The prognosis for patients with pancreatic can¬cer is still very poor. A complete (R0) surgical resection of the tumor poses the only chance of cure. At the moment only postoperative chemo-therapy with gemcitabine has significantly de-layed the development of recurrent disease and showed an improvement in long-term survival compared to observation alone. It is essential to develop more effective adjuvant therapy strate-gies with involvement of all therapeutic options to change the disappointing situation.
6.1 Prognosis
The only chance of cure for patients with pan-creatic cancer is a complete (R0) surgical resec¬tion of the tumor. Unfortunately, only 10%-25% of cases are potentially resectable at the time of diagnosis. The precondition for R0 resection is the absence of distant metastasis. Especially, the dimension of infiltration of peripancreatic tissue and the big vessels, the size and localization of the primary tumor, and the concomitance of in-volved lymph nodes are constitutive criteria for a curative-intent resection [19, 35-37]. Nonethe¬less, prognosis is still poor, even for those un¬dergoing complete (R0) resection. Therefore, the development and clinical approval of effective adjuvant therapies is necessary.
6.2 Adjuvant Chemotherapy
Pancreatic cancer is a systemic disease. It has been shown that 42%-53% of resected cases de-velop distant metastasis in the peritoneum, 27% of cases develop extra abdominal metastasis, and more than 60% of recurrent cancer occurs in the liver. Only 20% of cases develop a solitary local recurrence. However, these patients frequently develop distant metastases soon after [13, 17, 33]. Until recently, the available drugs for pallia-tive chemotherapy for patients with progressive pancreatic cancer were not effective. The strate-gies for chemotherapies have shown a high toxic-ity accompanied by a questionable benefit. Until the mid-1990s, all common chemotherapy regi¬mens included 5-fluorouracil (5-FU) solely or in combination with other drugs such as metho-trexate, vincristine, cyclophosphamide, cisplatin, mitomycin C, or doxorubicin.
The first and for a long time only randomized study of adjuvant systemic chemotherapy [5-FU, mitomycin C, and doxorubicin (FAM)-protocol] showed a statistically significant improvement in overall survival (OS) for the treatment group (23 months vs 11 months) [3]. However, there was a poor improvement of long-term survival (5-year survival was 4% vs 8%) and the small number of only 61 randomized patients made this study less than convincing. As published in an earlier case-control study by Splinter [32], the chemotherapy in the postoperative period was not well tolerated by patients. Only 13 of the 30 patients in the (randomized) treatment arm re-ceived all planned therapy cycles; in fact, only 24 patients started the treatment. The oral adminis-tration of 5-FU (150 mg/m2 daily for 1 year) and mitomycin C i.v. (6 mg/nr* on the day of surgery) resulted in a high toxicity, including one case of death. Actually, there is no convincing proof for the successful use of 5-FU in a palliative situation of pancreatic cancer.
To reduce the subjective and objective side ef-fects of aggressive chemotherapy regimens on the one hand and to increase the effect of the loco-regional control of the disease on the other hand, regional applied adjuvant chemotherapies have been investigated in the recent years (Table 6.1). In two nonrandomized studies, long-term sur¬vival could be improved by application of che-motherapeutics via truncus coeliacus, a. hepatica or v. portae in contrast to untreated historical control groups. A survival time of 4 years was achieved in half of the treated patients after R0 resection [4, 5, 15]. However, these data are not sufficient for a definite judgment.
6.3 Current Adjuvant Therapy Studies
In 1994, before gemcitabine was established as the palliative therapy standard, the random-ization for the phase III study of the European Study Group for Pancreatic Cancer (ESPAC-1) for adjuvant therapy of resected pancreatic can-cer had started. Within 7 years, 541 patients in total were recruited into this study [23, 24]; 285 patients were randomized according to the origi-nally designated 2x2-factorial design. It divided the group into four study arms: observation (n = 69), radiochemotherapy alone (n = 70), chemotherapy alone (n = 74), and combined chemotherapy and radiochemotherapy (n = 72). The adjuvant chemotherapy consisted of 5-FU/ folinic acid according to the Mayo scheme (fo-linic acid 20 mg/m*+5-FU 425 mg/m* d1-5 ev¬ery 4 weeks x 6 cycles); radiochemotherapy was applied according to the European standard (5-FU 500 mg/m* d1-3 and d15-17+20 Gy in 10 daily fractions over 2 weeks).
In the first publication of the pooled analysis, no survival difference was shown between the compared 175 patients receiving postoperative chemoradiotherapy and the 178 patients who did not receive such therapy. The median OS was 15.5 months vs 16.1 months. In contrast, a significant survival benefit for the 238 patients who received an adjuvant chemotherapy com-pared to the 235 patients who did not receive it. The median OS was 19.7 months vs 14 months, p = 0.0005. This study has been criticized for its complex design and, hence, the difficulties in interpreting the results: Patients and clinicians were allowed to select which trial to enter and, according to their own preferences, to perform a "background" chemoradiation or chemotherapy independent from their treatment arm. In the pooled "intent-to-treat-analysis," nearly one-third of the patients in the "no chemotherapy" group and in the group for "chemotherapy alone" were treated with chemoradiotherapy [23, 24].
In a second publication after a median fol-low-up of 47 months the authors concluded that adjuvant radiation had a deleterious effect, possi¬bly because it delayed sequential chemotherapy, while chemotherapy with 5-FU had a significant beneficial effect. Indeed, given the marginal ac¬tivity of 5-FU in the palliative setting, the sur¬vival advantage obtained with adjuvant 5-FU in ESPAC-1 appears very surprising. A statistical comparison of the four original groups based on the 2 x 2 randomization was not possible due to lack of adequate power. For example, median survival among the 75 patients randomized to
5-FU chemotherapy was 21.6 months (95% CI, 14.2-22.5) compared with 16.9 months (95% CI, 12.3-24.8) for the 69 patients randomized to ob-servation. Thus, 95% confidence intervals were large and widely overlapping. Since disease-free survival as well as 3-year OS data were not re-ported, a comparison with the results of our study is not possible [25]. In the simple and straight¬forwardly designed German- Austrian CONKO-001 study, an open, multicenter, randomized, controlled phase III trial, from July 1998 to De¬cember 2004, a total of 368 patients with gross complete (R0 or R1) resection of pancreatic can¬cer and no prior radiation or chemotherapy were enrolled. Gemcitabine was chosen by the authors as the adjuvant treatment because it was, and still is, considered the most active single agent in the treatment of locally advanced or metastasized pancreatic cancer [8, 27, 34]. Patients were pro¬spectively randomized, with stratification for re¬section, tumor status, and nodal status, to receive either adjuvant chemotherapy with six cycles of gemcitabine 1,000 mg/m2 day 1, 8, and 15 every 4 weeks (arm A) or observation (arm B). This year the primary endpoint analysis of this trial demonstrated that in accordance with study hy-pothesis, 6 months of adjuvant treatment with gemcitabine improved median disease-free sur-vival (DFS) highly significantly in patients with completely resected pancreatic cancer by more than 6 months compared with observation alone (13.4 vs. 6.9 months, p < 0.001). With a median follow-up of 53 months, the disease-free sur¬vival analysis was based on a total number of 294 (83%) observed relapses among 354 eligible patients; only 14 patients (7 in each arm) out of a total of 368 enrolled had to be excluded from the intent-to-treat population due to major vio¬lations of the entry criteria. The beneficial effect of adjuvant gemcitabine on DFS was evident in both subgroups for patients with R0 (13.1 vs 7.3 months; p < 0.001) and R1 resection (15.8 vs 5.5 months; p < 0.001). The estimated DFS at 3 and 5 years was 23.5% and 16.5% in the treat¬ment arm, and 7.5% and 5.5% in the observation arm, respectively.
OS failed slightly to show a significant differ-ence in the intent-to-treat analysis at the time of publication (p = 0.061), with 27% of all patients still being alive. Median survival times were 22.1 vs 20.2 months in arm A and B, respectively. This relatively small difference in median sur¬vival may be explained by the fact that patients in the observation arm were regularly offered gemcitabine for palliation as soon as a relapse occurred. The divergence between the survival curves increased with longer follow-up, and estimated survival at 3 years was 34.0% in the treatment arm compared with 20.5% in the ob-servation arm. At 5 years, approximately twice as many patients in the adjuvant treatment arm compared with observation are estimated to be alive (22.5 vs 11.5%). On the other hand, the qualified survival analysis was prespecified and designed to provide results that more closely reflect the "true" therapeutic potential of adju-vant gemcitabine in this setting. Therefore, in this analysis, only patients from the active arm who received at least one full cycle (three weekly doses) of gemcitabine, and patients from the control arm who did not receive any cytotoxic agents or radiation therapy prior to relapse were included. Patients from both arms were excluded from the analysis if minor violations of the entry criteria were identified. As anticipated from this selection process, the advantage in DFS and OS conferred by adjuvant gemcitabine over observa-tion alone was greater in the qualified compared with the intent-to-treat (ITT) population and included a highly significant improvement in median OS (24.2 vs 20.5 months, p = 0.015) [26]. Postoperative gemcitabine significantly delayed the development of recurrent disease after com-plete resection of pancreatic cancer compared with observation alone, and the increase in long-term survival was encouraging. Based on these results, gemcitabine, despite minimal toxicity and no compromise in quality of life, offers high promise to become the new standard treatment in the adjuvant pancreatic cancer setting.
6.4 Multimodal Adjuvant Therapy
Regimes
In the phase II trials of the Gastrointestinal Tu-mor Study Group (GITSG) [12, 16], 51 patients were treated with weekly bolus 5-FU for 2 years after radiochemotherapy. The results of OS were superior to OS results of a nonpublicized fol-low-up study of the UK Pancreatic Cancer Trial Group. One reason could be the inclusion of R1 patients in the follow-up study. In both studies the side effects were moderate.
Preliminary study results from Johns Hopkins University demonstrated an advantage in DSF using treatment with a systemic chemotherapy comprising 5-FU, folinic acid, mitomycin C, and dipyridamole for 4 months after radiochemo-therapy compared to a nonrandomized control group with no adjuvant treatment [9]. The side effects were much more aggressive compared to the study design of the GITSG. In the American phase III study, RTOG 9704, from July 1998 to July 2002, 538 patients were included, 381 with cancer of the pancreatic head. After stratifica¬tion for resection, tumor size, and nodal status, patients were randomized either to receive pre-and post-chemoradiotherapy with 5-FU (contin¬ued infusion 250 mg/m2 per day) or gemcitabine (1 g/m2 weekly). In both arms the treatment was performed for 3 weeks before and then again for 3 weeks after 12 weeks of chemoradiotherapy with 50.4 Gy in daily fractions of 1.8 Gy and con¬tinued infusion of 5-FU (250 mg/m2 per day). The ASCO 2006 preliminary results showed—ex¬clusively for the subgroup of patients with pan¬creatic head cancer (n = 381) among the eligible patients (n = 442)—a significant improvement of the medial OS and the 3-year survival rate, with 36.9 months and 32% for the gemcitabine group vs 20.6 months and 21% for patients in the 5-FU-group (p = 0.047). On the other hand, a signifi¬cant difference in OS for the total study popula¬tion, including cancer of pancreatic corpus and tail, failed [31]. The Picozzi phase II trial inves¬tigated 43 patients with a multimodal therapy regime consisting of cisplatin (30 mg/m2), 5-FU (200 mg/m2), interferon alpha, and simultane¬ous radiation (45-54 Gy in 25 daily fractions) followed by 5-FU (200 mg/m*). After an average follow-up time of 31.9 months, 67% of patients were still alive and 1-/2-/ and 5-year survival rates of 95%, 64%, and 55% were demonstrated. However, this therapy regime was very toxic. Of the patients, 70% had to interrupt the therapy and 42% had to be hospitalized because of side effects such as nausea, vomiting, and diarrhea [29, 30] (Table 6.2). These encouraging results need to be validated in prospective multicenter
5-FU, 5-fluorouracil; 1-/2-/-3-/5-Y-S, 1-, 2-, 3-, or 5-year survival; ADR, doxorubicin; CDDP, cisplatin; ci, continued infusion; FA, folinic acid; fx, fraction; gemcitabine 2#, gemcitabine for two cycles (or for 2 months pre-RCT); IFN, interferon; IORT, intraoperative radiotherapy; MMC, mitomycin C; pre-op., before surgery; RCT, radiochemotherapy a Randomized study
studies. Furthermore, therapy regimes have to be modified to minimize the toxic effect for patients in the adjuvant situation. Experiences with new substances such as gemcitabine as the radiosen-sitive agent and as systemic treatment remain to be made [14, 18].
6.5 Adjuvant Immunotherapy
Systemic treatment with monoclonal antibod¬ies was not beneficial in the adjuvant situation. The disappointing results of four studies with antibody MAb 17-1A in the palliative therapy of pancreatic cancer led to abandonment for the present in the adjuvant situation. In a phase II study, the murine antibody MAb BW494 showed only limited activity in nonresectable pancreatic cancer cases [6]. The results of a small, random-ized study with 61 eligible patients treated with MAb BW494 after resection did not reach a sta-tisticall significance in median OS: 428 days for the treatment group and 386 days for the control group [7]. Lygidakis et al. investigated the effi¬cacy of a combined locoregional chemotherapy and immunotherapy. In matched groups, 80 patients were enrolled to receive either no spe¬cific therapy or a regional therapy administered via a. lienalis and a. mesenterica superior. This complex therapy regime consists of combined chemotherapy with 5-FU, folinic acid, cisplatin, mitomycin C, and immunotherapy with inter-leukin-2 and interferon-gamma for 3 years af¬ter resection. It was shown that the median OS was significant higher for the treatment group in contrast to the untreated patients (30 months vs 16.8 months, p < 0.001). A further investiga¬tive trial demonstrated a higher rate of complete remission of the disease with the same immu-notherapy combined with a modified chemo¬therapy consisting of carboplatin, docetaxel, and gemcitabine after a curative intended resection [21]. A subsequent randomized phase III study with 128 patients could underline the benefit of a locoregional chemotherapy combined with im-munotherapy. Patients were randomized in three groups: arm A (observation only), arm B (locore-gional chemotherapy via SMA with carboplatin, mitoxantrone, mitomycin C, 5-FU, folinic acid), and arm C (locoregional chemotherapy like arm B and additional immunotherapy with interleu-kin-2). The analysis demonstrated significant re¬sults in the survival rates after 2 and 5 years (29% and 0% in arm A, 52% and 0% in arm B, 65% and 18% in arm C) [20]. To gain confidence in the feasibility of this complex therapy, these promis¬ing results have to be supported in further mul-ticenter studies, including an examination of the intraoperative implantation of the catheter in the mesenterica superior.
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