Background
Methods
Search strategy
Inclusion and exclusion criteria
Data extraction and definitions
Statistical methods
Results
Patient and study characteristics
N
| % | |||
---|---|---|---|---|
Total number of studies included | 96 | |||
Original articles | 82 | 85.4 | ||
Abstracts | 14 | 14.6 | ||
Year of publication | ||||
2009 | 6 | 6.3 | ||
2010 | 7 | 7.3 | ||
2011 | 8 | 8.3 | ||
2012 | 12 | 12.5 | ||
2013 | 17 | 17.7 | ||
2014 | 29 | 30.2 | ||
2015 | 17 | 17.7 | ||
Global distribution of location of institutions of selected studies | ||||
North America | 54 | 56.3 | ||
Europe | 21 | 21.9 | ||
Asia | 18 | 18.7 | ||
Australia/Africa/South America (1 each) | 3 | 3.1 | ||
Single vs multi-institutional | ||||
Single institution | 83 | 86.5 | ||
Multi-institutional | 13 | 13.5 | ||
Type of study | ||||
Retrospective series | 54 | 56.3 | ||
Phase 2 studies | 22 | 22.9 | ||
Prospective series | 11 | 11.5 | ||
Phase 1 studies | 5 | 5.2 | ||
Phase 1/2 studies | 3 | 3.1 | ||
Phase 3 studies | 1 | 1 | ||
Criteria for resectability | ||||
NCCN/AHPBA/SSO/SSAT consensus | 38 | 39.6 | ||
MD Anderson | 8 | 8.3 | ||
Other | 29 | 30.2 | ||
Not mentioned | 21 | 21.9 | ||
Number of studies of each local/anatomical stage | ||||
Resectable | 18 | 18.8 | ||
Borderline resectable (BR) | 15 | 15.6 | ||
Locally advanced unresectable (LA) | 29 | 30.2 | ||
R + BR | 5 | 5.2 | ||
BR + LA | 24 | 25 | ||
R + BR + LA | 5 | 5.2 | ||
Number of patients in each anatomical stage | ||||
Resectable | 1056 | 19.1 | ||
Borderline resectable (BR) | 935 | 16.9 | ||
Locally advanced unresectable (LA) | 1840 | 33.3 | ||
R + BR | 202 | 3.7 | ||
BR + LA | 1014 | 18.4 | ||
R + BR + LA | 473 | 8.6 | ||
Criteria for of radiology response assessment | ||||
RECIST | 48 | 50 | ||
WHO | 5 | 5.2 | ||
Other | 2 | 2.1 | ||
Not mentioned | 41 | 42.7 | ||
Criteria for toxicity assessment | ||||
NCI CTCAE | 43 | 44.8 | ||
WHO | 5 | 5.2 | ||
RTOG | 2 | 2.1 | ||
Not mentioned/not applicable | 46 | 47.9 | ||
Type of neoadjuvant therapy | ||||
Chemoradiotherapy | 33 | 34.4 | ||
Chemotherapy alone | 20 | 20.8 | ||
Chemotherapy with chemoradiation | 41 | 42.7 | ||
Radiation alone | 2 | 2.1 | ||
Chemotherapy drugs | ||||
Monotherapy (Gem/5FU/Cape/UFT/Cis) | 26 | 27.1 | ||
FOLFIRINOX | 20 | 20.8 | ||
Gemcitabine + oxaliplatin* | 8 | 8.3 | ||
Gemcitabine or 5FU + cisplatin | 7 | 7.3 | ||
Gemcitabine + Docetaxel | 3 | 3.1 | ||
GTX (gemcitabine, taxane, capecitabine) | 6 | 6.3 | ||
Gem + biologic (bevacizumab, cetuximab) | 3 | 3.1 | ||
Gem + S1 | 5 | 5.2 | ||
Gem + Nab-paclitaxel | 2 | 2.1 | ||
5FU + cisplatin + interferon | 1 | 1 | ||
Multiple | 11 | 11.5 | ||
Not mentioned | 2 | 2.1 | ||
None | 2 | 2.1 | ||
Radiotherapy | ||||
Yes | 76 | 79.2 | ||
No | 20 | 20.8 |
Toxicity
Grade 3 or higher toxicities | Number of studies reporting the studied outcome | % | 95% confidence interval |
---|---|---|---|
Overall | 39 | 36% | 27–45% |
Hematologic | 16 | 25% | 14–38% |
Anemia | 33 | 4% | 3–6% |
Leukopenia | 26 | 25% | 18–32% |
Lymphopenia | 8 | 13% | 4–24% |
Neutropenia | 38 | 23% | 17–29% |
Febrile neutropenia | 17 | 3% | 1–5% |
Thrombocytopenia | 41 | 7% | 5–10% |
Non hematologic | 17 | 16% | 7–27% |
Nausea/vomiting | 40 | 7% | 4–10% |
Diarrhea | 38 | 4% | 2–6% |
Anorexia | 19 | 3% | 1–6% |
Fatigue | 26 | 4% | 1–7% |
Biliary obstruction/cholangitis | 22 | 5% | 3–7% |
GI bleed, gastritis, or duodenitis, | 14 | 3% | 1–7% |
Hospitalization rate | 15 | 21% | 14–27% |
% of patients completing neoadjuvant therapy | 42 | 90% | 87%–93% |
Mortality | 48 | 0% | 0–1% |
Radiologic response
Radiologic response | ||||
---|---|---|---|---|
Complete response | Partial response | Stable disease | Progressive disease | |
Resectable |
0%
|
11%
|
77%
|
11%
|
[0–0%] | [8–16%] | [62–89%] | [4–19%] | |
I
2 = 0% |
I
2 = 10.6% |
I
2 = 85.12% |
I
2 = 82.31% | |
(n = 8) | (n = 8) | (n = 9) | (n = 11) | |
Borderline resectable |
1%
|
20%
|
56%
|
19%
|
[0–4%] | [8–35%] | [47–64%] | [11–28%] | |
I
2 = 52.03% |
I
2 = 84.28% |
I
2 = 33.25% |
I
2 = 58.95% | |
(n = 8) | (n = 8) | (n = 8) | (n = 9) | |
Locally advanced |
1%
|
28%
|
48%
|
20%
|
[0–3%] | [21–35%] | [38–58%] | [13–29%] | |
I
2 = 57.02% |
I
2 = 82.61% |
I
2 = 88.09% |
I
2 = 89.43% | |
(n = 17) | (n = 19) | (n = 17) | (n = 18) | |
BR + LA |
0%
|
20%
|
59%
|
14%
|
[0–1%] | [11–31%] | [49–69%] | [8–22%] | |
I
2 = 7.57% |
I
2 = 84.70% |
I
2 = 76.89% |
I
2 = 72.59% | |
(n = 16) | (n = 16) | (n = 16) | (n = 16) | |
All patients | 0% |
20%
|
59%
|
16%
|
[0–1%] | [16–25%] | [54–65%] | [12–20%] | |
I
2 = 38.25% |
I
2 = 81.52% |
I
2 = 85.12% |
I
2 = 82.84% | |
(n = 52) | (n = 56) | (n = 56) | (n = 62) |
Exploration and resection rates
Surgical treatment | Explored/N
| Resected/N
| R0/N
| Resected/explored | R0/resected |
---|---|---|---|---|---|
Resectable |
86%
|
76%
|
63%
|
92%
|
88%
|
[79–92%] | [68–84%] | [51–75%] | [85–97%] | [80–94%] | |
I
2 = 83.91% |
I
2 = 86.02% |
I
2 = 90.69% |
I
2 = 83.37% |
I
2 = 81.82% | |
(n = 18) | (n = 18) | (n = 14) | (n = 18) | (n = 14) | |
Borderline resectable |
77%
|
69%
|
54%
|
91%
|
84%
|
[66–86%] | [59–78%] | [37–71%] | [84–96%] | [67–96%] | |
I
2 = 87.62% |
I
2 = 88.98% |
I
2 = 95.15% |
I
2 = 70.68% |
I
2 = 93.75% | |
(n = 15) | (n = 18) | (n = 16) | (n = 15) | (n = 16) | |
Locally advanced |
32%
|
26%
|
23%
|
86%
|
82%
|
[23–42%] | [19–34%] | [15–33%] | [73–95%] | [69–93%] | |
I
2 = 91.44% |
I
2 = 89.42% |
I
2 = 91.18% |
I
2 = 86.04% |
I
2 = 82.75% | |
(n = 22) | (n = 24) | (n = 18) | (n = 19) | (n = 15) | |
BR + LA |
65%
|
53%
|
39%
|
89%
|
85%
|
[49–79%] | [36–70%] | [27–52%] | [80–96%] | [79–90%] | |
I
2 = 95.67% |
I
2 = 96.04% |
I
2 = 92.74% |
I
2 = 85.80% |
I
2 = 35.55% | |
(n = 20) | (n = 22) | (n = 20) | (n = 19) | (n = 19) | |
All patients |
64%
|
55%
|
45%
|
91%
|
85%
|
[57% -71%] | [48–62%] | [38–52%] | [87–94%] | [80–89%] | |
I
2 = 95.27% |
I
2 = 95.34% |
I
2 = 94.94% |
I
2 = 84.53% |
I
2 = 85.05% | |
(n = 84) | (n = 90) | (n = 74) | (n = 79) | (n = 70) |
Pathologic response
Surgical morbidity and mortality
Overall survival
Overall survival (months) | ||||
---|---|---|---|---|
All patients | Resected | Not resected | ||
Resectable | Median (range) | 18.2 (13–28) | 30.0 (24.5–46) | 10 (9–11) |
n
| 9 | 8 | 5 | |
Borderline resectable | Median (range) | 19.2 (9.1–45) | 27.4 (19.3–41.2) | 12.9 (9–15.5) |
n
| 11 | 8 | 7 | |
Locally advanced | Median (range) | 13.6 (7.3–32.5) | 18.7 (14.4–24.9) | 12.6 (8–19.7) |
n
| 28 | 8 | 7 | |
BR + LA | Median (range) | 14.7 (10.6–47.2) | 26 (13–47.4) | 12.4 (8.8–17) |
n
| 16 | 11 | 9 | |
All patients | Median (range) | 15.3 (7.3–47.2) | 24.4 (11.7–47.4) | 11.5 (5.7–19.7) |
n
| 63 | 39 | 32 | |
Progression-free survival (months) | ||||
All patients | Resected | Not resected | ||
Resectable | Median (range) | 8.4 (6.2–10.4) | 14.9 (8.4–23) | 11*
|
n
| 2 | 4 | 1 | |
Borderline resectable | Median (range) | 9 (2.4–21.1) | 15.4 (4.7–23.2) | 2.1*
|
n
| 6 | 6 | 1 | |
Locally advanced | Median (range) | 9.3 (4–17.6) | 12.9 (9.6–22.5) | 5.7 (4–8) |
n
| 20 | 6 | 3 | |
BR + LA | Median (range) | 9.9 (6.5–27.4) | 12.5 (9–19.7) | 7.5 (7.1–7.6) |
n
| 9 | 4 | 2 | |
All patients | Median (range) | 9.3 (2.4–27.4) | 12.9 (4.7–23.2) | 5.8 (2.1–11) |
n
| 31 | 20 | 7 |