Ann Surg Oncol DOI 10.1245/s10434-015-4711-0
ORIGINAL ARTICLE – PANCREATIC TUMORS
Efficacy of Neoadjuvant Versus Adjuvant Therapy for Resectable Pancreatic Adenocarcinoma: A Decision Analysis Gaurav Sharma, MD1, Edward E. Whang, MD1,2, Daniel T. Ruan, MD1, and Hiromichi Ito, MD3 Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 2Department of Surgery, VA Boston Healthcare System, West Roxbury, MA; 3Department of Surgery, Michigan State University, College of Human Medicine, East Lansing, MI 1
ABSTRACT Background. Neoadjuvant therapy-based protocols for potentially resectable pancreatic adenocarcinoma (PAC) have not been directly compared with adjuvant protocols in large prospective randomized trials. This study aimed to compare the efficacy of neoadjuvant versus adjuvant therapy-based management by using a formal decision analytic model. Methods. A decision analytic model was created with a Markov process to compare neoadjuvant and adjuvant chemo- and/or chemoradiation therapy-based strategies for simulated cohorts of patients with potentially resectable PAC. Base-case probabilities were derived from the published data of 21 prospective phases 2 and 3 trials (3708 patients) between 1997 and 2014. The primary outcome measures determined in an intent-to-treat fashion were overall and quality-adjusted survival rates. One- and twoway sensitivity analyses were performed to assess the effects of model uncertainty on outcomes. Results. The median overall survival and 2-year survival rates for the patients in the standard adjuvant therapy arm of the study were 20 months and 42.2 % versus 22 months and 46.8 % for those in the neoadjuvant strategy arm. Quality-adjusted survival was 18.4 and 19.8 months, respectively. Sensitivity analysis demonstrated that when recurrence-free survival after completion of neoadjuvant therapy and resection is less than 13.9 months or when the rate for progression of disease precluding resection during
Ó Society of Surgical Oncology 2015 First Received: 11 March 2015 G. Sharma, MD e-mail: [email protected]
neoadjuvant therapy is greater than 44 %, the neoadjuvant strategy is no longer the favored option. Conclusions. The decision analytic model suggests that neoadjuvant therapy-based management improves the outcomes for patients with potentially resectable pancreatic cancer. However, the benefits in terms of overall and quality-adjusted survival are modest.
Although complete surgical resection is the cornerstone of curative therapy for pancreatic adenocarcinoma (PAC), early recurrence after surgery is common and responsible for mortality in most patients.1 Adjuvant chemotherapy with or without chemoradiation has been shown to improve overall survival compared with surgery alone and thus is standard treatment for all patients with resectable PAC.2–6 The mortality associated with pancreatic resection has improved significantly in the last decade, but the morbidity rate remains as high as 30–40 %.7,8 Postoperative complications can preclude or delay adjuvant therapy in 25–30 % of eligible patients after curative resection.9 This high rate has stimulated interest in neoadjuvant therapybased strategies. This approach has several theoretical advantages. It maximizes the number of patients completing planned therapy in a timely fashion, identifies patients who experience early metastases and spares them from nonbeneficial surgery, and downstages the tumor, potentially increasing the feasibility of R0 resection. Phase 2 trials have shown promising overall survival rates for patients treated with neoadjuvant-based regimens.9–19 However, no data from randomized controlled trials comparing neoadjuvant with adjuvant therapy-based regimens have been published. This study sought to compare the efficacy of these two strategies for potentially resectable PAC by using existing data to construct an intention-to-treat Markov decision analysis model.
G. Sharma et al.
METHODS
1.
Model Design We constructed a decision model with an iterative Markov process—conducted using TreeAge Pro 2009 (TreeAge Software, Williamstown, MA, USA)—to compare the neoadjuvant and adjuvant management strategies in an ‘‘intent-to-treat’’ fashion for a simulated cohort of patients with potentially resectable PAC. The patients in the adjuvant group underwent surgical resection and subsequently were treated with adjuvant systemic chemotherapy (CT), chemoradiation therapy (CRT), or both. In the neoadjuvant group, the patients were first treated with an average of 3 months of neoadjuvant therapy (CT, CRT, or both), then underwent surgical resection (Fig. 1a). After completing treatment, the hypothetical cohorts entered into a Markov health-state transition model with a 1-month transition cycle interval (Fig. 1b). The patients were followed until death or for 60 months if they remained alive.
2.
3.
Outcome Measures 4. The outcomes of interest were unadjusted overall survival (OS) and quality-of-life (QOL)-adjusted survival. Quality adjustment was calculated monthly for each patient in the cohort, varying from 1.0 (perfect health) to 0 (dead). Data Sources and Base Estimates Source data were identified by a systematic search of the English language literature via PubMed. Only prospective trials consisting of patients with potentially resectable PAC published from 1997 through February 2014 were included in the study. The exclusion criteria ruled out retrospective reviews, trials using regimens not based on conventional chemotherapeutic agents (e.g., biologic or immunologic agents), and trials including locally advanced pancreatic cancer or borderline resectable pancreatic cancer.20 The estimated probabilities represent the weighted mean of the reported values from the literature based on study sample size. Recurrence-free survival (RFS) was calculated as the time from resection until discovery of recurrence. Model Assumptions According to the standard in decision analysis, our model relied on several assumptions supported by previously published data. The assumptions of the model were as follows:
Surgical mortality was similar between the patients who had successfully completed neoadjuvant therapy and the patients in the adjuvant therapy arm of the study who had not undergone any therapy before surgery. Previous studies have shown that neoadjuvant chemoradiation did not increase mortality and actually was associated with a decreased risk of certain postoperative complications.21 The probabilities of recurrence of cancer or death from cancer were determined solely by the treatment options the patients had received, and they were constant throughout the course of the follow-up evaluation. The probability of the event (recurrence or cancer death) per month (p) could be calculated from the mean median survival in months (T) reported in the literature using the following formula: p ¼ ln T0:5 We assumed that the QOL experienced by patients is compromised only by recurrence of cancer and chronic complications from pancreatic resection because adjuvant therapy has not been shown to have a significant negative impact on QOL.22 We used the utility estimates that Weinberg et al.23 used to assess QOL after pancreatic surgery. The rate of chronic complications after nontherapeutic laparotomy for unresectable disease is negligible, and these complications do not affect the QOL of patients.
Sensitivity Analysis A series of one- and two-way sensitivity analyses systematically comparing the effect of altering each variable through a range of potential values derived from the literature was performed to evaluate the effects of model assumptions and parameter uncertainty on results. Threshold values were calculated and reported in cases for which a change in the preferred strategy was traversed. RESULTS The inclusion criteria were met by 21 prospective trials, resulting in a total patient sample of 3708 (599 in studies of neoadjuvant therapy and 3109 in studies of adjuvant therapy) (Table 1). Probability estimates, averages of median RFS and OS weighted by sample size of contributing studies, QOL estimates, and range for sensitivity analyses obtained are listed in Table 2. Among the patients who completed the planned therapy, the reported median RFS after resection was longer for those who received neoadjuvant therapy (16.9 months) than for those who received adjuvant therapy (13.7 months).
Pancreatic Cancer Therapy: Decision Analysis
Potentially resectable pancreatic cancer
a
Adjuvant
Neoadjuvant
0.12
0.85 Surgically resected
0.03
0.64
Surgically death
Unresectable
0.36
Completed neoadjuvant Rx
Disease progress
M
M
0.81
0.19
W/o Complications
With Complications
0.97
0.03
Surgically resected
0.14
0.86
Surgically death
0.81
Complete adjuvant Rx
No adjuvant Rx
No adjuvant Rx
W/o Complications
M
M
M
M
b
0.19 With Complications
M
recurrence
Alive w/o cancer
Alive with cancer
Non-cancer death
Cancer death
Non-cancer death
Dead
c
Proportion
FIG. 1 a Decision tree for adjuvant- versus neoadjuvantbased strategies for the treatment of patients with resectable pancreatic cancer. The probability of each state appears above the respective box. Patients found to be unresectable at the time of laparotomy after neoadjuvant therapy are included in the ‘‘disease progress’’ group. M indicates the points at which patients enter into the Markov model. b Markov health-state transition diagram for patients after initial treatment. All states are mutually exclusive, and transitions from one state to another occur at the end of each 1-month cycle at a rate reflecting disease recurrence after the treatment received, as well as age-specific, non– cancer-related mortality and the ongoing risk of mortality from pancreatic cancer. c Overall survival curve for the theoretical cohort of patients during 60 cycles (months) of Markov simulation
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Neoadjuvant Adjuvant
0
6
12
18
24
30
Months
36
42
48
54
60
2002 2004 2006
Pisters et al.16
Joensuu et al.13
Talamonti et al.17
MDACC
Helsinki
Northwestern University
2008 2009 2009
Palmer et al.15
Heinrich et al.11
Le Scodan et al.14
Turrini et al.18
University of Birmingham
University Hospital of Zurich
SFRO-FFCD
University Mediterranean
2009 2010 2010
Ueno et al.32
Van Laethem et al.5
Neoptolemos et al.33
JSAP-02
EORTC/FFCD/GERCOR
ESPAC-3
Japan
EORTC
c
Johns Hopkins
1999 2002
Kinkenbijl et al.2
Takada et al.29
1997
2008
Regine et al.31
RTOG
Yeo et al.6
2007
Oettle et al.30
CONKO
Surgery alone
2006
Kosuge et al.3
2004
Japan
Neoptolemos et al.
2002
Takada et al.29
Japan
ESPAC-1
1999
1997
Kinkenbijl et al.2
1997
Spitz et al.9
EORTCc
MDACC
Yeo et al.6
4
2008
Varadhachary et al.19
MDACC
Adjuvant strategy Johns Hopkins
2008
Evans et al.
MDACC 2008
1998
10
1997
Hoffman et al.12
ECOG
Year
Spitz et al.9
Author
MDACC
Neoadjuvant strategy
Trial or institution
73
Surg ? 5Fu/XRT
Surg alone
Surg alone
Surg alone
77
57
120
537 551
45
Surg ? Gem/XRT Surg ? Gem Surg ? 5Fu/FA
45
58
Surg ? Gem
Surg ? Gem
221 230
Surg ? Gem
179
Surg ? 5Fu
Surg ? Gem
45
75
Surg ? 5Fu/Cis
72
Surg ? 5Fu/XRT?5Fu
81
63
25
53
102
41
28
50
78
84
20
28
34
53
81
na
Surg ? 5Fu
Surg ? 5Fu/MMC
Surg ? 5Fu/XRT
Surg ? 5Fu/XRT
Surg ? 5Fu/XRT
5Fu-Cis/XRT ? surg
5Fu-Cis/XRT ? surg
Gem-Cis ? surg
Gem ± Cis ? surg
Gem-Cis ? Gem/XRT ? surg
Gem/XRT ? surg
Gem/XRT ? surg
Gem/XRT ? surg
Paclitaxel ? IORT ? surg
5Fu/MMC/XRT ? surg
5Fu/XRT ? surg
Treatment regimen
2.1
2.8
2
3.8
4.3
3.0
3.8
3.5
1.8
2.8
3.1
Duration of CT/CRT (months)
No
No
No
No
No
No
No
No
No
No
No
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Enrollment before surgery?
40 (39)
15 (37)
2 (7)
23 (46)
26 (33)
20 (24)
3 (15)
4 (14)
15 (44)
29 (55)
39 (48)
Disease progression before resection n (%)
TABLE 1 Data sources: prospective trials of neoadjuvant vs adjuvant therapy for patients with potentially resectable pancreatic adenocarcinoma
486 (91) 499 (91)
38 (85)
40 (89)
44 (92)
193 (84)
199 (90)
111 (62)
34 (76)
NR
NR
NR
78 (96)
NR
19 (76)
53 (100)
62 (61)
26 (63)
26 (93)
27 (54)
52 (67)
64 (76)
17 (85)
20 (71)
19 (56)
24 (45)
41 (51)
Completion of planned therapy n (%)
NR
NR
NR
14.3d 14.1d
11.8
10.9
11.4
NR
NR
13.4
8.0
NR
NR
NR
NR
NR
NR
NR
22.0
5.0
9.2
NR
NR
28.6
NR
18
9
8.5
NR
Median RFSb (months)
12.4
12.0
13.5
23.6d 23.0d
24.3
24.4
22.3
16.9
20.6
22.1
12.5
13.9
21.6
19.9
12.8
15.6
22.0
19.5
23.0
11.7
26.5
13.6
28.3
34.0
26
25
19
15.7
19.2
Median OSb (months)
G. Sharma et al.
2009
Le Scodan et al.14
SFRO-FFCD No resection
No resection
No resection
No resection
No resection
No resection
No resection
Surg alone
Surg alone
Surg alone
Surg alone
Treatment regimen
40
15
18
27
22
15
17
60
175
44
69
na Duration of CT/CRT (months)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
Enrollment before surgery?
Disease progression before resection n (%) Completion of planned therapy n (%)
5.0
6.9
9.0
NR
Median RFSb (months)
11
5.6
8.6
10.5
7.1
10
8.0
18.4
20.2
15.8
16.9
Median OSb (months)
d
c
b
a
Survival data were reported for all patients enrolled in the trial regardless of therapeutic arm of the study
Patients with periampullary cancer were included in the study
For the patients who completed the planned therapy including surgical resection, time is reported as from operation to recurrence for RFS and from initiation of therapy to death for OS
Patients who withdrew from the protocol were lost follow-up, and those with no histologic evidence of pancreatic adenocarcinoma were excluded from the study
n sample size, CT chemotherapy, CRT chemoradiotherapy, RFS recurrence-free survival, OS overall survival, XRT radiation therapy, NR not reported, MMC mitomycin C, IORT intraoperative radiation therapy, Gem gemcitabine, Cis cisplatin, Surg surgical resection, 5Fu 5-fluorouracil, FA folinic acid
Turrini et al. 2009
2008
Palmer et al.15
Univ. Birmingham
Univ. Mediterranean
2008
Varadhachary et al.19
MDACC
18
2008
Evans et al.10
2002
Pisters et al.
MDACC
16
MDACC
ECOG 1998
Ueno et al.32
JSAP-02
Hoffman et al.12
2009
Oettle et al.30
Unresectable
2007
Kosuge et al.
CONKO
2006
2004
Neoptolemos et al.4 3
Year
Author
Japan
ESPAC-1
Trial or institution
TABLE 1 continued
Pancreatic Cancer Therapy: Decision Analysis
G. Sharma et al. TABLE 2 Probability estimates and utilitiesa Variable
Weighted mean
Range in literature
Range in sensitivity analysis
Data source
Age (years)
60
N/A
40–80
Probability of dying of non–cancer-related causes
Age- dependent N/A
Surgical mortality rate of pancreatic surgery Probability of being found unresectable at laparotomy
0.03 0.12
0–0.17 0.09–0.23
0–0.25 0.05–0.4
28,35
Probability of completing adjuvant therapy after pancreatectomy
0.86
0.76–1.0
0.7–1.0
3,5,9,29–33,37
Probability of chronic complication after pancreatic surgery
0.19
0.15–0.30
0.06–0.30
28,35
Probability cancer will progress during neoadjuvant therapy
0.37
0.07–0.55
0–0.6
9,10,12–19,38
Median RFS after surgery followed by adjuvant therapy
13.7 months
8.0–14.3
8.0–16.0
3,5,30,32,33
Median RFS after surgery alone
6.8 months
5.0–9.0
4.0–10.0
3,30,32
Median RFS after neoadjuvant therapy followed by surgery
16.9 months
5.0–25.6
5.0–26.0
11–14,16,18,19,39
Median OS without resection
9.1 months
5.6–11.0
5.0–12.0
12,14,16,18,19,39
34
36
Median OS after recurrence
9.6 months
N/A
1.0–22.1
*
QOL (utility) of patients with unresectable or recurrent cancera
0.62
N/A
0.4–0.9
23
0.65
0.42–1.0
0.4–1.0
23
QOL (utility) of patients who underwent resection without complications
1.0
N/A
0.4–1.0
23
QOL (utility) of patients who underwent resection with chronic complication and experienced recurrent disease
0.4
N/A
0.16–1
**
QOL (utility) of patients who underwent resection with chronic complication
b
N/A not available, RFS recurrence-free survival, OS overall survival, QOL quality of life *Median survival after recurrence was calculated by subtraction of RFS from OS in the literature **This is a product of QOL of a and b
Breakdown of Model Scenarios and Outcomes The probabilities shown in Table 2 and the decision tree in Fig. 1a yielded the following rates for the final patient populations according to the treatments received. In the adjuvant strategy group, 59 % of the patients received complete therapy including both surgery and adjuvant chemotherapy or chemoradiation, 12 % had unresectable disease at exploration, 26 % underwent surgery but did not complete a full course of adjuvant therapy, and 3 % died perioperatively. In the neoadjuvant group, 62 % of the patients completed planned therapy, 36 % progressed to unresectable disease during neoadjuvant therapy, and 2 % died perioperatively. Overall and QOL-Adjusted Survival The median OS was slightly longer in the neoadjuvant cohort (22 months) than in the adjuvant cohort (20 months), and the 1-, 2-, and 5-year survival rates were respectively 71, 47, and 11 % for the patients in the neoadjuvant cohort versus 70, 42, and 7 % for those in the adjuvant cohort (Fig. 1c). Quality-adjusted survival was analyzed using previously published utilities.23 After 60 cycles of Markov simulation,
the cumulative quality-adjusted survival for the patients in the neoadjuvant strategy arm of the study was 19.8 months compared with 18.4 months for the patients in the adjuvant strategy arm. Sensitivity Analysis One-way sensitivity analysis showed that the adjuvant strategy yielded higher quality-adjusted survival rates only when RFS in the neoadjuvant arm was shorter than 13.9 months or when more than 44 % of the patients experienced disease progression during neoadjuvant therapy and failed to undergo surgical resection (Fig. 2a and b). The neoadjuvant strategy yielded superior OS and quality-adjusted survival across the full range of possible values for all other variables. Two-way sensitivity analysis demonstrated the relationship between RFS after neoadjuvant therapy followed by surgical resection and the probability of disease progression during neoadjuvant therapy (Fig. 2c). DISCUSSION Neoadjuvant therapy for resectable PAC is controversial. In addition to the lack of randomized control trials,
Pancreatic Cancer Therapy: Decision Analysis
a
13.9 mo
24.0 22.0
QoLE (mo)
Neoadjuvant 20.0 18.0
Adjuvant
16.0 14.0 12.0 5
7.1
9.2 11.3 13.4 15.5 17.6 19.7 21.8 23.9 26
RFS after Neoadjuvant Therapy followed by Surgical Resection (mo)
QoLE (mo)
b
0.44 28 27 26 25 Neoadjuvant 24 23 22 21 20 19 18 Adjuvant 17 16 15 0.00 0.06 0.12 0.18 0.24 0.30 0.36 0.42 0.48 0.54 0.60
Probability of Progression during Neoadjuvant Therapy (mo)
c Probability of Progression during Neoadjuvant Therapy
0.60
0.45
Adjuvant
0.30 Neoadjuvant 0.15
0.00 5.0
7.1
9.2 11.3 13.4 15.5 17.6 19.7 21.8 23.9 26.0
RFS after Neoadjuvant Therapy followed by Surgery (mo)
FIG. 2 One-way sensitivity analysis (a) varying median recurrencefree survival (RFS) after completion of neoadjuvant therapy followed by surgical resection and (b) varying the probability of cancer progression during neoadjuvant therapy. c Two-way sensitivity analysis varying these two variables. c The dark region (adjuvant) represents the values for RFS after neoadjuvant therapy followed by surgical resection and the probability of cancer progression during neoadjuvant therapy at which the adjuvant strategy preferred, and the light region (neoadjuvant) represents the values at which the neoadjuvant strategy is preferred. QoLE quality-adjusted life expectancy
direct comparison of individual adjuvant and neoadjuvant trials can be misleading because more than one-fourth of the patients in either strategy failed to complete planned therapy, and those patients often were excluded from the analysis of overall outcomes.24 In this study, we created a comprehensive, evidencebased Markov decision analytic model and compared the long-term outcomes for patients with resectable PAC treated using these two approaches. The model allowed us to simulate the spectrum of possible scenarios that patients could experience during the course of either of these treatments. Although our decision analysis favored the neoadjuvant strategy over the traditional adjuvant strategy in terms of OS and quality-adjusted survival, its real benefit appeared to be modest. The neoadjuvant strategy resulted in a median OS 2 months longer and a median qualityadjusted survival 1.4 months longer than the adjuvant strategy. To date, two meta-analyses have evaluated the outcomes of neoadjuvant therapy for PAC. Assifi et al.25 reviewed 14 phase 2 controlled trials of neoadjuvant therapy for either resectable or borderline resectable PAC, and Gillen et al.26 reviewed 111 studies. The inclusion of retrospective data and borderline resectable cases left in question which strategy is superior for potentially resectable cases based on the best available data unanswered. Pooled data from prospective controlled trials meeting our inclusion criteria indicated that neoadjuvant strategy resulted in longer baseline RFS (16.9 months) for the patients who completed the planned therapy than for those who completed the adjuvant therapy after surgical resection (13.7 months). However, 36 % of the patients assigned to the neoadjuvant strategy failed to undergo resection in our model compared with only 12 % deemed unresectable in the adjuvant strategy. This difference may reflect the patients with occult metastatic disease at presentation who were unlikely to benefit from surgery or the patients who lost the opportunity for potential curative resection due to local progression of disease only. Neoadjuvant trials have inconsistently reported the degree to which each of these possibilities accounted for failure to proceed to surgical resection. Where it has been reported, local progression is responsible in 10–16 % of cases.12,18 Notably, our decision model was sensitive to both the estimated RFS for the patients who received neoadjuvant therapy and the estimated probability that patients would fail to undergo surgical resection after neoadjuvant therapy. Although the neoadjuvant strategy provides longer survival for selected patients who undergo resection, this benefit will be attenuated when the percentage of patients who do not proceed to surgical resection exceeds the threshold rate.
G. Sharma et al.
This is likely because the number of patients who miss the opportunity for potentially curative resection due to local progression of disease during neoadjuvant therapy will increase. Our study focused on patients with resectable PAC. Those with borderline resectable PAC were excluded because this stage of disease is characterized by higher unresectability and positive margin rates than clearly resectable PAC even with aggressive vascular resection. The use of neoadjuvant therapy before surgical resection has been recommended as the preferred approach for this group of patients based on expert consensus.20,27 The radiographic criteria for ‘‘resectable’’ PAC versus ‘‘borderline resectable’’ PAC in the neoadjuvant trials, however, has not been uniformly defined. It is important to note that most of the neoadjuvant trials adopted ‘‘MD Anderson criteria,’’ whereby the tumors with superior mesenteric or portal vein (SMV/PV) abutment, impingement, and encasement are considered resectable, whereas the current National Comprehensive Cancer Network (NCCN) guideline defines such tumors as borderline unless these veins are occluded. The calculated OS for the theoretical cohort of patients in the adjuvant strategy arm of our study was shorter than in many previously reported studies. Our model was designed to follow the patients based on intention to treat. The majority of clinical trials evaluating adjuvant therapy excluded patients deemed unresectable at laparotomy and patients who could not receive adjuvant therapy due to postoperative complications.2–6,27,28 This selection bias skews direct comparison of neoadjuvant and adjuvant trials. Our model design addressed this bias by including a branch for these subgroups of patients for whom adjuvant therapy is planned but who are found to be unresectable or are precluded from receiving CT, CRT, or both after surgery. The study results must be interpreted within the context of our study design. A major limitation of our study was that estimates of QOL after pancreatic surgery or with unresectable pancreatic cancer were limited to original data from four studies and previously published extrapolations from other cancers.23 To evaluate this issue of uncertainty, we performed sensitivity analyses across a range of estimated utilities and found that these did not affect the higher quality-adjusted survival rates associated with the neoadjuvant therapy strategy. Other factors (e.g. psychological fear/concern for disease progression during neoadjuvant therapy) may have a smaller effect on utility than symptoms resulting from recurrent/persistent cancer or surgical complications (e.g., pain, pruritus) but were not included in our model. Despite these limitations, the base estimates for surgical resectability, the short-term outcomes after pancreatic
surgery, and the RFS for each case scenario were based on the best available data. Our model indicated that more than one-third of patients cannot complete planned therapy regardless of the strategy chosen. Thus, selection among treatment options should involve contingency planning and frank consideration of relative QOL among potential outcomes. CONFLICT OF INTEREST
None.
REFERENCES 1. Hernandez JM, Morton CA, Al-Saadi S, et al. The natural history of resected pancreatic cancer without adjuvant chemotherapy. Am Surg. 2010;76:480–5. 2. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230:776–82; discussion 782–774 3. Kosuge T, Kiuchi T, Mukai K, Kakizoe T. A multicenter randomized controlled trial to evaluate the effect of adjuvant cisplatin and 5-fluorouracil therapy after curative resection in cases of pancreatic cancer. Jpn J Clin Oncol. 2006;36:159–65. 4. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350:1200–10. 5. Van Laethem JL, Hammel P, Mornex F, et al. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC40013-22012/FFCD-9203/GERCOR phase II study. J Clin Oncol. 2010;28:4450–6. 6. Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival: a prospective, single-institution experience. Ann Surg. 1997;225:621–33 7. Glasgow RE, Jackson HH, Neumayer L, et al. Pancreatic resection in Veterans Affairs and selected university medical centers: results of the patient safety in surgery study. J Am Coll Surg. 2007;204:1252–60. 8. Parikh P, Shiloach M, Cohen ME, et al. Pancreatectomy risk calculator: an ACS-NSQIP resource. HPB 2010;12:488–97. 9. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15:928–37. 10. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3496–502. 11. Heinrich S, Schafer M, Weber A, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg. 2008;248:1014–22. 12. Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson AB III. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study. J Clin Oncol. 1998;16:317–23. 13. Joensuu TK, Kiviluoto T, Karkkainen P, et al. Phase I–II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended
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14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
lymphadenectomy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;60:444–52. Le Scodan R, Mornex F, Girard N, et al. Preoperative chemoradiation in potentially resectable pancreatic adenocarcinoma: feasibility, treatment effect evaluation and prognostic factors, analysis of the SFRO-FFCD 9704 trial, and literature review. Ann Oncol. 2009;20:1387–96. Palmer DH, Stocken DD, Hewitt H, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol. 2007;14:2088–96. Pisters PW, Wolff RA, Janjan NA, et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J Clin Oncol. 2002;20:2537–44. Talamonti MS, Small W Jr, Mulcahy MF, et al. A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol. 2006;13:150–8. Turrini O, Viret F, Moureau-Zabotto L, et al. Neoadjuvant 5-fluorouracil-cisplatin chemoradiation effect on survival in patients with resectable pancreatic head adenocarcinoma: a tenyear single institution experience. Oncology. 2009;76:413–9. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3487–95. Abrams RA, Lowy AM, O’Reilly EM, Wolff RA, Picozzi VJ, Pisters PW. Combined modality treatment of resectable and borderline resectable pancreas cancer: expert consensus statement. Ann Surg Oncol. 2009;16:1751–6. Lowy AM, Lee JE, Pisters PW, et al. Prospective, randomized trial of octreotide to prevent pancreatic fistula after pancreaticoduodenectomy for malignant disease. Ann Surg. 1997;226: 632–41. Glimelius B, Hoffman K, Sjoden PO, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7:593–600. Weinberg BM, Spiegel BM, Tomlinson JS, Farrell JJ. Asymptomatic pancreatic cystic neoplasms: maximizing survival and quality of life using Markov-based clinical nomograms. Gastroenterology. 2010;138:531–40. Hoffman JP, Stitzenberg KB. Preoperative versus postoperative adjuvant therapy for adenocarcinoma of the pancreas. Adv Surg. 2009;43:189–98. Assifi MM, Lu X, Eibl G, Reber HA, Li G, Hines OJ. Neoadjuvant therapy in pancreatic adenocarcinoma: a meta-analysis of phase II trials. Surgery. 2011;150:466–73. Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7:e1000267.
27. Lopez NE, Prendergast C, Lowy AM. Borderline resectable pancreatic cancer: definitions and management. WJG World J Gastroenterol. 21 2014;20:10740–51. 28. McPhee JT, Hill JS, Whalen GF, et al. Perioperative mortality for pancreatectomy: a national perspective. Ann Surg. 2007;246: 246–53. 29. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. 2002;95: 1685–95. 30. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297:267–77. 31. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299:1019–26. 32. Ueno H, Kosuge T, Matsuyama Y, et al. A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer. 2009;101:908–15. 33. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304:1073–81. 34. Arias E. United States life tables, 2004. Natl Vital Stat Rep. 2007;56:1–39. 35. Patel SR, Vadhan-Raj S, Papadopolous N, et al. High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies—dose-response and schedule dependence. J Clin Oncol. 1997;15:2378–84. 36. Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al. Thinsection contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg. 1994;167:104–11; discussion 111–103 37. Neoptolemos JP, Stocken DD, Tudur Smith C, et al. Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials. Br J Cancer. 2009;100:246–50. 38. Henricks WH, Chu YC, Goldblum JR, Weiss SW Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol. 1997;21:271–81. 39. Evans DB, Pisters PW, Lee JE, et al. Preoperative chemoradiation strategies for localized adenocarcinoma of the pancreas. J Hepatobiliary Pancreat Surg. 1998;5:242–50.
ORIGINAL ARTICLE – PANCREATIC TUMORS
Efficacy of Neoadjuvant Versus Adjuvant Therapy for Resectable Pancreatic Adenocarcinoma: A Decision Analysis Gaurav Sharma, MD1, Edward E. Whang, MD1,2, Daniel T. Ruan, MD1, and Hiromichi Ito, MD3 Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 2Department of Surgery, VA Boston Healthcare System, West Roxbury, MA; 3Department of Surgery, Michigan State University, College of Human Medicine, East Lansing, MI 1
ABSTRACT Background. Neoadjuvant therapy-based protocols for potentially resectable pancreatic adenocarcinoma (PAC) have not been directly compared with adjuvant protocols in large prospective randomized trials. This study aimed to compare the efficacy of neoadjuvant versus adjuvant therapy-based management by using a formal decision analytic model. Methods. A decision analytic model was created with a Markov process to compare neoadjuvant and adjuvant chemo- and/or chemoradiation therapy-based strategies for simulated cohorts of patients with potentially resectable PAC. Base-case probabilities were derived from the published data of 21 prospective phases 2 and 3 trials (3708 patients) between 1997 and 2014. The primary outcome measures determined in an intent-to-treat fashion were overall and quality-adjusted survival rates. One- and twoway sensitivity analyses were performed to assess the effects of model uncertainty on outcomes. Results. The median overall survival and 2-year survival rates for the patients in the standard adjuvant therapy arm of the study were 20 months and 42.2 % versus 22 months and 46.8 % for those in the neoadjuvant strategy arm. Quality-adjusted survival was 18.4 and 19.8 months, respectively. Sensitivity analysis demonstrated that when recurrence-free survival after completion of neoadjuvant therapy and resection is less than 13.9 months or when the rate for progression of disease precluding resection during
Ó Society of Surgical Oncology 2015 First Received: 11 March 2015 G. Sharma, MD e-mail: [email protected]
neoadjuvant therapy is greater than 44 %, the neoadjuvant strategy is no longer the favored option. Conclusions. The decision analytic model suggests that neoadjuvant therapy-based management improves the outcomes for patients with potentially resectable pancreatic cancer. However, the benefits in terms of overall and quality-adjusted survival are modest.
Although complete surgical resection is the cornerstone of curative therapy for pancreatic adenocarcinoma (PAC), early recurrence after surgery is common and responsible for mortality in most patients.1 Adjuvant chemotherapy with or without chemoradiation has been shown to improve overall survival compared with surgery alone and thus is standard treatment for all patients with resectable PAC.2–6 The mortality associated with pancreatic resection has improved significantly in the last decade, but the morbidity rate remains as high as 30–40 %.7,8 Postoperative complications can preclude or delay adjuvant therapy in 25–30 % of eligible patients after curative resection.9 This high rate has stimulated interest in neoadjuvant therapybased strategies. This approach has several theoretical advantages. It maximizes the number of patients completing planned therapy in a timely fashion, identifies patients who experience early metastases and spares them from nonbeneficial surgery, and downstages the tumor, potentially increasing the feasibility of R0 resection. Phase 2 trials have shown promising overall survival rates for patients treated with neoadjuvant-based regimens.9–19 However, no data from randomized controlled trials comparing neoadjuvant with adjuvant therapy-based regimens have been published. This study sought to compare the efficacy of these two strategies for potentially resectable PAC by using existing data to construct an intention-to-treat Markov decision analysis model.
G. Sharma et al.
METHODS
1.
Model Design We constructed a decision model with an iterative Markov process—conducted using TreeAge Pro 2009 (TreeAge Software, Williamstown, MA, USA)—to compare the neoadjuvant and adjuvant management strategies in an ‘‘intent-to-treat’’ fashion for a simulated cohort of patients with potentially resectable PAC. The patients in the adjuvant group underwent surgical resection and subsequently were treated with adjuvant systemic chemotherapy (CT), chemoradiation therapy (CRT), or both. In the neoadjuvant group, the patients were first treated with an average of 3 months of neoadjuvant therapy (CT, CRT, or both), then underwent surgical resection (Fig. 1a). After completing treatment, the hypothetical cohorts entered into a Markov health-state transition model with a 1-month transition cycle interval (Fig. 1b). The patients were followed until death or for 60 months if they remained alive.
2.
3.
Outcome Measures 4. The outcomes of interest were unadjusted overall survival (OS) and quality-of-life (QOL)-adjusted survival. Quality adjustment was calculated monthly for each patient in the cohort, varying from 1.0 (perfect health) to 0 (dead). Data Sources and Base Estimates Source data were identified by a systematic search of the English language literature via PubMed. Only prospective trials consisting of patients with potentially resectable PAC published from 1997 through February 2014 were included in the study. The exclusion criteria ruled out retrospective reviews, trials using regimens not based on conventional chemotherapeutic agents (e.g., biologic or immunologic agents), and trials including locally advanced pancreatic cancer or borderline resectable pancreatic cancer.20 The estimated probabilities represent the weighted mean of the reported values from the literature based on study sample size. Recurrence-free survival (RFS) was calculated as the time from resection until discovery of recurrence. Model Assumptions According to the standard in decision analysis, our model relied on several assumptions supported by previously published data. The assumptions of the model were as follows:
Surgical mortality was similar between the patients who had successfully completed neoadjuvant therapy and the patients in the adjuvant therapy arm of the study who had not undergone any therapy before surgery. Previous studies have shown that neoadjuvant chemoradiation did not increase mortality and actually was associated with a decreased risk of certain postoperative complications.21 The probabilities of recurrence of cancer or death from cancer were determined solely by the treatment options the patients had received, and they were constant throughout the course of the follow-up evaluation. The probability of the event (recurrence or cancer death) per month (p) could be calculated from the mean median survival in months (T) reported in the literature using the following formula: p ¼ ln T0:5 We assumed that the QOL experienced by patients is compromised only by recurrence of cancer and chronic complications from pancreatic resection because adjuvant therapy has not been shown to have a significant negative impact on QOL.22 We used the utility estimates that Weinberg et al.23 used to assess QOL after pancreatic surgery. The rate of chronic complications after nontherapeutic laparotomy for unresectable disease is negligible, and these complications do not affect the QOL of patients.
Sensitivity Analysis A series of one- and two-way sensitivity analyses systematically comparing the effect of altering each variable through a range of potential values derived from the literature was performed to evaluate the effects of model assumptions and parameter uncertainty on results. Threshold values were calculated and reported in cases for which a change in the preferred strategy was traversed. RESULTS The inclusion criteria were met by 21 prospective trials, resulting in a total patient sample of 3708 (599 in studies of neoadjuvant therapy and 3109 in studies of adjuvant therapy) (Table 1). Probability estimates, averages of median RFS and OS weighted by sample size of contributing studies, QOL estimates, and range for sensitivity analyses obtained are listed in Table 2. Among the patients who completed the planned therapy, the reported median RFS after resection was longer for those who received neoadjuvant therapy (16.9 months) than for those who received adjuvant therapy (13.7 months).
Pancreatic Cancer Therapy: Decision Analysis
Potentially resectable pancreatic cancer
a
Adjuvant
Neoadjuvant
0.12
0.85 Surgically resected
0.03
0.64
Surgically death
Unresectable
0.36
Completed neoadjuvant Rx
Disease progress
M
M
0.81
0.19
W/o Complications
With Complications
0.97
0.03
Surgically resected
0.14
0.86
Surgically death
0.81
Complete adjuvant Rx
No adjuvant Rx
No adjuvant Rx
W/o Complications
M
M
M
M
b
0.19 With Complications
M
recurrence
Alive w/o cancer
Alive with cancer
Non-cancer death
Cancer death
Non-cancer death
Dead
c
Proportion
FIG. 1 a Decision tree for adjuvant- versus neoadjuvantbased strategies for the treatment of patients with resectable pancreatic cancer. The probability of each state appears above the respective box. Patients found to be unresectable at the time of laparotomy after neoadjuvant therapy are included in the ‘‘disease progress’’ group. M indicates the points at which patients enter into the Markov model. b Markov health-state transition diagram for patients after initial treatment. All states are mutually exclusive, and transitions from one state to another occur at the end of each 1-month cycle at a rate reflecting disease recurrence after the treatment received, as well as age-specific, non– cancer-related mortality and the ongoing risk of mortality from pancreatic cancer. c Overall survival curve for the theoretical cohort of patients during 60 cycles (months) of Markov simulation
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Neoadjuvant Adjuvant
0
6
12
18
24
30
Months
36
42
48
54
60
2002 2004 2006
Pisters et al.16
Joensuu et al.13
Talamonti et al.17
MDACC
Helsinki
Northwestern University
2008 2009 2009
Palmer et al.15
Heinrich et al.11
Le Scodan et al.14
Turrini et al.18
University of Birmingham
University Hospital of Zurich
SFRO-FFCD
University Mediterranean
2009 2010 2010
Ueno et al.32
Van Laethem et al.5
Neoptolemos et al.33
JSAP-02
EORTC/FFCD/GERCOR
ESPAC-3
Japan
EORTC
c
Johns Hopkins
1999 2002
Kinkenbijl et al.2
Takada et al.29
1997
2008
Regine et al.31
RTOG
Yeo et al.6
2007
Oettle et al.30
CONKO
Surgery alone
2006
Kosuge et al.3
2004
Japan
Neoptolemos et al.
2002
Takada et al.29
Japan
ESPAC-1
1999
1997
Kinkenbijl et al.2
1997
Spitz et al.9
EORTCc
MDACC
Yeo et al.6
4
2008
Varadhachary et al.19
MDACC
Adjuvant strategy Johns Hopkins
2008
Evans et al.
MDACC 2008
1998
10
1997
Hoffman et al.12
ECOG
Year
Spitz et al.9
Author
MDACC
Neoadjuvant strategy
Trial or institution
73
Surg ? 5Fu/XRT
Surg alone
Surg alone
Surg alone
77
57
120
537 551
45
Surg ? Gem/XRT Surg ? Gem Surg ? 5Fu/FA
45
58
Surg ? Gem
Surg ? Gem
221 230
Surg ? Gem
179
Surg ? 5Fu
Surg ? Gem
45
75
Surg ? 5Fu/Cis
72
Surg ? 5Fu/XRT?5Fu
81
63
25
53
102
41
28
50
78
84
20
28
34
53
81
na
Surg ? 5Fu
Surg ? 5Fu/MMC
Surg ? 5Fu/XRT
Surg ? 5Fu/XRT
Surg ? 5Fu/XRT
5Fu-Cis/XRT ? surg
5Fu-Cis/XRT ? surg
Gem-Cis ? surg
Gem ± Cis ? surg
Gem-Cis ? Gem/XRT ? surg
Gem/XRT ? surg
Gem/XRT ? surg
Gem/XRT ? surg
Paclitaxel ? IORT ? surg
5Fu/MMC/XRT ? surg
5Fu/XRT ? surg
Treatment regimen
2.1
2.8
2
3.8
4.3
3.0
3.8
3.5
1.8
2.8
3.1
Duration of CT/CRT (months)
No
No
No
No
No
No
No
No
No
No
No
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Enrollment before surgery?
40 (39)
15 (37)
2 (7)
23 (46)
26 (33)
20 (24)
3 (15)
4 (14)
15 (44)
29 (55)
39 (48)
Disease progression before resection n (%)
TABLE 1 Data sources: prospective trials of neoadjuvant vs adjuvant therapy for patients with potentially resectable pancreatic adenocarcinoma
486 (91) 499 (91)
38 (85)
40 (89)
44 (92)
193 (84)
199 (90)
111 (62)
34 (76)
NR
NR
NR
78 (96)
NR
19 (76)
53 (100)
62 (61)
26 (63)
26 (93)
27 (54)
52 (67)
64 (76)
17 (85)
20 (71)
19 (56)
24 (45)
41 (51)
Completion of planned therapy n (%)
NR
NR
NR
14.3d 14.1d
11.8
10.9
11.4
NR
NR
13.4
8.0
NR
NR
NR
NR
NR
NR
NR
22.0
5.0
9.2
NR
NR
28.6
NR
18
9
8.5
NR
Median RFSb (months)
12.4
12.0
13.5
23.6d 23.0d
24.3
24.4
22.3
16.9
20.6
22.1
12.5
13.9
21.6
19.9
12.8
15.6
22.0
19.5
23.0
11.7
26.5
13.6
28.3
34.0
26
25
19
15.7
19.2
Median OSb (months)
G. Sharma et al.
2009
Le Scodan et al.14
SFRO-FFCD No resection
No resection
No resection
No resection
No resection
No resection
No resection
Surg alone
Surg alone
Surg alone
Surg alone
Treatment regimen
40
15
18
27
22
15
17
60
175
44
69
na Duration of CT/CRT (months)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
Enrollment before surgery?
Disease progression before resection n (%) Completion of planned therapy n (%)
5.0
6.9
9.0
NR
Median RFSb (months)
11
5.6
8.6
10.5
7.1
10
8.0
18.4
20.2
15.8
16.9
Median OSb (months)
d
c
b
a
Survival data were reported for all patients enrolled in the trial regardless of therapeutic arm of the study
Patients with periampullary cancer were included in the study
For the patients who completed the planned therapy including surgical resection, time is reported as from operation to recurrence for RFS and from initiation of therapy to death for OS
Patients who withdrew from the protocol were lost follow-up, and those with no histologic evidence of pancreatic adenocarcinoma were excluded from the study
n sample size, CT chemotherapy, CRT chemoradiotherapy, RFS recurrence-free survival, OS overall survival, XRT radiation therapy, NR not reported, MMC mitomycin C, IORT intraoperative radiation therapy, Gem gemcitabine, Cis cisplatin, Surg surgical resection, 5Fu 5-fluorouracil, FA folinic acid
Turrini et al. 2009
2008
Palmer et al.15
Univ. Birmingham
Univ. Mediterranean
2008
Varadhachary et al.19
MDACC
18
2008
Evans et al.10
2002
Pisters et al.
MDACC
16
MDACC
ECOG 1998
Ueno et al.32
JSAP-02
Hoffman et al.12
2009
Oettle et al.30
Unresectable
2007
Kosuge et al.
CONKO
2006
2004
Neoptolemos et al.4 3
Year
Author
Japan
ESPAC-1
Trial or institution
TABLE 1 continued
Pancreatic Cancer Therapy: Decision Analysis
G. Sharma et al. TABLE 2 Probability estimates and utilitiesa Variable
Weighted mean
Range in literature
Range in sensitivity analysis
Data source
Age (years)
60
N/A
40–80
Probability of dying of non–cancer-related causes
Age- dependent N/A
Surgical mortality rate of pancreatic surgery Probability of being found unresectable at laparotomy
0.03 0.12
0–0.17 0.09–0.23
0–0.25 0.05–0.4
28,35
Probability of completing adjuvant therapy after pancreatectomy
0.86
0.76–1.0
0.7–1.0
3,5,9,29–33,37
Probability of chronic complication after pancreatic surgery
0.19
0.15–0.30
0.06–0.30
28,35
Probability cancer will progress during neoadjuvant therapy
0.37
0.07–0.55
0–0.6
9,10,12–19,38
Median RFS after surgery followed by adjuvant therapy
13.7 months
8.0–14.3
8.0–16.0
3,5,30,32,33
Median RFS after surgery alone
6.8 months
5.0–9.0
4.0–10.0
3,30,32
Median RFS after neoadjuvant therapy followed by surgery
16.9 months
5.0–25.6
5.0–26.0
11–14,16,18,19,39
Median OS without resection
9.1 months
5.6–11.0
5.0–12.0
12,14,16,18,19,39
34
36
Median OS after recurrence
9.6 months
N/A
1.0–22.1
*
QOL (utility) of patients with unresectable or recurrent cancera
0.62
N/A
0.4–0.9
23
0.65
0.42–1.0
0.4–1.0
23
QOL (utility) of patients who underwent resection without complications
1.0
N/A
0.4–1.0
23
QOL (utility) of patients who underwent resection with chronic complication and experienced recurrent disease
0.4
N/A
0.16–1
**
QOL (utility) of patients who underwent resection with chronic complication
b
N/A not available, RFS recurrence-free survival, OS overall survival, QOL quality of life *Median survival after recurrence was calculated by subtraction of RFS from OS in the literature **This is a product of QOL of a and b
Breakdown of Model Scenarios and Outcomes The probabilities shown in Table 2 and the decision tree in Fig. 1a yielded the following rates for the final patient populations according to the treatments received. In the adjuvant strategy group, 59 % of the patients received complete therapy including both surgery and adjuvant chemotherapy or chemoradiation, 12 % had unresectable disease at exploration, 26 % underwent surgery but did not complete a full course of adjuvant therapy, and 3 % died perioperatively. In the neoadjuvant group, 62 % of the patients completed planned therapy, 36 % progressed to unresectable disease during neoadjuvant therapy, and 2 % died perioperatively. Overall and QOL-Adjusted Survival The median OS was slightly longer in the neoadjuvant cohort (22 months) than in the adjuvant cohort (20 months), and the 1-, 2-, and 5-year survival rates were respectively 71, 47, and 11 % for the patients in the neoadjuvant cohort versus 70, 42, and 7 % for those in the adjuvant cohort (Fig. 1c). Quality-adjusted survival was analyzed using previously published utilities.23 After 60 cycles of Markov simulation,
the cumulative quality-adjusted survival for the patients in the neoadjuvant strategy arm of the study was 19.8 months compared with 18.4 months for the patients in the adjuvant strategy arm. Sensitivity Analysis One-way sensitivity analysis showed that the adjuvant strategy yielded higher quality-adjusted survival rates only when RFS in the neoadjuvant arm was shorter than 13.9 months or when more than 44 % of the patients experienced disease progression during neoadjuvant therapy and failed to undergo surgical resection (Fig. 2a and b). The neoadjuvant strategy yielded superior OS and quality-adjusted survival across the full range of possible values for all other variables. Two-way sensitivity analysis demonstrated the relationship between RFS after neoadjuvant therapy followed by surgical resection and the probability of disease progression during neoadjuvant therapy (Fig. 2c). DISCUSSION Neoadjuvant therapy for resectable PAC is controversial. In addition to the lack of randomized control trials,
Pancreatic Cancer Therapy: Decision Analysis
a
13.9 mo
24.0 22.0
QoLE (mo)
Neoadjuvant 20.0 18.0
Adjuvant
16.0 14.0 12.0 5
7.1
9.2 11.3 13.4 15.5 17.6 19.7 21.8 23.9 26
RFS after Neoadjuvant Therapy followed by Surgical Resection (mo)
QoLE (mo)
b
0.44 28 27 26 25 Neoadjuvant 24 23 22 21 20 19 18 Adjuvant 17 16 15 0.00 0.06 0.12 0.18 0.24 0.30 0.36 0.42 0.48 0.54 0.60
Probability of Progression during Neoadjuvant Therapy (mo)
c Probability of Progression during Neoadjuvant Therapy
0.60
0.45
Adjuvant
0.30 Neoadjuvant 0.15
0.00 5.0
7.1
9.2 11.3 13.4 15.5 17.6 19.7 21.8 23.9 26.0
RFS after Neoadjuvant Therapy followed by Surgery (mo)
FIG. 2 One-way sensitivity analysis (a) varying median recurrencefree survival (RFS) after completion of neoadjuvant therapy followed by surgical resection and (b) varying the probability of cancer progression during neoadjuvant therapy. c Two-way sensitivity analysis varying these two variables. c The dark region (adjuvant) represents the values for RFS after neoadjuvant therapy followed by surgical resection and the probability of cancer progression during neoadjuvant therapy at which the adjuvant strategy preferred, and the light region (neoadjuvant) represents the values at which the neoadjuvant strategy is preferred. QoLE quality-adjusted life expectancy
direct comparison of individual adjuvant and neoadjuvant trials can be misleading because more than one-fourth of the patients in either strategy failed to complete planned therapy, and those patients often were excluded from the analysis of overall outcomes.24 In this study, we created a comprehensive, evidencebased Markov decision analytic model and compared the long-term outcomes for patients with resectable PAC treated using these two approaches. The model allowed us to simulate the spectrum of possible scenarios that patients could experience during the course of either of these treatments. Although our decision analysis favored the neoadjuvant strategy over the traditional adjuvant strategy in terms of OS and quality-adjusted survival, its real benefit appeared to be modest. The neoadjuvant strategy resulted in a median OS 2 months longer and a median qualityadjusted survival 1.4 months longer than the adjuvant strategy. To date, two meta-analyses have evaluated the outcomes of neoadjuvant therapy for PAC. Assifi et al.25 reviewed 14 phase 2 controlled trials of neoadjuvant therapy for either resectable or borderline resectable PAC, and Gillen et al.26 reviewed 111 studies. The inclusion of retrospective data and borderline resectable cases left in question which strategy is superior for potentially resectable cases based on the best available data unanswered. Pooled data from prospective controlled trials meeting our inclusion criteria indicated that neoadjuvant strategy resulted in longer baseline RFS (16.9 months) for the patients who completed the planned therapy than for those who completed the adjuvant therapy after surgical resection (13.7 months). However, 36 % of the patients assigned to the neoadjuvant strategy failed to undergo resection in our model compared with only 12 % deemed unresectable in the adjuvant strategy. This difference may reflect the patients with occult metastatic disease at presentation who were unlikely to benefit from surgery or the patients who lost the opportunity for potential curative resection due to local progression of disease only. Neoadjuvant trials have inconsistently reported the degree to which each of these possibilities accounted for failure to proceed to surgical resection. Where it has been reported, local progression is responsible in 10–16 % of cases.12,18 Notably, our decision model was sensitive to both the estimated RFS for the patients who received neoadjuvant therapy and the estimated probability that patients would fail to undergo surgical resection after neoadjuvant therapy. Although the neoadjuvant strategy provides longer survival for selected patients who undergo resection, this benefit will be attenuated when the percentage of patients who do not proceed to surgical resection exceeds the threshold rate.
G. Sharma et al.
This is likely because the number of patients who miss the opportunity for potentially curative resection due to local progression of disease during neoadjuvant therapy will increase. Our study focused on patients with resectable PAC. Those with borderline resectable PAC were excluded because this stage of disease is characterized by higher unresectability and positive margin rates than clearly resectable PAC even with aggressive vascular resection. The use of neoadjuvant therapy before surgical resection has been recommended as the preferred approach for this group of patients based on expert consensus.20,27 The radiographic criteria for ‘‘resectable’’ PAC versus ‘‘borderline resectable’’ PAC in the neoadjuvant trials, however, has not been uniformly defined. It is important to note that most of the neoadjuvant trials adopted ‘‘MD Anderson criteria,’’ whereby the tumors with superior mesenteric or portal vein (SMV/PV) abutment, impingement, and encasement are considered resectable, whereas the current National Comprehensive Cancer Network (NCCN) guideline defines such tumors as borderline unless these veins are occluded. The calculated OS for the theoretical cohort of patients in the adjuvant strategy arm of our study was shorter than in many previously reported studies. Our model was designed to follow the patients based on intention to treat. The majority of clinical trials evaluating adjuvant therapy excluded patients deemed unresectable at laparotomy and patients who could not receive adjuvant therapy due to postoperative complications.2–6,27,28 This selection bias skews direct comparison of neoadjuvant and adjuvant trials. Our model design addressed this bias by including a branch for these subgroups of patients for whom adjuvant therapy is planned but who are found to be unresectable or are precluded from receiving CT, CRT, or both after surgery. The study results must be interpreted within the context of our study design. A major limitation of our study was that estimates of QOL after pancreatic surgery or with unresectable pancreatic cancer were limited to original data from four studies and previously published extrapolations from other cancers.23 To evaluate this issue of uncertainty, we performed sensitivity analyses across a range of estimated utilities and found that these did not affect the higher quality-adjusted survival rates associated with the neoadjuvant therapy strategy. Other factors (e.g. psychological fear/concern for disease progression during neoadjuvant therapy) may have a smaller effect on utility than symptoms resulting from recurrent/persistent cancer or surgical complications (e.g., pain, pruritus) but were not included in our model. Despite these limitations, the base estimates for surgical resectability, the short-term outcomes after pancreatic
surgery, and the RFS for each case scenario were based on the best available data. Our model indicated that more than one-third of patients cannot complete planned therapy regardless of the strategy chosen. Thus, selection among treatment options should involve contingency planning and frank consideration of relative QOL among potential outcomes. CONFLICT OF INTEREST
None.
REFERENCES 1. Hernandez JM, Morton CA, Al-Saadi S, et al. The natural history of resected pancreatic cancer without adjuvant chemotherapy. Am Surg. 2010;76:480–5. 2. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230:776–82; discussion 782–774 3. Kosuge T, Kiuchi T, Mukai K, Kakizoe T. A multicenter randomized controlled trial to evaluate the effect of adjuvant cisplatin and 5-fluorouracil therapy after curative resection in cases of pancreatic cancer. Jpn J Clin Oncol. 2006;36:159–65. 4. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350:1200–10. 5. Van Laethem JL, Hammel P, Mornex F, et al. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC40013-22012/FFCD-9203/GERCOR phase II study. J Clin Oncol. 2010;28:4450–6. 6. Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival: a prospective, single-institution experience. Ann Surg. 1997;225:621–33 7. Glasgow RE, Jackson HH, Neumayer L, et al. Pancreatic resection in Veterans Affairs and selected university medical centers: results of the patient safety in surgery study. J Am Coll Surg. 2007;204:1252–60. 8. Parikh P, Shiloach M, Cohen ME, et al. Pancreatectomy risk calculator: an ACS-NSQIP resource. HPB 2010;12:488–97. 9. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15:928–37. 10. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3496–502. 11. Heinrich S, Schafer M, Weber A, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg. 2008;248:1014–22. 12. Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson AB III. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study. J Clin Oncol. 1998;16:317–23. 13. Joensuu TK, Kiviluoto T, Karkkainen P, et al. Phase I–II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended
Pancreatic Cancer Therapy: Decision Analysis
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
lymphadenectomy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;60:444–52. Le Scodan R, Mornex F, Girard N, et al. Preoperative chemoradiation in potentially resectable pancreatic adenocarcinoma: feasibility, treatment effect evaluation and prognostic factors, analysis of the SFRO-FFCD 9704 trial, and literature review. Ann Oncol. 2009;20:1387–96. Palmer DH, Stocken DD, Hewitt H, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol. 2007;14:2088–96. Pisters PW, Wolff RA, Janjan NA, et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J Clin Oncol. 2002;20:2537–44. Talamonti MS, Small W Jr, Mulcahy MF, et al. A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol. 2006;13:150–8. Turrini O, Viret F, Moureau-Zabotto L, et al. Neoadjuvant 5-fluorouracil-cisplatin chemoradiation effect on survival in patients with resectable pancreatic head adenocarcinoma: a tenyear single institution experience. Oncology. 2009;76:413–9. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3487–95. Abrams RA, Lowy AM, O’Reilly EM, Wolff RA, Picozzi VJ, Pisters PW. Combined modality treatment of resectable and borderline resectable pancreas cancer: expert consensus statement. Ann Surg Oncol. 2009;16:1751–6. Lowy AM, Lee JE, Pisters PW, et al. Prospective, randomized trial of octreotide to prevent pancreatic fistula after pancreaticoduodenectomy for malignant disease. Ann Surg. 1997;226: 632–41. Glimelius B, Hoffman K, Sjoden PO, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7:593–600. Weinberg BM, Spiegel BM, Tomlinson JS, Farrell JJ. Asymptomatic pancreatic cystic neoplasms: maximizing survival and quality of life using Markov-based clinical nomograms. Gastroenterology. 2010;138:531–40. Hoffman JP, Stitzenberg KB. Preoperative versus postoperative adjuvant therapy for adenocarcinoma of the pancreas. Adv Surg. 2009;43:189–98. Assifi MM, Lu X, Eibl G, Reber HA, Li G, Hines OJ. Neoadjuvant therapy in pancreatic adenocarcinoma: a meta-analysis of phase II trials. Surgery. 2011;150:466–73. Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7:e1000267.
27. Lopez NE, Prendergast C, Lowy AM. Borderline resectable pancreatic cancer: definitions and management. WJG World J Gastroenterol. 21 2014;20:10740–51. 28. McPhee JT, Hill JS, Whalen GF, et al. Perioperative mortality for pancreatectomy: a national perspective. Ann Surg. 2007;246: 246–53. 29. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. 2002;95: 1685–95. 30. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297:267–77. 31. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299:1019–26. 32. Ueno H, Kosuge T, Matsuyama Y, et al. A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer. 2009;101:908–15. 33. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304:1073–81. 34. Arias E. United States life tables, 2004. Natl Vital Stat Rep. 2007;56:1–39. 35. Patel SR, Vadhan-Raj S, Papadopolous N, et al. High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies—dose-response and schedule dependence. J Clin Oncol. 1997;15:2378–84. 36. Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al. Thinsection contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg. 1994;167:104–11; discussion 111–103 37. Neoptolemos JP, Stocken DD, Tudur Smith C, et al. Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials. Br J Cancer. 2009;100:246–50. 38. Henricks WH, Chu YC, Goldblum JR, Weiss SW Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol. 1997;21:271–81. 39. Evans DB, Pisters PW, Lee JE, et al. Preoperative chemoradiation strategies for localized adenocarcinoma of the pancreas. J Hepatobiliary Pancreat Surg. 1998;5:242–50.
