Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer

Background In nonrandomized trials, neoadjuvant treatment was reported to prolong survival in patients with pancreatic cancer. As neoadjuvant chemoradiation is established for the treatment of rectal cancer we examined the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a randomized phase II trial. Radiological staging defining resectability was basic information prior to randomization in contrast to adjuvant therapy trials resting on pathological staging. Patients and methods Patients with resectable adenocarcinoma of the pancreatic head were randomized to primary surgery (Arm A) or neoadjuvant chemoradiotherapy followed by surgery (Arm B), which was followed by adjuvant chemotherapy in both arms. A total of 254 patients were required to detect a 4.33-month improvement in median overall survival (mOS). Results The trial was stopped after 73 patients; 66 patients were eligible for analysis. Twenty nine of 33 allocated patients received chemoradiotherapy. Radiotherapy was completed in all patients. Chemotherapy was changed in 3 patients due to toxicity. Tumor resection was performed in 23 vs. 19 patients (A vs. B). The R0 resection rate was 48 % (A) and 52 % (B, P = 0.81) and (y)pN0 was 30 % (A) vs. 39 % (B, P = 0.44), respectively. Postoperative complications were comparable in both groups. mOS was 14.4 vs. 17.4 months (A vs. B; intention-to-treat analysis; P = 0.96). After tumor resection, mOS was 18.9 vs. 25.0 months (A vs. B; P = 0.79). Conclusion This worldwide first randomized trial for neoadjuvant chemoradiotherapy in pancreatic cancer showed that neoadjuvant chemoradiation is safe with respect to toxicity, perioperative morbidity, and mortality. Nevertheless, the trial was terminated early due to slow recruiting and the results were not significant. ISRCTN78805636; NCT00335543. Electronic supplementary material The online version of this article (doi: 10.1007/s00066-014-0737-7) contains supplementary material, which is available to authorized users.


Background
Survival rates of patients with pancreatic cancer have improved only marginally during the last 30 years with a 5-year survival rate of only 6%. [1] In contrast the prognosis of patients with rectal carcinoma has improved substantially during the same timeframe. [2] This progress was caused by standardizing surgical therapy [3] worldwide and by the implementation of multimodal therapy. [4,5,6] Moreover in rectal cancer it was found early, that a clear circumferential margin is important and that even margins below 1mm cause a significant increase in the rate of local recurrence. [7] All these measures caused a decline in local recurrence from 50% to about 10% and an increase of 5-year survival rates up to more than 50% worldwide. This progress led to the hypothesis that in analogy the much worse prognosis of ductal adenocarcinoma of the pancreas might be improved. In pancreatic cancer only in recent years it became obvious, that up to 75% of macroscopically clear resection margins during more precisely work up became R1 resections with tumor extensions up to the circumferential margin [8], which classifies the result of the surgery as palliative. [9,10] These patients have no chance of cure but have surgery with the significant risk of postoperative complications of up to 40% and a postoperative letality of up to 5%. [11,12,13] Adjuvant therapy has been tested in a series of RCT (randomized controlled trial) phase III trials, the most important of these are the ESPAC-1 trial, the CONKO-001 trial, the RTOG 97-04 trial and the ESPAC-3 trial. [14,15,16,17] But these trials were still running or results were not yet available when the here described trial was planned and conducted. The results of these trials led to a change in standard treatment recommending adjuvant treatment with chemotherapy since 2007 in Germany. [18] The concept of neoadjuvant rather than adjuvant treatment in pancreatic cancer appears attractive for a number of reasons. Firstly, up to 30% of the tumors staged as resectable cannot be resected due to undetected metastatic disease or underestimated tumor contact to peripancreatic vessels detected not until explorative laparotomy. [19] Secondly, up to 30% of the patients cannot receive adjuvant therapy because of poor post-operative performance status. [20] Both groups of patients are not included into adjuvant trials, though improving overall survival in both arms (adjuvant therapy vs. no adjuvant therapy) by simple patient selection. Neoadjuvant treatment is thought to be better tolerated, than adjuvant treatment and avoids postsurgical morbidity in patients with rapidly metastasizing tumors. Non-randomized trials using the neoadjuvant approach support this rationale: Median OS beyond 30 months for patients after neoadjuvant treatment and tumor resection were described in a number of retrospective data analyses. [21,22,23,24] Therefore, in 1999 we started to plan this multi-center randomized phase II-study in patients with locally resectable cancer or probably locally resectable cancer of the pancreatic head with strict imaging eligibility criteria defining vascular involvement.
Meanwhile the technical term "borderline resectable cancer" evolved for "probably resectable cancer". High-quality chemoradiation aimed to maximize tolerance and efficacy of neoadjuvant treatment, both of which have been problematic in previous trials of chemoradiation in pancreatic cancer. To our knowledge, this is the first RCT for patients with primary and borderline resectable cancer of the pancreatic head comparing primary surgery with neoadjuvant treatment followed by surgery, starting with randomization in 2003. Here, we report the full results of this trial, which was not picked up by the majority of the research community at the time of the conduction of the trial. In consequence, the trial could not be completed and therefore shows a lack of statistical significance due to poor accrual rate. On the other hand the reporting of negative trials (i.e. a trial with no clear interpretable results) is important for the improvement of the conduction of new trials.

Study design and inclusion criteria
Patients with resectable, histology or cytology proven adenocarcinoma of the pancreatic head were randomized between surgery alone (Arm-A) and neoadjuvant chemoradiation followed by surgery (Arm-B) ( Fig. 1). [25] Randomization was carried out centrally by fax by an independent contract research organization with stratification according to the clinical center and according to whether or not a laparoscopy has been performed (amendment 2004). Randomization was performed in blocks with randomly selected sizes of blocks of 4 and 6 patients. Resectability was defined as no organ infiltration except the duodenum and maximal involvement of peripancreatic vessels ≤180° (portal vein, confluent, superior mesenteric artery (SMA), celiac trunk with its major branches splenic artery and hepatic artery, superior mesenteric vein (SMV)) confirmed by high resolution CT analogue to Lu et al. [26] Surgical staging by laparoscopy or laparotomy to exclude distant metastases prior to randomization was at the discretion of the local investigator after an amendment in 2004. Other recommended tests before inclusion into the study were physical examination, hematology, biochemistry, CA19-9 and chest X-ray. All inclusion criteria are completely enlisted in  Tab. S1.
The protocol was reviewed and funded by Deutsche Krebshilfe, approved "Gütesiegel A" by Deutsche Krebsgesellschaft and approved by the ethics committees of the participating institutions. All patients provided written informed consent.

Treatment Chemoradiation
Chemoradiation and surgery were described in detail in the trial protocol. Briefly patients in Arm-B received 300 mg/m2 gemcitabine and 30 mg/m2 cisplatin on days 1, 8, 22 and 29 of radiotherapy. The combination of gemcitabine and cisplatin was chosen, due to good experience with this regimen combined with radiotherapy at the time of study planning in 2000 and beyond. [27,28] The sideeffects of both substances do only slightly overlap. 3D-treatment planning was mandatory for radiotherapy at 1.8 Gy to 55.8 Gy (tumor) or 50.4 Gy (regional lymph nodes, PTV ≤800 mL). [29] Supportive therapy consisted of dietary advice, anemia compensation <11 g/dL hemoglobin during chemoradiation, adequate analgesia and anti-emetics as well as implantation of a bile duct stent if bilirubin exceeded 1,5 mg/dl. Dosis modifications in case of toxicity of chemotherapy (hematologic, renal, neurologic, other) were specified in the trial protocol separetaly for gemcitabin and cisplatin. Criteria for patient withdrawal (for example: febrile neutropenia with sepsis, Karnofsky-Index < 50%, interruption of radiotherapy for > 10d) were specified in the trial protocol, too. Six weeks after chemoradiation, a restaging CT-scan was scheduled.

Surgery
The surgical procedure was described in detail in the protocol, divided into the three steps of exploration, tumor resection and lymph node dissection. At exploration distant metastases had to be ruled out, fresh frozen biopsies were taken as appropriate. Local resectability was assessed by dissection of SMV, portal vein and common hepatic artery, occasionally preliminary dissection of SMA. In case of vascular tumor infiltration the decision to resect the tumor with adjacent vessels was completely left to the surgeon and the individual situation. The minimal requirements for tumor resection were: Partial duodenopancreatectomy (± pyloruspreserving), transection of the pancreas minimally at the level of the left edge of the portal vein and transection of the common hepatic duct slightly distally to the junction of the right and left hepatic duct. The extent of lymph node dissection was, in short, at least: complete dissection of hepaticoduodenal ligament, common hepatic artery, circular dissection of the celiac trunk and right and dorsal of the SMA from its origin until the derivation of the first jejunal artery to the left. Preservation of the nervous plexus at the trunk of the SMA was mandatory. At least three lymph nodes had to be excised from interaortocaval lymph nodes (between the left renal vein and the inferior mesenteric artery) for staging purposes. All three resection planes of the specimen were recommended to be analyzed histologically at intraoperative fresh frozen section. It was mandatory to perform histological analysis of the postoperatively paraffin embedded tissue to exclude positive margins (R1-resection).

Adjuvant chemotherapy
In both arms, adjuvant chemotherapy according to the CONKO-001 study protocol was recommended in an amendment from 2005. [15] Assessment and follow-up Resection specimens were graded and classified according to the fifth and sixth UICC TNM system (1997 and 2002) with documentation of resection margins, tumor size, number of examined and involved lymph nodes, and presence of lymphatic, venous or perineural invasion. [30,31] Tumor regression was classified for tumors and lymph nodes in Arm-B. [32] Assessment of response to neoadjuvant therapy was based on contrast enhanced re-staging CTscans six weeks after completion of chemoradiation. RECIST criteria were used to classify response. [33] Involvement of peripancreatic vessels was also reassessed. Acute toxicity and adverse effects were reported using the National Cancer Institute Common Toxicity Criteria v2.0 and RTOG / EORTC  recommendations for classifying late toxic effects of radiotherapy. [34,35] Perioperative complications and corresponding interventions were documented and graded by Dindo`s classification. [36] Patients were followed up for at least 36 months at 3-month-intervals until 2 years and 6-month-intervals thereafter. Follow-up consisted of physical examination, hematology, biochemistry and CA19-9 as well as abdominal CT-scan and chest X-ray every 6 months.

Procedures before Randomization
End points, sample size and statistical analysis

Patients
Between June 2003 and December 2009, 73 patients were recruited in 8 university hospitals and tertiary referral centers in Germany and Switzerland. In December 2009, enrollment was terminated because of the poor recruitment rate. Seven patients (4 Arm-A; 3 Arm-B) were deemed ineligible because of withdrawal of consent, lack of data and other tumor entity (two patients). Both patients were intra-/ postoperatively diagnosed in spite of the histological proven diagnosis of adenocarcinoma of the pancreatic head before inclusion into the trial ( Fig. 1). Two patients had metastases at randomization (n=1 distant lymph nodes, n=1 liver), both in Arm-B. These patients were not excluded, as it reflects real life, where reviewing of initial data at the time of documentation in the case report form sometimes changes first impressions. Due to this low number of patients, the power for the formal statistical analysis was limited. All eligible patients were evaluable for survival. Patient characteristics are listed in  Tab. 1.

Treatment
In Arm-B, median start of treatment was 13 days after randomization (range 0-31days). 29/33 patients received chemoradiotherapy. Three patients refused and one was not fit for chemoradiation, but all four underwent surgery. All 29 patients who underwent chemoradiation completed radiotherapy and were treated with a median of 55.8 Gy (range 45.0-57.6). Chemoradiation took 36 -49 days (median 44 days). Three patients had changes in chemotherapy on day 29 due to leukopenia. One patient received 5fluorouracil/ cisplatin instead of gemcitabine/ cisplatin (local investigator judgement). All other patients received chemotherapy as planned, resulting in a dose intensity of 99% for cisplatin and 95% for gemcitabin.
Toxicity of chemoradiation (Arm-B) is shown in  Tab. 2. During chemoradiotherapy and until surgery 15 severe adverse events were reported, mostly cholangitis requiring a change of stent (n=9). Radiological response on re-staging CT-scan was rarely seen (n=4 partial response), whereas most patients had no change (n=8) or progression (n=12; missing data n=5). In Arm-A patients had surgery 4 days (median) after randomization (range 0-19 days). In the intention-to-treat analysis, in Arm-A, 23/33 had tumor resection and five patients had vascular resections to achieve clinical R0-resection. Ten of 33 patients had an explorative laparotomy. In Arm-B [36] One patient died as the result of an intraoperative myocardial infarction after tumor resection (Arm-A) and one patient died due to sepsis possibly due to cholangitis after explorative laparotomy (Arm-A). One patient had insufficiency of the pancreatico-jejunal anastomosis followed by multi-organ dysfunction (grade 4b; Arm-A, none in Arm-B

Discussion
The planning of this trial was started in 1999 with activation in 2003 before neoadjuvant treatment had become standard for other diseases, e.g. rectal carcinoma, and therefore had to overcome resistance by physicians and patients likewise against the idea of neoadjuvant treatment as such. Additionally, competing adjuvant trials (CONKO-001 [15], ESPAC-3 [17]) reduced participation. Another issue was histological or cytological proof of disease before randomization. To overcome this obstacle to recruitment, the protocol allowed randomization after histological proof during explorative laparotomy. Nevertheless, recruitment speed was significantly hampered by these factors. However, to our knowledge this remains the first planned and evaluated multicenter RCT comparing immediate surgery with surgery after neoadjuvant therapy in resectable pancreatic cancer, defined as vascular abutment of less than 180°. But due to low patient numbers this is a negative trial and no clear conclusion can be drawn from underpowered data and whether there is an advantage for one therapy strategy or not. The following issues of a randomized controlled trial for resectable pancreatic cancer have to be addressed in future trial protocols: working in interdisciplinary teams, predicting resectabilitiy, surgical staging prior to preoperative therapy, definition of vascular resection aims, definition of criteria for cancelling tumor resection during explorative laparotomy and adjuvant chemotherapy. With the nationwide launching of interdisciplinary tumor boards during the last 5 years patients can be screened during theese sessions and it does not longer depend on which specialist the patient contacts first during the course of finding the diagnosis of pancreatic cancer. One of the main problems remains how to predict resectable tumor stage at diagnosis as 20% of tumors without contact to the peripancreatic vessels at diagnosis were not resected with and without neoadjuvant chemoradiation (data not shown). Clearly, the new definition of borderline resectable pancreatic cancer is helpful, but has to be evaluated in future trials. One more point of discussion is vascular resection. Because it was left up to the surgeon to perform a vascular resection to achieve R0-resection this might cause a bias, which is difficult to figure out. A further point of discussion is the different judgement between centers with reference to cancelling surgery, as only one center did abandon resection of the tumor after detection of distant lymph node metastasis (2 pts.) or did not proceed to surgery when progression (locally, distant, clinically) at restaging after chemoradiation was seen ( Fig. 1 and duodenal cancer, respectively. Both patients were better not included into the study if they had properly diagnosed with tumor of the papilla of vateri. Not all centers had excellent interventional radiologists experienced in core needle biopsy of the head of the pancreas. Therefore two centers randomized patients during explorative laparotomy after establishing histological diagnosis on fresh frozen biopsies. The initially mandatory laparoscopy was reclassified as optional due to objections of potential trial participants in an amendment in 2004. Because discrete peritoneal carcinomatosis or subserous small liver metastases can escape detection by CT-scan and will only be detected by staging laparoscopy or -tomy, patient randomization was stratified for laparoscopy, but unfortunately not surgical staging therefore not including explorative laparotomy. Altogether, surgical staging was conducted only in 54% of all patients and mOS for patients in Arm-B with prior surgical staging outmatched mOS for patients without surgical staging (data not shown), confirming an observation already made by others, too. [21] Therefore prior surgical staging should be considered further trials on preoperative treatment strategies. Actual survival was significantly higher in both arms compared to the historic controls used for statistical planning of this trial. The closest possible comparison of this trial is with adjuvant treatment, especially with the CONKO-001 trial conducted in the same population and with an observation arm. [15,37] However, the fundamental difference between the here reported trial and adjuvant treatment is, that the latter only includes patients after resection and pathological staging, whereas in this study 24 Additionally, less severe complications were seen after chemoradiation therapy, probably due to induction of fibrosis, which improves the suitability of pancreatic tissue for anastomosis. A recent metaanalysis also found similar perioperative morbidity with and without neoadjuvant treatment. [24] Toxicity of chemoradiotherapy was well manageable in this trial, because no patient receiving chemoradiation had an interruption of radiotherapy and only 3/30 patients had delay, reduction or omission of the last dose of chemotherapy. Due to education of the participating doctors and patients, the well. The well known risk of biliary stent dysfunction was managed by prompt stent replacement, but was the most frequent reason for severe adverse events. On the other hand there is a great debate on the minimum case load for pancreatic cancer surgery, because of the high morbidity and mortality of the procedure if it is not done by experienced surgeons. Surely the same issue applies to the chemoradiation therapy, which shouldn`t be conducted by health care institutions not accustomed to this difficult organ and without the prompt support from other medical disciplines as endoscopy or hematology.
Gemcitabine-based chemoradiation [14,38] is increasingly accepted as an alternative standard to fluoropyrimidine-based chemoradiation [39] and was recently shown to be superior to chemotherapy only in locally advanced pancreatic cancer. [40] Hematologic toxicity of gemcitabinebased CRT is directly related to radiotherapy volume and therefore volumes were strictly limited. [38,41,42] Additionally, consequent supportive therapy may explain the improved tolerability of treatment in this trial compared to others avoiding loss of weight which was described to be a negative prognostic factor after neoadjuvant chemoradiotherapy. [43] The patients in this trial were treated Strahlentherapie und Onkologie, Suppl. data 9 gemcitabine/ cisplatin and surgery versus immediate surgery in resectable pancreatic cancer. Results of the first prospective randomized phase II trial. (ISRCTN78805636).
with 3D-conformal plans which have recently been shown to be equally effective and not significantly more toxic as IMRT plans in the neoadjuvant setting. [44] Furthermore, predicting resectability based on CT-scans was difficult and proceeding to resection hereby defining the golden goal of R0resection remains controversely. Thus, the CONKO-007 (NCT01827553) trial will study the role of chemoradiation in borderline resectable and nonresectable pancreatic cancer. A panel of highly experienced surgeons will review all CT-scans before registering to the trial and at restaging and give their statement about resectability. With the experience of such a trial the criteria of R0 resectability will be evaluated and adjusted and after knowing the significance of chemoradiation for locally advanced and borderline resectable pancreatic cancer the next step might be a phase II trial testing the R0 resectability with neoadjuvant therapy. Furthermore molecular markers to predict locally predominant growth are emerging, and we should aim to personalize management decisions with regard to neoadjuvant treatment intensification on the basis of these biological characteristics. [45,46] In conclusion, we here present the results of an RCT implicating the strategy of multimodal therapy for (borderline) resectable pancreatic cancer which was visionary at the time of planning and conduction of the trial; it has been nearly 15 years ahead of time before this approach was again implemented into prospective trials in Europe. In the meantime the conditions for conduction of interdisciplinary trials have improved much due to governmental regulations and nationwide implementation of certified cancer centers with interdisciplinary tumor boards and the requestion of qualified study nurses supporting the medical study team in the long term. The improvement of interdisciplinary study structures and the lack of better therapies evolving in the meantime led to boycotting this trial to copying the treatment strategy of neoadjuvant chemoradiation with starting a nearly identical study protocol in August 2013 (NCT01900327).
Prediction of resectability preoperatively is still an unresolved problem and the longterm results of treatment for pancreatic cancer are still frustrating even after complete resection of the tumor, therefore at the moment we don`t have a better choice but investigating new treatment strategies suitable for as many patients with pancreatic cancer as possible.