Median survival of pancreatic patients in the advanced stage is approx. 3-5 months, with a 12-month survival probability of 10% despite ad-vances in cancer therapy. On the other hand, the 5-year survival probability is 0.4%-3.0% (Bram-hall et al. 1995, 1998).
The causes of such a dismal prognosis can be understood first of all in the commonly late diag-nosis (Haycox et al. 1998), second in the aggres-sive tumor cell biology with continuing therapy resistance (Magee et al. 2001), and finally because an acceptable resection rate can be achieved only in specialized centers (Birkmeyer et al. 2002; Ne-optolemos et al. 1997).
Only 10%-15% of patients can be resected af-ter the diagnosis of pancreatic cancer. Resection is considered a potential curative therapy. How¬ever, median survival of these patients amounts to only 13-18 months, with a 5-year survival of 10%-20% (Bramhall et al. 1995; Yeo et al. 1997). The survival rate did not improve with a radical resection and extended lymphadenectomy (Pedrazzoli et al. 1998).
Furthermore, 15%-30% of primary nonmeta-static pancreatic cancer is unresectable due to extended vessel infiltration at time of diagnosis. The prognosis for these patients is very dismal due to lack of specific therapy; moreover, median overall survival is a maximum of 6-8 months (Niederhuber et al. 1995; Shinchi et al. 2002).
10.1 Chemotherapy of Advanced
Pancreatic Cancer
Although more chemotherapeutic agents have been examined for the purposes of the therapy of advanced pancreatic cancer, only 5-FU, mito-mycin-C (MMC) (Haycox et al. 1998) and, lately, gemcitabine (Burris et al. 1997; Moore et al. 1995; Rothenberg et al. 1996) have shown reproduct¬ible outcomes with objective results.
A 5-FU-based combined chemotherapy has shown a clear survival advantage compared to patients without treatment in randomized con-trolled studies (Glimelius et al. 1996; Mallinson et al. 1980; Palmer et al. 1994). However, com¬pared to monotherapy with 5-FU, a toxicity in¬crease without additional improvement of sur¬vival has been reported (Cullinan et al. 1990).
Gemcitabine belongs to a series of new che-motherapeutic agents tested for pancreatic can¬cer. It has shown superior efficacy both in mono-therapy and in combined therapies (Berlin et al. 2002; Burris et al. 1997; Heinemann et al. 1999b, 2000). Nevertheless, the application of fluoro-pyrimidine continues to be of interest in trials where the efficacy of 5-FU after portal vein in¬fusion (PVI) application and the development of orally applicable chemotherapeutic agents is sought (Neoptolemos et al. 2004). The National Cancer Research Institute in Britain has recently started a Gem-Cap phase III trial where gem-citabine (Gem) will be applied with capecitabine
(Cap).
The survival advantage with gemcitabine is minor compared to bolus 5-FU (Burris et al. 1997). Nevertheless, it is being used in advanced pancreatic cancer increasingly as the standard therapy.
However, a significant breakthrough in the therapy of advanced pancreatic cancer with che-motherapy has not been found yet.
10.2 Chemoradiation in Locally
Advanced Pancreatic Cancer
A favorable positive effect has been reached with different radiotherapy proceedings such as in-traoperative radiation therapy (IORT) with or without external chemo-/radiation therapy or with chemoradiation (CRT) alone with regard to both local tumor symptomatic (local tumor pain), local tumor remission, or local control of disease and overall survival (Fossati et al. 1995; Nishimura et al. 1997; Staley et al. 1996). There-fore, chemoradiation with a total irradiation dose of 45.0-50.0 Gy (eventually up to 60.0 Gy) with conventional fractionation and a concur¬rent chemotherapy with 5-FU (eventually PVI during the whole therapy with 200-225 mg/m2 per day) was recommended as the standard and most effective therapy procedure for patients in good general condition (German Cancer Asso¬ciation 2002).
Randomized trials reporting significant im-provement of median survival after chemoradia-tion are listed in Table 10.1 (Moertel et al. 1981; Li et al. 2003; Shinchi et al. 2002).
For decades, 5-FU has been considered the agent of choice with regard to the chemothera-peutic agents administered concurrently or sequentially to radiation. Combined chemo¬therapies such as FAM (5-FU, doxorubicin, mito-mycin-C) or SMF (streptozotocin, mitomycin-C, 5-FU), or the Mallinson regimen (5-FU, cyclo-phosphamide, methotrexate and vincristine) re¬sulted in increased toxicity and no improvement as to survival (Bruckner et al. 1993; Cullinan et al. 1990). Even newer agents tested recently for pancreatic cancer such as paclitaxel, docetaxel, irinotecan, topotecan, and oxaliplatin could not be established as treatment (Ashamalla et al. 2003; Kamthan et al. 1997). Only after the intro-duction of the pyrimidine analog gemcitabine it was possible to reach an improved response rate for unresectable (Epelbaum et al. 2002; Kornek et al. 2001; Okusaka et al. 2004; Safran et al. 2002) or metastatic (Burris et al. 1997; Carmichael et al. 1996; Casper et al. 1994; Heinemann et al. 1999a; Rothenberg et al. 1996) patients in different stud-ies. Gemcitabine has a favorable side effect pro-file: positive clinical benefit response, practically no hepato- or nephrotoxicity. Only hematotoxic-ity can be seen as a dose-limiting factor. Because of that, radiation-sensitizing effects have been experimentally proved for gemcitabine (Law¬rence et al. 1996; McGinn et al. 1996; Mose et al. 1999; Shewach et al. 1994), which suggests some hope for successful administration of this agent concurrent to radiation.
10.3 Local Remission After Primary (Chemo-)Radiation Therapy
Radiation therapy alone or the combination of external beam radiation therapy (EBRT) with IORT leads to local remission only rarely. The administration of IORT has been explained pri-marily with providing the benefit of good to best pain palliation [pain control in 57% (Okamoto et al. 1994; Tuckson et al. 1988) to 100% (Manabe et al. 1988)].
Whittington et al. (1984) and Mohiuddin et al. (1988) have reported on a patient cohort where the combination of EBRT with iodine-125 seed implantation increased local control (clinical, lo¬cal symptomatic) from 22% (historical patient group) to 81%.
It has been possible to observe objective re-mission in images only recently, since the advent of the concurrent administration of radiation sensitizing agents (chemotherapeutic agents, in the first-line 5-FU or combination therapies with 5-FU) for EBRT (Aristu et al. 2003; Luderhoff
et al. 1996).
The frequency of local remission in up to 50% of patients can be observed when administering up-to-date primary chemoradiation (Ikeda et al. 2002; Li et al. 2003; Rich and Evans 1995; Spitz et al. 1997; Wolff et al. 2000).
It is possible to achieve these response rates especially with gemcitabine-associated chemo-radiation therapy. Remission was seen in 50% vs 13% of the patients in a randomized comparison
of gemcitabine-CRT with 5-FU-CRT. Of a total
of 18 gemcitabine-CRT patients, 4 have shown total remission (Li et al. 2003).
Bruckner et al. (1998) observed downstag-ing in 30% of a group of unresectable patients in International Union Against Cancer (UICC) stages II and III. The therapy concept included radiation therapy (54 Gy) with 5-FU and strep-tozotocin and cisplatin, followed by systemic chemotherapy with 5-FU-folic acid. Local tumor regression was surprisingly positive in resected patients. Fibroses were found in the histology of five of the resected patients, but no cancer cells.
A histological response (tumor cell destruc-tion) has been seen in more than 5 in 10 (50%) of the resected patients from a group of 34 that were examined (Joensuu et al. 2004). These pa-tients were treated primarily with concurrent chemoradiation with gemcitabine. Of these,
3 patients (11%) had a tumor cell destruction of more than 90%.
Wilkowski et al. (2004) have shown in an analysis of 47 patients with primary unresectable carcinoma that, especially during a concurrent sequential CRT with gemcitabine and cisplatin (GC), a high rate of local remission (69% dur¬ing GC-ssqCRT) can be achieved, which can be proved by imaging diagnostics. It is possible to reach complete pathological remissions: R0 re-section was achieved in 13 patients. Of these,
4 patients had no histologically verified tumor.
10.4 Secondary Resection After Primary
(Chemo-)Radiation Therapy
Better resectability and the reduction of postop-erative positive lymph node metastasis has been seen especially in patients with resectable or pos-sibly resectable pancreatic cancer after neoadju-vant chemoradiation.
The restaging after chemoradiation has led the enrolled cancer patients in UICC stage II and III to resection rates between 43% and 74% in Evans et al. (1992), Ishikawa (1996), Rich et al. (1985), and Hoffman et al. (1998). Patients in UICC stage IV were studied by Jeekel and Treurniet-Donker (1991), Bruckner et al. (1998), Todd et al. (1998), and Kim et al. (2002)). Accordingly, resection rates were between 3.4% and 19% af¬ter neoadjuvant multimodality therapy in UICC stage IV.
Resectability can be achieved in patients with primary unresectable pancreatic cancer with primary chemoradiation too. This has been re-ported first of all after concurrent chemora-diation with gemcitabine (Ammori et al. 2003; Brunner et al. 2003; Crane et al. 2002; Epelbaum et al. 2002; Pipas et al. 2001; Wilkowski et al. 2004). R0 resection has been reached only in in¬dividual cases after concurrent administration of PVI 5-FU (application during radiation). Con¬current combination chemotherapies (CDDP+5-FU+/-paclitaxel) (Aristu et al. 2003) has led to complete remission in the framework of a resec¬tion only in individual cases.
10.5 Local and Systemic Progression After Primary (Chemo-)Radiation Therapy
It can be shown at the evaluation of patients' pro-gression samples—either treated neoadjuvant or primarily with (chemo-) radiotherapy (with conventional radiation technique)—that the rate of local recurrence or local progression can be reduced in comparison with historical cohorts; moreover, it can be expected only in 6%-27% of the patients (Ishikawa et al. 1994, 1998; Kornek et al. 2001; Luderhoff et al. 1996; Okusaka et al.
2001).
By contrast, the rate on distant metastases, especially peritoneal carcinosis and liver metas-tasis, was not affected. This rate was assessed in 97% of the patients as a cause for therapy failure
(Okusaka et al. 2004; Poggi et al. 2002; Shinchi et al. 2002).
Time to distant metastasis was even extended in the patient groups if a systemic chemother¬apy was integrated in the treatment regimen as sequential chemotherapy. Kornek et al. (2000) report a progression-free survival of 10 months after concurrent sequential chemoradiation with 5-FU/leucovorin and cisplatin. Favorable ef¬fect was achieved with local liver perfusion with 5-FU too (Ishikawa et al. 1998).
The prognosis was favorable for the group of patients undergoing resection after neoadjuvant or primary (chemo-) radiation therapy (Al-Suk-hun et al. 2003). Downstaging has been found in only 2 of 16 patients in a historical comparison by Jessup (1993), who administered neoadjuvant radiotherapy with 54 Gy and continuous 5-FU infusion. Median survival was 8 months in this group. The two successfully treated and resected neoadjuvant patients had a tumor-free interval of 20 and 22 months, respectively.
Ishikawa et al. (1994) have found in a case control study that preoperative radiation therapy resulted in downstaging and consequently in oncological resection in 17 of 23 patients. These patients had a reduction in local recurrence and have not died of the consequences of them. The first manifestations of disease development in the group of Ishikawa were frequently liver metasta-ses. These metastases have caused lethal conse¬quences more frequently in a year compared to a historical control group.
Median time to progression (TTP) of only 4.4 months was observed by Azria et al. (2002) after sequential chemo-radiotherapy (sCRT) with 5-FU (600 mg/m2, day 1-5, week 1 and 5) and cisplatin (100 mg/nr*, day 2, weeks 1 and 5).
Okusaka et al. reporton a median progres-sion-free interval of 5.8 months and a therapy failure due to distant metastasis (78%) in a series of 41 primary unresectable patients treated with ssqCRT (concurrent cisplatin 5 mg/m2 per day, sequential 5-FU). Only 21% of the patients de-veloped a local recurrence.
A median TTP of 2.7 vs 7.1 months (p = 0.019), a median TTLP of 2.7 vs 7.4 months (p = 0.0016), and a median time to systemic progression (TTSP) of 3.1 vs 6.1 months (n.s.) have been ob¬served in a randomized trial by Li et al. (2003) where 5-FU-CRT vs gemcitabine-CRT has been compared.
10.6 Overall Survival After Primary (Chemo-)Radiotherapy
In 1969, Moertel et al. were able to achieve a bet-ter median survival in locally advanced pancre-atic cancer with the administration of the com-bination of external radiation (EBRT) and 5-FU compared to radiation alone. Hereby was the im-portance of radio sensitizing through concurrent chemotherapy established.
5-FU, as an integrative part in CRT, has not been substituted yet by other agents, new combi-nations, or regional applications. The role of PVI 5-FU application, the administration of gem-citabine as radio sensitizer, or hyperfractionation of radiation during CRT is not clear.
Significant advantage of gemcitabine-CRT (concurrent gemcitabine, weekly 600 mg/m2 per day 6x and sequential gemcitabine) compared
to 5-FU-CRT (bolus 5-FU 500 mg/m2 per day,
days 1-3 and sequential gemcitabine) has been shown only in one randomized study (Li et al. 2003). However, there have been only 18 vs 16 patients compared, and 5-FU has been applied as bolus on three subsequent days of weeks 1, 3, and 5 of radiotherapy. Median survival of 14.5 months was achieved with gemcitabine-CRT, 6.7 months with 5-FU-CRT.
However, a median survival of 13.2 months has been reported in a further randomized trial
by Shinchi et al. (2002) with PVI 5-FU-CRT
(200 mg/m2 per day). Median survival was 6.4 months in case of an untreated group of pa¬tients.
We should conclude in comparing these two studies alone that gemcitabine-CRT can be seen as equivalent to PVI 5-FU-CRT. A retrospective analysis by Mehta et al. (2001) does not support this conclusion. He has compared 27 patients
with either bolus 5-FU or PVI 5-FU CRT. Me¬dian survival was 6 months for both groups in this trial. However, bolus 5-FU-CRT shows no improvement as to overall survival in compari¬son with untreated patients.
Whereas concurrent CRT leads to favorable local tumor control, this procedure has a minor effect as to the survival in most of the studies. This is because of the development of metastases out of the irradiation field. The concept of com-bined CRT with continuing chemotherapy was developed as a logical consequence due to these metastases and because of partly advanced local tumor progression. The Gastrointestinal Tumour Study Group (GITSG) completed a trial in 1981 that divided the patients in three study arms as follows: 60 Gy EBRT without radio sensitizing with 5-FU, 60 Gy EBRT with radio sensitizing with 5-FU and subsequent 5-FU application, 40 Gy EBRT with radio sensitizing with 5-FU and subsequent 5-FU application. Median sur¬vival was 23, 40, and 42 weeks, respectively. That is, a high dose of chemotherapy had no addi¬tional use. Better results were reached especially with concurrent or subsequent chemotherapy.
A median survival of 8.2 months after chemo-therapy alone with weekly bolus 5-FU has been reported in the phase III study of the Eastern Cooperative Oncology Group (ECOG) of a to¬tal of 91 patients with unresectable pancreatic cancer. A median survival of 8.3 months has been seen in the direct comparison within the group treated with 5-FU-CRT and subsequent chemotherapy (Klaasen et al. 1985). Significantly higher toxicity (51%) has been observed in the study arm with combination therapy compared to 5-FU therapy alone (27%).
It has been possible to show in the phase I/II study of the Radiation Therapy Oncology Group (RTOG) enrolling 81 patients that, in spite of the fact that a prophylactic liver radiation can reduce the incidence of hepatic metastasis, this proce-dure can affect neither the local tumor control nor the intraabdominal tumor spread, and con-sequently, prophylactic liver irradiation cannot be generally recommended (Komaki et al. 1992).
A median survival of 17 months was seen in recent studies after CRT combined with triple chemotherapy (5-FU, streptozocin, and cispla-tin) (Terk et al. 1997). Favorable median survival of 14 months was shown in a further trial of combined chemoradiation with 5-FU, leucovo-rin, and cisplatin (Kornek et al. 2000).
Hypofractionation (Luderhoff et al. 1996) or hyperfractionation (Crane et al. 2001; de Lange et al. 2002) of the irradiation in the framework of chemoradiation and sequential chemotherapy has been also administered. These regimens can¬not be recommended as routine therapies due to considerable toxicities.
No survival advantage was achieved for pa-tients with combined or IORT or brachytherapy alone (Nishimura et al. 1988; Calvo et al. 1991; Fossati et al. 1995; Kasperk et al. 1995; Okamoto
et al. 2004).
Although recent studies have been report¬ing about acceptable survival after CRT, the results are not convincing in comparison with chemotherapy alone (especially using gem-citabine) (Fisher et al. 1999; Saad et al. 2002); possibly, it would be seen as even more unfavor¬able for the total cohort of patients (Chauffert
et al. 2006).
10.7 Effect of Radiation Dose
on Progression and Overall Survival After Primary (Chemo-)Radiotherapy
The initial data about the irradiation of pancreatic cancer have shown that "very high" doses would have been considered necessary in order to treat local tumors effectively. The effect of radiation has been reported as depending on dose, and a median survival of 10 months was achieved with a total dose of 68-75 Gy in the target field (Wie-gel et al. 2000). A cure after radiation alone has been assessed as barely possible. Accordingly, the further aspect of local palliation (reduction of pain symptomatic in 65%-70% of the cases) has been formulated as the treatment aim. Necessary dose escalation was reached through IORT, even¬tually followed by EBRT. It was not possible to show a convincing remission rate or a substantial improvement of progression-free and total sur¬vival in studies with EBRT alone (Moertel et al. 1969, 1981), with IORT (Abe et al. 1993; Goldson 1991; Nishimura et al. 1988), or with a combina¬tion of EBRT and IORT (Kawamura et al. 1992;
Gilly et al. 1990), although a median survival of 12.0 months has been reported in patients in stages I and II, respectively, with the combined use of EBRT and IORT (Manabe et al. 1988; Abe et al. 1991, 1993; Okamoto et al. 1994).
Downstaging for potential resectable patients has been reported first with the administration of chemoradiation with 5-FU and the adminis¬tration of a radiation dose of 45-54 Gy (Scherer 1987). However, it has been shown that with the additional administration of IORT, a me¬dian survival of 18 months can be reached only for resectable patients, and the median survival amounts to 8.0-16.5 months for unresectable pa-tients in this case (Kojima et al. 1991; Wood et al. 1982; Shipley et al. 1984).
The concept of dose escalation with IORT has been discussed in recent studies in combination with chemoradiation as a rule (Okamoto et al. 2003). Convincing data were not shown in com-parison with chemoradiation alone. Accordingly, Okamoto et al. (2003) have reported a median overall survival of 8.6 months.
Thus, it can be formulated that the "effectuat-ing" of the therapy for locally advanced pancre-atic patients can be strived for with radiation dose escalation only in cases where the "optimization" of the concurrent or sequential chemotherapy regimen can affect the systemic progression pro¬cedure of the carcinoma significantly. This is sup¬ported by the fact that local progression results after chemoradiation can be seen substantially later in the median survival than in the overall survival of the patients. That means that patients have no local relapses or local progression after chemoradiation with a local dose of 50.0 Gy, which is considered moderate regarding possible late consequences.
10.8 Primary Concurrent
Chemoradiation with Gemcitabine
Since the effectiveness of gemcitabine compared to 5-FU or 5-FU-associated polychemotherapies has been proved in the treatment of pancreatic patients with metastasis (Burris et al. 1997), this agent has been examined also as a combination agent for concurrent chemoradiation in the treat-ment of locally advanced pancreatic cancer.
The selected therapy applications of concur-rent chemotherapy with gemcitabine were and are:
- Normal gemcitabine chemotherapy dose (or combination therapy (Muler et al. 2004)) with total radiation dose- and/or volume reduc¬tion with accelerated radiation (McGinn et al. 2001; Muler et al. 2004)
- Reduced gemcitabine chemotherapy with to¬tal dose reduction with accelerated radiation (Crane et al. 2001)
- Reduced gemcitabine chemotherapy dose with hypofractionated radiation (de Lange
et al. 2002)
- Escalation of gemcitabine chemotherapy dose with weekly applications up to a toxic dose with normal dose radiation (Morganti et al. 2003; Poggi et al. 2002; Safran et al. 2002)
- De-escalation of gemcitabine chemotherapy dose with weekly applications to a tolerable dose with normal dose radiation (Brunner
et al. 2003)
- Reduced gemcitabine chemotherapy dose with weekly applications and a normal dose radiation (Ikeda et al. 2002; Okusaka et al.
2004)
- Reduced gemcitabine chemotherapy dose with 24-h infusion and weekly applications and normal dose radiation ((Kudrimoti et al. 1999; Mohiuddin et al. 2002) respectively)
- Reduced gemcitabine chemotherapy dose with weekly applications and "split course" ra-diation (Van Laethem et al. 2003)
- Reduced gemcitabine chemotherapy doses twice a week and normal dose radiation (Pi-pas et al. 2001; Blackstock et al. 1999, 2003)
- Reduced gemcitabine chemotherapy doses three times a week and normal dose radiation
(Epelbaum et al. 2002)
- Combined chemotherapy, gemcitabine with 5-FU and normal dose radiation (Talamonti
et al. 2000; Wilkowski et al. 2000)
- Combined chemotherapy, gemcitabine with cisplatin (dose reduced or normal dose) and normal dose or accelerated radiation (Mar-
tenson et al. 2003; Wilkowski et al. 2002)
Tolerable concurrent gemcitabine doses with weekly application are defined as 250 mg/m*-300 mg/m2 with conventional dose radiation (up to 50.4 Gy and 28 fractions) and with the involvement of regional lymph nodes in the ra-diation volume (TV II) (Wolff et al. 2001; Ikeda
et al. 2002; Morganti et al. 2003). Gemcitabine
doses could be increased to 440 mg/m2 per day with weekly applications when there is a reduc-tion of radiation volume (only with the involve-ment of macroscopic tumor = TV I) (Poggi et al.
2002).
A gemcitabine dose of 300 mg/m2 has been applied with hypofractionated radiation (3 x 8.0 Gy) (de Lange et al. 2002).
A maximum gemcitabine dose of 300 mg/m2 or 75 mg/m2 per day, and weekly application for each, has been determined for the purposes of a concurrent combined chemotherapy with cis-platin or paclitaxel, respectively (Brunner et al.
2003; Safran et al. 2002).
It has also been proved to be possible to ap¬ply a dose of 40-90 mg/m2 per day gemcitabine every 2 weeks concurrent with normal dose ra-diation (Blackstock et al. 1999, 2003; Yavuz et al.
2001).
Kornek et al. have examined the concurrent 24-h infusion of gemcitabine and determined an applicable dose of 130 mg/nr* per day and weekly application.
It can be seen on the basis of the data above that neither the gemcitabine dose, the applica¬tion rhythm, nor the applicable radiation dose or radiation volume could have been recommended as standard up to now.
The problem is that the different combinations of gemcitabine with radiation have led to differ-ent toxicity profiles which partly correspond to grade 3 or 4 toxicity.
Generally, a normal dose or weekly reduced gemcitabine dose, even with a reduced radiation dose or reduced volume, has led to increased gastrointestinal complications (McGinn et al. 2001; Muler et al. 2004). Hematotoxicity (leuko-cytopenia and/or thrombocytopenia grade 3-4 up to 66%) has been seen with high probability with the dose reduction of gemcitabine and normal dose radiation (Wolff et al. 2001;
Blackstock et al. 2003; Okusaka et al. 2004).
Dose-reduced combined chemotherapies with normal dose radiation have led to significant hematotoxicity too (Wilkowski et al. 2002; Brun-
ner et al. 2003).
One possible solution for the problem has been seen in the application of gemcitabine as sequential chemotherapy alone (Li et al. 2003; Kachnic et al. 2001; Ben-Josef et al. 2004) and the concurrent application of a chemotherapy with 5-FU or capecitabine (Ben-Josef et al. 2004).
It has been shown that for the majority of pa-tients treated concurrently with gemcitabine, a local remission could have been achieved with the possibility of secondary R0 resection in comparison with patients treated with concur¬rent 5-FU (Crane et al. 2002), independently from toxicity, which was assessed as moderate (Brunner et al. 2003) to intolerable (Talamonti et al. 2000). Response rates have been reported in
29%-50% of the patients (de Lange et al. 2002;
Ikeda et al. 2002; Li et al. 2003), and absence of tumor after neoadjuvant treatment and second-ary resection (ypT0 stages) has been observed
(Brunner et al. 2003; Epelbaum et al. 2002). Thus, pathologically complete remissions are possible after gemcitabine-associated CRT.
Median TTP has been reported between 4.4 (Okusaka et al. 2004) and 7.1 months (de Lange et al. 2002; Li et al. 2003). Local therapy failure (local progression or local relapse after remis¬sion) has been observed in up to 65% (de Lange et al. 2002) and distant metastasis in 75% of the patients (de Lange et al. 2002). Median overall survival was between 8.3 (Kornek et al. 2001)
and 14.5 months (Li et al. 2003).
Concurrent chemoradiation with 5-FU has been compared with gemcitabine monotheapy only in one prospective randomized study; se-quential chemotherapy has been administered in both arms with gemcitabine monotherapy until progress (Li et al. 2003). Significantly bet¬ter remission rates (13% vs 50%) and signifi¬cantly improved median progression-free (2.7 vs 7.1 months) and median overall survival (6.7 vs 14.1 months) have been observed only in the case of a few patients (16 vs 18 patients) during gemcitabine-CRT.
10.9 Primary (Chemo-)Radiotherapy: Does It Make Sense and Is It Efficient?
Different studies (Crane et al. 2002; Li et al. 2003) point out that sequential concurrent chemora-diation, especially with gemcitabine, positively affect the progression-free and overall survival in primary unresectable pancreatic patients in comparison with concurrent chemoradiation and radiotherapy alone. Prospective randomized studies are warranted to prove the significant differences as to different combinations of con¬current and sequential chemotherapy with 5-FU +/-gemcitabine or gemcitabine+/-cisplatin.
IORT alone or in combination should not be induced because there have been negative results with possible deterioration of the prognosis.
The most important positive prognostic fac¬tor is remission after chemoradiation. Especially patients undergoing secondary R0 resection after image-proved remission show a significant im-provement in progression-free and overall sur-vival and reach can 5-year survival (24.9% of the patient cohort; R. Wilkowski, unpublished).
The therapy aim for locally advanced primary unresectable nonmetastatic pancreatic cancer is the local treatment of the disease, considering its systemic aggressiveness. A proper combination agent should be found for concurrent chemora-diation that has a high systemic effect and/or is capable of achieving this effectiveness in sequen¬tial application.
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