Abstract
Background
Neoadjuvant chemoradiation therapy for locally unresectable and borderline resectable pancreatic cancer may allow some patients to a undergo a resection, but whether or not this increases post-operative morbidity remains unclear.
Methods
The post-operative morbidity of 29 patients with initially locally unresectable/borderline pancreatic cancer who underwent a resection were compared with 29 patients with initially resectable tumours matched for age, gender, the presence of comorbidities (yes/no), American Society of Anesthesiology (ASA) score, tumour location (head/body-tail), procedure (pancreaticoduodenectomy/distal pancreatectomy) and vascular resection (yes /no). Wilcoxon's signed ranks test was used for continuous variables and McNemar's chi-square test for categorical variables.
Results
Compared with patients with initially resectable tumours, patients who underwent a resection after pre-operative chemoradiation therapy had similar rates of overall post-operative complications (55% versus 41%, P = 0.42), major complications (21% versus 21%, P = 1), pancreatic leaks and fistulae (7% versus 10%, P = 1) and mortality (0% versus 1.7%, P = 1).
Conclusion
Although some previous studies have suggested differences in post-operative morbidity after chemoradiation, our case-matched analysis did not find statistical differences in surgical morbidity and mortality associated with pre-operative chemoradiation therapy.
Introduction
Pancreatic adenocarcinoma is the fourth leading cause of cancer death in North America and accounts for over 30 000 deaths annually.1 The incidence and mortality rates are similar and a major reason for the high fatality rate is that pancreatic carcinoma often presents at a late stage.2 The greatest chance for long-term survival is when a complete resection can be performed; however, this is only possible in about 20% of patients at presentation.3 Neoadjuvant treatment has been investigated both in the setting of resectable disease at diagnosis and in an attempt to downstage locally unresectable (stage III) disease for resection.4–8
For locally unresectable or borderline resectable tumours, partial or complete responses after radiochemotherapy have been observed with up to 32% of patients coming to resection.4,9,10 As previously described by this group, the median overall survival (OS) of patients who initially presented with locally unresectable pancreatic cancer and experienced enough of a response to undergo a resection was 25 months from resection and 30 months since treatment initiation. There was no difference in OS from the time of resection between the initial stage III patients who became resectable and those who presented with resectable disease.11 The morbidity and mortality after chemoradiation therapy for initially locally unresectable pancreatic adenocarcinoma has not been thoroughly investigated, and could counterbalance the potential benefit of an R0 resection.
The objective of the present study was to compare post-operative morbidity in a case-matched analysis between patients with initially unresectable or borderline resectable pancreatic cancer who were resected after pre-operative chemoradiation therapy, and patients with resectable pancreatic cancer who underwent a resection without previous treatment.
Material and methods
Subjects and data collection
This study was approved by the institutional review board. Demographic, radiographical and pathological data were obtained from prospective databases with an additional retrospective medical record review performed when necessary. All patients underwent pre-operative radiation and a resection at the Memorial Sloan-Kettering Cancer Center. Included in the pre-operative chemoradiation group were patients who initially presented with either locally unresectable or borderline resectable tumours who experienced a sufficient response with multimodality therapy to allow a complete resection. A chart review was performed to define the reason for initial unresectability and the method by which that decision was made. Lesions were considered unresectable when the vascular invasion precluded the R0 resection.12 Tumours were defined as locally advanced based on intra-operative assessment or on cross-sectional imaging determining extensive vascular involvement precluding a resection. Pre-operatively, routine high-quality abdominal and pelvic computed tomography (CT) scans were performed. Border-line lesions were defined as those whose tumours exhibit encasement of a short segment of the hepatic artery, without evidence of tumour extension to the celiac axis, that is amenable to resection and reconstruction; tumour abutment of the superior mesenteric artery involving ≤180° of the circumference of the artery; or short-segment occlusion of the superior mesenteric vein, portal vein, or their confluence with a suitable option available for vascular reconstruction because the veins are normal above and below the area of tumour involvement.12 All patients were reviewed at a weekly hepatobiliary disease management conference attended by surgeons, oncologists, radiologists and gastroenterologists prior to resection.
Demographic characteristic as well as variables that might influence morbidity and mortality were recorded. Weight loss was defined to compare the weight at the time of diagnosis with the patients' pre-illness weight. Operative and peri-operative variables recorded included: type of resection, operative approach, the need for vascular resection, type of reconstruction, tumour size, estimated blood loss and total operative time. Post-operative complications (90 days) were prospectively recorded in a departmental database as previously reported.13 Complication data were then reviewed by surgical attendings and house staff at monthly service meetings and audited after patient discharge by a clinical nurse specialist. In addition, the social security database was checked quarterly to confirm mortality status. High-grade complications were defined as any complication recorded as grade 3–5. Pancreatic complications included pancreatic anastomotic leak (i.e. clinical signs and symptoms or radiological confirmation of a pancreatic anastomotic leak with amylase-rich drainage >50 ml/day beyond postoperative day 5, without development of a fistula), pancreatic fistula (i.e. clinical signs and symptoms with amylase-rich drainage >50 ml/day beyond post-operative day 10) or an intra-abdominal abscess (i.e. clinical signs and symptoms or radiological diagnosis of an intra-abdominal abscess or peritonitis).14 Post-operative pancreatic fistulae were classified according to the International Study Group on Pancreatic Fistula classification (IGSPF).15
Matching-process
A case-matched study design was used in an attempt to eliminate the confounding effects of clinically established factors.16 Comparisons were performed between 29 patients who underwent a pancreatectomy after pre-operative chemoradiation therapy and a matched group of 29 patients who underwent a resection without any neoadjuvant treatment during the same time period (2000–2010). Patients were matched 1:1 by age, gender, the presence of comorbidities (yes/no), American Society of Anesthesiology (ASA) score, tumour location (head/body-tail), procedure (pancreaticoduodenectomy/distal pancreatectomy) and vascular resection (yes/no). The selection process was random, and the investigator was blinded to the other clinical, radiographical and outcome data.
Statistical analysis
Values were expressed as median (interquartile), or percentage, as appropriate. Differences between the matched groups were evaluated using Wilcoxon's signed ranks test for continuous variables and the McNemar's chi-square test for paired proportions for categorical variables. For all tests, statistical significance was defined by P < 0.05. Data were analysed with the STATA 8 statistical software (StataCorp, College Station, TX, USA), and matching was done using the Match and Balance Match functions from the Matching library in R (http://www.r-project.org).
Results
Between September 2001 and July 2011, 29 patients underwent a pancreatic resection after pre-operative chemoradiation therapy for initially locally unresectable/borderline resectable pancreatic cancer. These were matched with 29 patients with resectable tumours. Patients and lesion characteristics are summarized in Table 1. Between the two groups, there were 30 females (52%) and 28 males (48%) (P = 1). Characteristics of the groups were similar with respect to the median age at operation [66 years, p25 (60) – p75 (72), P = 0.774], tumour location (head – 90% versus body and tail – 10%), procedure (93% pancreaticoduodenectomy versus 7% distal pancreatectomy) and the need for vascular resection (14%, P = 1). An ASA physical status score higher than 2 (46%), median body mass index (BMI) (25 kg/m2), median carbohydrate antigen 19-9 (170 mg/dl), use of staging laparoscopy (57%), median total operative time (291 min), median estimated blood loss (600 ml) and administered blood transfusions (29%) were also statistically similar.
Table 1.
Clinicopathological and operative parameters
| Characteristics | Total N = 58 (%) | Chemoradiation N = 29 (%) | Surgery N = 29 (%) | P-value |
|---|---|---|---|---|
| Age (years)a | 66 (60–72) | 64 (61–72) | 67 (60–70) | 0.77 |
| Gender (Male) | 28 (48) | 14 (48) | 14 (48.) | 1 |
| Body mass indexa | 25 (23–28) | 25 (22–28) | 26 (23–28) | 0.58 |
| ASA (higher than 2) | 27 (47) | 14 (48) | 13 (45) | 1 |
| Weight loss (%) | 5 (0–10) | 0 (0–8) | 6 (0–10) | 0.003 |
| CA 19-9 at diagnosis (ng/dl)a | 170 (49–679) | 249 (80–1217) | 87 (25–464) | 0.33 |
| Tumour site | 1 | |||
| Head | 52 (90) | 26 (90) | 26 (90) | |
| Tail | 6 (10) | 6 (10) | 6 (10) | |
| Previous cardiovascular disease | 12 (21) | 6 (21) | 6 (21) | 1 |
| Diabetes | 6 (10) | 3 (10) | 3 (10) | 1 |
| Pulmonary disease | 2 (3.5) | 1 (3.5) | 1 (3.5) | 1 |
| Alb (mg/dl)a | 4.1 (3.9–4.2) | 4.1 (3.8–4.2) | 4.1 (4–4.2) | 0.49 |
| Haemoglobin (mg/dl)a | 12.4 (11.3–13.6) | 11.7 (10.8–13) | 13.4 (11.8–14.3) | 0.03 |
| Previous surgery | 15 (26) | 14 (48) | 1 (3.5) | <0.001 |
| Procedure | 1 | |||
| Distal pancreatectomy | 4 (7) | 2 (7) | 2 (7) | |
| Pancreaticoduodenectomy | 54 (93) | 27 (93) | 27 (93) | |
| Vascular resection | 8 (14) | 4 (14) | 4 (14) | 1 |
| Operative time (min)a | 291 (255–335) | 271 (251–360) | 297 (260–330) | 0.88 |
| Estimated blood loss (ml)a | 600 (350–1000) | 600 (300–1000) | 600 (355–1000) | 0.24 |
| Transfusion | 17 (29) | 9 (31) | 8 (28) | 1 |
| Any positive margin | 8 (14) | 1 (3.5) | 7 (24) | 0.07 |
| Tumour size (cm)a | 3 (2.1–3.9) | 2.5 (1.5–3) | 3.2 (2.8–4.2) | 0.011 |
| T Stage | 0.016 | |||
| (0, 1, 2) | 7 (12) | 7 (24) | 0 | |
| 3 | 51 (88) | 22 (76) | 29 (100) | |
| N Stage | <0.001 | |||
| N0 | 31 (53) | 27 (93) | 4 (14) | |
| N1 | 27 (47) | 2 (7) | 25 (86) | |
| Any complications | 28 (48) | 12 (41) | 16 (55) | 0.42 |
| Any grade 3–5 complications | 12 (21) | 6 (21) | 6 (21) | 1 |
| Presence of leaks and fistulae | 5 (9) | 2 (7) | 3 (10) | 1 |
| 90-day mortality | 1 (1.7) | 0 | 1 (3.5) | 1 |
Median (interquartile). Univariate analyses: McNemar's chi-square and Wilcoxon's sign-rank tests comparing homogenicity between the case and control groups.
Characteristic of patients operated after pre-operative chemoradiation therapy for initially locally unresectable pancreatic cancer
The characteristics of the pre-operative chemoradiation group are shown in Table 2. Vascular encasement (>180°) was present in 17 patients and the superior mesenteric vein was the most prevalent vessel involved in this subgroup (56%). Twenty-three patients (80%) underwent induction chemotherapy based on gemcitabine. All patients in this group underwent radiation therapy with concomitant chemotherapy [5-fluorouracil (5-FU) 28%, gemcitabine 65% and non-specified 7%]. The patients were treated with conformal radiation therapy (59%) or intensity-modulated radiation therapy (IMRT, 41%). The mean total dose was 52 ± 3 Gy. The median duration of treatment was 38 days (ranging 35–58). The median treatment effect within the pathological specimens was 80% [p25 (50) – p75 (95)].
Table 2.
Pretreatment clinicoradiological characteristics (29 patients)
| Characteristics | Number of events (%) | |
|---|---|---|
| Vessel encasement | Vessel encasement >180° in 17 patients (58.6%) | |
| Superior mesenteric vein | 17 (36) | 10 (56) |
| Superior mesenteric artery | 13 (28) | 7 (39) |
| Portal vein | 6 (13) | — |
| Others | 11 (22) | 1 (6) |
| Total number of events | 47 | 18 |
| Neoadjuvant chemotherapy | ||
| Induction (gemcitabine) | 23 (80) | |
| Concomitant | ||
| 5-FU | 8 (28) | |
| Gemcitabine | 19 (65) | |
| 5 FU + Gemcitabine | 2 (7) | |
| Neoadjuvant radiation therapy | ||
| Modality | ||
| Three-dimensional | 17 (59) | |
| IMRT α | 12 (42) | |
| Total dose (Gy) | ||
| 45–50.4 | 16 (55) | |
| 54–60 | 11 (38) | |
| Non- specified | 2 (7) | |
| Total duration (days)b | 38 (37–41) | |
| Time from diagnosis to resection (months)a | 8 (6–9.3) | |
| Time from the end of radiation to resection (months)a | 2.7 (1.9–4.1) | |
| Pathological treatment effect (%)a | 80 (50–95) | |
Median (interquartile).
IMRT, intensity-modulated radiation therapy.
Neoadjuvant treatment plan
Chemotherapy
Among the 29 patients treated with radiation therapy, 23 patients (80%) underwent gemcitabine-based induction chemotherapy prior to radiation therapy. Seven patients (30%) received monotherapy with gemcitabine. The remaining 16 patients received gemcitabine-based two-drug therapy (gemcitabine combined with oxaliplatin, n = 5; cisplatin, n = 4; capecitabine, n = 3; erlotinib, n = 2) or three-drug therapy (gemcitabine combined with docetaxel and capecitabine, n = 2). The patients received a median duration of 2 months of induction chemotherapy prior to chemoradiation (range, 0.2–4.2). The response to induction chemotherapy was evaluable on a computed tomography scan before the start of chemoradiation in 15 patients. Seven patients had a partial response and 8 patients had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1 criteria.17
All 29 patients received chemotherapy concurrently with radiotherapy. Nineteen patients (65%) received concurrent gemcitabine twice weekly (40 mg/m2 twice per week), with the other eight (28%) receiving infusional 5-FU (200–225 mg/m2 daily throughout radiation treatments) or capecitabine (1300 mg/m2 divided into twice-daily doses given from Monday to Friday with radiation treatment) and two patients (7%) received both drugs.
Radiotherapy
All 29 patients received radiotherapy before surgery. The radiated volume included a radiographically apparent gross tumour and suspicious/enlarged lymph nodes on CT simulation. The clinical target volume included the draining lymph node basins including celiac, superior mesenteric and retroperitoneal nodes. A planning target volume (PTV) was generated to account for a daily setup error and an internal tumuor motion related to respiration. A median dose of 50.4 Gy in 28 daily fractions was delivered to the PTV (range, 45–60 Gy). Twelve patients were treated with IMRT. The median time from diagnosis to surgical treatment was 8 months and the median time from the end of radiation treatment to surgery was 2.7 months.
Adverse events and toxicity
During chemoradiotherapy, treatment-related grade 3 or 4 adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) occurred in two patients (7%) with one case of grade 3 nausea and one case of grade 3 gastritis.
Matched-cohort analysis of post-operative morbidity after a pancreatectomy with or without neoadjuvant treatment
Both groups were comparable regarding age, gender, comorbidities (renal failure, neurological disorders, bleeding disorder, hypothyroidism, liver disease, depended functional healthy status and previous sepsis, cardiac congestive failure, diabetes mellitus, pulmonary disease), tumour location and procedure, the need for vascular resection, ASA group and BMI, as shown in Table 1. The variables of previous surgery, pathological parameters such as tumour size, the presence of positive margins and nodal stage, were different between the groups; however, these factors have not been clearly shown to be associated with post-operative complications. Post-operative complications are also presented in Table 1. Post-operative complications occurred in 48% of patients [41 (chemoradiation group) versus 55 (surgery group), P = 0.42]. The presence of complications grade 3–5 was 21% in both groups, (P = 1). Specifically, the presence of a pancreatic leak and fistula was 9% [7 (chemoradiation group) versus 10 (surgery group), P = 1], and mortality at 90-day was 1.7% [0 (chemoradiation group) versus 3.5 (surgery group), P = 1].
The distribution of complications by organ system is presented in Table 3. In general, the most prevalent complications by body system recorded were in the wound or skin category with 34% experiencing a wound complication. In the control group, the most prevalent category was also wound or skin with 48% and in the chemoradiation group were the gastrointestinal system category with 36%. When only grade 3–5 complications were evaluated, the gastrointestinal system was the most common with 35% of complications grade 3–5 (33% in the chemoradiation group versus 29% in the surgery group). Table 3b summarizes the complications related to pancreatic leaks and fistulae classified by the International Study Group on Pancreatic Fistula criteria. Five leaks were recorded; two grade B [1 (chemoradiation group) versus 1 (surgery group)] and three grade C [1 (chemoradiation group) versus 2 (surgery group)]. The median length of stay was 7 days (range 5–26). Post-operative mortality occurred in a single patient who died secondary to cardiovascular events in the control group.
Table 3a.
Morbidity and 90-day mortality in the 58 patients with complications recorded by body systems
| System | Total complications (%) | Complication crades 3–5 (%) | ||
|---|---|---|---|---|
| Chemoradiation | Surgery | Chemoradiation | Surgery | |
| Gastrointestinal | 8 (36) | 3 (14) | 3 (33) | 2 (29) |
| Wound or skin | 4 (18) | 10 (48) | — | 1 (14) |
| Infection | 3 (14) | 4 (19) | 2 (22) | 2 (29) |
| Cardiovascular | 3 (14) | 1 (5) | 2 (22) | 1 (14) |
| Haematological/vascular | 2 (9.) | 1 (5) | 2 (22) | — |
| Others | 2 (9) | 2 (10) | — | 1 (14) |
| Number of events | 22 | 21 | 9 | 7 |
Table 3b.
Leak and fistula rates
| ISGPF classification | Total complications (%) | Chemoradiation | Surgery |
|---|---|---|---|
| A | 0 | 0 | 0 |
| B | 2 (40) | 1 (50) | 1 (33) |
| C | 3 (60) | 1 (50) | 2 (67) |
Discussion
Although by definition neoadjuvant therapy is intended to be delivered to patients with resectable disease, patients with unresectable disease have been included in several series of ‘neoadjuvant therapy’ in pancreatic cancer.10,18,19 The primary goal in delivering radiation to patients with locally unresectable tumours is to change patients from an unresectable to resectable state, with the hope that their prognosis will improve. Guillen et al. in a recent meta-analysis of neoadjuvant therapy in patients with locally unresectable pancreatic cancer, found that patients with locally advanced disease who underwent a resection after neoadjuvant treatment have the same median survival as patients with initially resectable disease; 20.5 and 20.1–23.6 months, respectively.18
In this study, intra-operative and clinicopathological data analyses suggest that complications are statistically similar between patients who were initially resectable and those who receive chemoradiation for locally unresectable or borderline disease. These data suggest that neoadjuvant chemoradiation therapy, in selected patients, should be considered as a therapeutic tool that does not increase post-operative complications rates. Gemcitabine has been utilized as a radiation sensitizer. Animal studies from the University of Michigan and MD Anderson Cancer Center have suggested that maximum radiation sensitization with gemcitabine is achieved with a lower dose administered twice weekly. This has been evaluated in several phase I and II trials and has been utilized by this group.4,20–26 The strength of these data lie within the matching process which was based on pre-operative variables previously found to be associated with post-operative morbidity and mortality.27–29 Variables such as weight loss, haemoglobin, previous surgery, the largest diameter of the tumour, and pathological T and N stages are critical in the matching process as they may reflect the more advanced nature of locally unresectable or borderline disease. Reported rates of venous resection and reconstruction vary in the literature from 12% to 65%, based on a recent meta-analysis published this year.30 The present data were not particularly surprising as most of these resected patients have been heavily pre-treated with both chemotherapy and chemoradiation. Other pathological findings that suggest a local effect of therapy is as a result of the fact that the vast majority of the patients were node negative. Furthermore, they did not change the extent of resection as procedures and the need for a vascular resection fitted well in the matching process. Differences in pathological data (T and N stage) were significantly different between the groups, and were considered as effects of pre-operative treatment.
The limitations of the study are those of a retrospective study, with a small sample size consequent to the matching process and this fact is a significant limitation of this study. The present database only identifies patients who are taken to the operating room for either exploration or resection. Therefore only patients who presented with downstaging and were able to undergo a resection (29/865 patients) could be accurately identified. It can be reasoned that downstaging is a rare event in our experience (5%), but the progression of disease rate could not be estimated.
It is agreed that the patients in this study represent a highly selected group. The fact that more patients in the pre-treatment group had undergone prior abdominal surgery is inherent to the condition of unresectable or border-line lesions at presentation. Regarding the difference of tumour size, the measures were collected based on the pathological findings only, after a treatment effect had been detected. Unfortunately, the initial measures on imaging were not fully described and we assume this as a limitation of this retrospective study. Complications may also have been underestimated if they occurred after discharge and the patient was followed up elsewhere. However, in this case this would be expected to be distributed equally between both groups.
In summary, although some previous studies have suggested differences in post-operative morbidity between these groups of patients, our case-match analysis did not find statistical differences in surgical morbidity and mortality associated with neoadjuvant chemoradiation therapy for patients with locally advanced pancreas cancer. Therefore it is felt that a resection should be considered for patients with locally unresectable/borderline pancreas cancer who are felt to be resectable after chemoradiation.
Acknowledgments
Sébastien Gaujoux was recipient of a grant from the European Society of Surgical Oncology (ESSO), the Association Française de Chirurgie Hépato-Biliaire et de Transplantation Hépatique (ACHBT).
Florence Huguet was recipient of a grant from the Nuovo-Soldati Foundation for Cancer Research
Conflicts of interest
None declared.
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