarded to be standard and the debate of superiority between the two drugs is going on. The aim of this retrospective analysis was to evaluate the effect of two concurrent chemoradiotherapy regimens using 5-fluorouracil or gemcitabine to compare their effect and tolerance. Methods We have performed a single centre retrospective analysis of 93 patients treated with conventionally fractionated radiotherapy of 55.8 Gray using either concurrent 5-fluorouracil, 1 g/m² on days 1-5 and 29-33 of radiotherapy and 10 mg/m² of mitomycin C on day 1, 29 of radiotherapy (FM group, 35 patients) versus gemcitabine (300 mg/m²) and cisplatin, (30 mg/m²) on days 1, 8, 22, and 29 (GC group, 58 patients). Primary endpoint was the median overall survival (OS) rate. Results The median OS rate was 12.7 months in the GC group and 9.7 months in the FM group. The 1-year OS rate was 53% versus 40%, respectively (p = 0.009). GC led to more grade 3 leukocytopenia and thrombocytopenia than FM, but not to more grade 4 myelosuppression. Thrombocytopenia was the most frequently observed grade 4 toxicity in both groups (11% after FM versus 12% after GC). No grade 3/4 febrile neutropenia was observed. Grade 3 nausea was more common in the FM group (20% versus 9%) and grade 4 nausea was observed in one patient per group only. Conclusions GC was superior to FM for overall survival and both regimens were similar in terms of tolerance. We conclude that GC leads to encouraging results and that the use of FM for chemoradiotherapy in LAPC cannot be recommended without concerns.

Sujets

• Pancreatic cancer
• Chemoradiotherapy
• Gemcitabine

Informations

• Publié par: biomed
• Publié le: 01 janvier 2011
• Nombre de lectures: 16
• Langue: English

Extrait

Brunner et al. Radiation Oncology 2011, 6:88
http://www.ro-journal.com/content/6/1/88
RESEARCH Open Access
Gemcitabine/cisplatin versus 5-fluorouracil/
mitomycin C chemoradiotherapy in locally
advanced pancreatic cancer: a retrospective
analysis of 93 patients
1,2* 1 1Thomas B Brunner , Rolf Sauer and Rainer Fietkau
Abstract
Background: Despite of a growing number of gemcitabine based chemoradiotherapy studies in locally advanced
pancreatic cancer (LAPC), 5-fluorouracil based regimens are still regarded to be standard and the debate of
superiority between the two drugs is going on. The aim of this retrospective analysis was to evaluate the effect of
two concurrent chemoradiotherapy regimens using 5-fluorouracil or gemcitabine to compare their effect and
tolerance.
Methods: We have performed a single centre retrospective analysis of 93 patients treated with conventionally
fractionated radiotherapy of 55.8 Gray using either concurrent 5-fluorouracil, 1 g/m² on days 1-5 and 29-33 of
radiotherapy and 10 mg/m² of mitomycin C on day 1, 29 of radiotherapy (FM group, 35 patients) versus
gemcitabine (300 mg/m²) and cisplatin, (30 mg/m²) on days 1, 8, 22, and 29 (GC group, 58 patients). Primary
endpoint was the median overall survival (OS) rate.
Results: The median OS rate was 12.7 months in the GC group and 9.7 months in the FM group. The 1-year OS
rate was 53% versus 40%, respectively (p = 0.009). GC led to more grade 3 leukocytopenia and thrombocytopenia
than FM, but not to more grade 4 myelosuppression. Thrombocytopenia was the most frequently observed grade
4 toxicity in both groups (11% after FM versus 12% after GC). No grade 3/4 febrile neutropenia was observed.
Grade 3 nausea was more common in the FM group (20% versus 9%) and grade 4 nausea was observed in one
patient per group only.
Conclusions: GC was superior to FM for overall survival and both regimens were similar in terms of tolerance. We
conclude that GC leads to encouraging results and that the use of FM for chemoradiotherapy in LAPC cannot be
recommended without concerns.
Keywords: Pancreatic cancer, chemoradiotherapy, gemcitabine, 5-fluorouracil
Background cancer [1,2]. Due to the declines in lethality in other
Pancreatic ductal adenocarcinoma (PDAC), commonly major cancers, pancreatic cancer is predicted to become
th
known as pancreatic cancer, is the 10 most common the fourth cause of cancer death in Europe [2]. Dramatic
cancer type with an incidence of 10/100,000 but highly progress was made during the past years to better
lethal (> 95%) and this is reflected by the fact that it is understand the biology of this disease (reviewed in [3]).
thranking as the 5 most lethal cancer in absolute patient Only 10-20% of the patients have resectable tumours at
numbers after lung, colorectal, breast and prostate diagnosis and resection is a prerequisite for cure but
even with adjuvant therapy median overall survival of
resected patients is still as low as 20% after 5 years in
* Correspondence: [e-mail]
1 randomised phase III studies (reviewed in [4]). The largeRadiation Oncology of the Friedrich-Alexander University of
ErlangenNuremberg, Universitätsstraße 22, 91054 Erlangen, Germany majority (> 80%) of patients with non-resectable disease
Full list of author information is available at the end of the article
© 2011 Brunner et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.Brunner et al. Radiation Oncology 2011, 6:88 Page 2 of 8
http://www.ro-journal.com/content/6/1/88
at diagnosis can be subdivided into metastatic and single-nucleotide polymorphisms in DNA the repair
locally advanced PDAC (LAPC) with both stages being damage genes ATM, Chek1 and ATR were found to be
about equally frequent. Compared with metastatic dis- significantly associated with OS after gemcitabine CRT
ease patients with LAPC have a better prognosis and - especially when analysed for the combined effect of all
though often grouped together with metastatic disease three genes [13]. In line with these observations,
gemcinot separated in randomised phase III trials - patients tabine containing schedules were described to achieve a
with LAPC should be separated from patients with higher rate of pathologic response compared to 5-FU
metastatic disease. based protocols [14]. The combination of gemcitabine
Chemotherapy is an essential element in the treatment with 5-FU or capecitabine which is commonly used as a
of LAPC to fight the high tendency of distant spread. chemotherapy combination was found to be too toxic
But the combination of systemic with local treatment for CRT in LAPC especially in terms of elevated
gastroprolonged survival in a number of recent studies [5,6] intestinal toxicity [15]. Therefore we decided a different
compared with systemic therapy only. Of note, second- chemotherapeutic combination, gemcitabine and
cisplaary resection after CRT was reported in a systematic tin, which had been investigated both preclinically and
review and meta-analysis in 1/3 of the patients leading clinically: the synergism between the two drugs is
attribto a median overall survival (mOS) rate of 20.5 months uted mainly to an increase in platinum-DNA adduct
forwhich is equally good as after primary resection [7] and mation which is possibly related to changes in DNA due
downstaging was also described [8]. On the other hand, to dFdC incorporation into the DNA [16-18]. The
comthe inferiority of chemoradiotherapy (CRT) vs che- bination of the two drugs is clinically in use mainly in
motherapy in a recent French trial [9] can most likely ovarian, non-small cell lung and pancreatic cancer and
be attributed to inadequate technique and quality of has been more effective than gemcitabine only in
metachemoradiotherapy highlighting the complexities of static and locally advanced PDAC in the group of
CRT for PDAC [10]. Of note, 60 Gy were delivered in 2 patients with good performance status [19].
Gy fractions to both the primary tumour and the elec- Despite of this rationale, gemcitabine initially was
diftive lymphatics resulting in large planning target ficult to be combined with radiotherapy due to its acute
volumes (PTV) as 2 cm expansion margins were used toxicity profile depending profoundly on the absolute
from the clinical target volumes. Also, the FFCD-SFRO radiotherapy treatment volume [18,20]. This potential
trial [9] is the only randomised phase III CRT trial dangerous effect can now be more easily
counterusing 5-fluorouracil (5-FU)/Cisplatin as concurrent che- balanced with highly conformal treatment planning and
motherapeutic agents and this resulted in a very high the use of IMRT/IGRT thereby increasing the tolerance
rate of grade 3/4 toxicity for the adjuvant chemotherapy of gemcitabine based CRT [21]. In this analysis we
comand prevented maintenance chemotherapy. Commonly, pare the outcome and the toxicity of two CRT regimens
the combination of a fluoropyrimidine with radiotherapy in 93 patients with LAPC treated at our centre: One
is regarded to be the standard of care for CRT [4] but a regimen was 5-FU/Mitomycin C (FM), the other
gemcisubstantial number of gemcitabine based CRT trials was tabine/cisplatin (GC) given concurrently with
radiotherreported with encouraging results such as in the ECOG- apy. These two regimens have not been compared in
4201 trial [6]. The latter trial used IMRT together with the literature up to now but they both have been used
2600 mg/m gemcitabine weekly, a relatively high dose, in a number of trials in PDAC and other upper GI
resulting in a high rate of grade 3/4 toxicity. tumours [22-25]. We report superior OS of the GC
regiThe rationale for preferring gemcitabine over 5-FU in men with comparable high grade toxicity (grade 4
haeCRT regimens is its hypothesised superiority both, matologic and grade 3/4 non-haematologic disease).
locally and systemically: in metastatic disease
gemcitabine was able to prolong survival and to lead to higher Methods
clinicalbenefitcomparedto5-FU[11].Forthelocal Patient population
effect when used with radiotherapy, gemcitabine is pre- This is a retrospective study identifying all patients
treadicted to lead to higher tumour cytotoxicity than 5-FU ted at the University Hospitals of Erlangen with
chemorbecause it is one of the most potent radiosensitising adiotherapy. Patients were identified by reviewing the
chemotherapeutic agents [12]. Gemcitabine is an S- tumour board minutes and the departmental minutes of
phase specific deoxycytidine analogue. It acts via compe- Radiation Oncology. Patients with locally advanced
pantitive incorporation of dFdCTP and dCTP into DNA creatic carcinoma (LAPC) were selected for primary
and results in DNA fragmentation and subsequent cell CRT at our local tumour board. The following eligibility
death. Furthermore, gemcitabine interferes with ribonu- criteria were used: Histological proof of ductal
adenocleotide reductase which is thought to have an impact carcinoma prior to CRT. In general, LAPC was defined
on cell death by affecting DNA repair. Also, specific along the lines of the Practice Guidelines in Oncology™Brunner et al. Radiation Oncology 2011, 6:88 Page 3 of 8