A Systematic Review of Resectability and Survival After ... - Springer Link

Ann Surg Oncol (2010) 17:194–205 DOI 10.1245/s10434-009-0762-4

ORIGINAL ARTICLE – RADIATION ONCOLOGY

A Systematic Review of Resectability and Survival After Concurrent Chemoradiation in Primarily Unresectable Pancreatic Cancer Alessio G. Morganti, MD1,2, Mariangela Massaccesi, MD1, Giuseppe La Torre, MD3, Luciana Caravatta, MD1, Adele Piscopo, MD1, Rosa Tambaro, MD2, Luigi Sofo, MD4, Giuseppina Sallustio, MD5, Marcello Ingrosso, MD6, Gabriella Macchia, MD1, Francesco Deodato, MD1, Vincenzo Picardi, MD1, Edy Ippolito, MD1, Numa Cellini, MD7, and Vincenzo Valentini, MD7 1

Department of Radiation Oncology, ‘‘John Paul II’’ Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy; 2Department of Palliative Therapies, ‘‘John Paul II’’ Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy; 3Unit of Clinical Medicine and Public Health, Sapienza University of Rome, Rome, Italy; 4Department of Surgery, ‘‘John Paul II’’ Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy; 5 Department of Radiology, ‘‘John Paul II’’ Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy; 6Department of Endoscopy, ‘‘John Paul II’’ Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy; 7Department of Radiotherapy, Policlinico Universitario ‘‘A. Gemelli,’’ Catholic University, Rome, Italy

ABSTRACT Purpose. The objective of this study was to determine the effect on resection rate and survival of neoadjuvant chemoradiotherapy for primarily unresectable locally advanced pancreatic carcinoma. Methods. A systematic review of recently published literature was performed. Resection rates and survival data were derived from reports published from 2000 onwards. Only recent studies, based on radiotherapy with standard dose and fractionation, have been analyzed. Results. Thirteen studies with a total of 510 patients met selection criteria. A resection rate of 8.3–64.2% was reported (median, 26.5%). Of the operated patients, 57.1– 100% (median, 87.5%) had R0 tumor resection. Most papers reported occasional pathological complete responses (CR, 3.0–8.8%). When outcome in all patients was considered, median survival ranged from 9 to 23 (median, 13.3) months, comparing favorably with literature data based on concurrent chemoradiation alone (range, 8.6–

Society of Surgical Oncology 2009 First Received: 21 May 2009; Published Online: 24 October 2009 G. Macchia, MD e-mail: [email protected]

13 months). Surprisingly, in patients with unresectable tumor at presentation, median survival after surgery ranged from 16.4 to 32.3 (median, 23.6) months. Conclusions. The finding of a high proportion of R0 resection among all resections performed confirms the activity of neoadjuvant radiochemotherapy and should not be neglected. Based on these data, patients with unresectable pancreatic cancer without disease progression after chemoradiotherapy should be considered for radical surgery.

Approximately 10 new cases of pancreatic cancer are diagnosed per 100,000 person-years in western countries.1,2 For these patients, radical surgery, achieving tumor-free margins (R0), represents the only chance of cure.3 Unfortunately, at presentation, only 10–20% of patients with pancreatic adenocarcinoma have potentially resectable tumors. The prognosis is always dismal. Even if pancreatic cancer is discovered at a resectable stage, only one or two of 10 patients are expected to survive for more than 5 years after curative resection.4–8 Advanced locoregional disease, precluding complete resection, is found in 40% of patients at presentation.9 Until recently, for this subset of patients, the standard practice has been to give chemoradiation with concurrent 5-fluorouracil therapy, as shown by two randomized studies.10,11 The standard

Preoperative Chemoradiation in Unresectable Pancreatic Cancer

practice began to be questioned since the preliminary publication of the Federation Francophone de Cancerologie Digestive-Socie´te´ Française de Radiothe´rapie Oncologie group’s FFCD-SFRO trial.12 In this latter study, a statistically significant advantage in survival together with better tolerability was described with gemcitabine-based chemotherapy alone as compared with an intensive regimen consisting of high-dose radiotherapy delivered concurrently with cisplatinum and 5-fluorouracil plus sequential gemcitabine. However, different results have been reported in a study, recently presented at the American Society of Clinical Oncology (ASCO) annual meeting, which compared gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with locally advanced pancreatic cancer.13 Addition of radiation therapy to gemcitabine significantly improved overall survival (P = 0.034) and tripled the survival rate at 24 months. Irrespective of adopted treatment strategy, in patients with unresectable locoregionally advanced pancreatic cancer, prognosis continues to be disappointing, with median survival ranging from 8 to 14 months.10–13 With rare exceptions, all patients will ultimately succumb to their disease, with practically no chance to be alive after 3 years. Nevertheless, the possibility of a small number of longterm survivors among this subset of patients has been described by several investigators after radical resection following preoperative chemoradiotherapy.14–19 Preoperative treatment in patients deemed to have unresectable pancreatic cancer at presentation may theoretically produce tumor downsizing and downstaging and allow for R0 tumor resection, thus improving chances of survival. Demonstrated advantages of preoperative chemoradiation strategy for pancreatic cancer also include the assurance that all resected patients receive multimodality therapy, and the possibility of occult metastases to become manifest. Ultimately, efficacy will be higher because chemotherapy and radiation treatment would be free of the postoperative drawbacks due to decreased oxygenation and drug delivery to the tumor bed.20 Furthermore, the periphery of the tumor, which is obviously important from a surgical perspective, is most likely to respond to radiochemotherapy because of better oxygenation. However, several authors reported a very low (\10%) rate of tumor resections in patients evaluated for surgery after chemoradiation.21–24 Therefore, the real impact of neoadjuvant combined modality therapy on resectability has been questioned.22 In this report only recent studies, based on radiotherapy with standard dose and fractionation, have been analyzed. The primary objective of this report was to conduct a systematic review of the recent literature (published from 2000 onwards) to assess the impact of preoperative combined chemoradiotherapy on resection rate and survival in patient with locally advanced pancreatic carcinoma.

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MATERIALS AND METHODS Criteria for Considering Studies to Be Included in this Review Type of Studies Clinical trials, whether or not randomized, in which an evaluation for surgery was systematically performed after combined chemoradiotherapy, were identified and assessed for inclusion. Types of Participants Patients with a diagnosis of pancreatic adenocarcinoma based on histological or cytological findings (investigations on body tissue or cells) were included. Trials enrolling patients with locally advanced/unresectable pancreatic adenocarcinoma were eligible for inclusion. Type of Interventions Radiotherapy Eligible interventions included megavoltage external-beam radiotherapy based on standard radiotherapy doses and fractionation (total dose: C45 Gy, dose/1.8–2 Gy daily fraction) delivered concurrently with chemotherapy. Chemotherapy Eligible interventions included both single-agent and combination chemotherapy. Chemotherapy with all cytotoxic or antineoplastic drug treatments, but excluding hormonal and biological therapies (e.g., interferon, somatostatin), was eligible regardless of dose or schedule. Chemotherapy had to be delivered concurrently with radiotherapy. Further chemotherapy administered sequentially to radiotherapy was allowed. Supportive care in advanced disease, defined as anything other than chemotherapy, including symptom control by palliative surgery, biliary stent insertion, analgesia, blood transfusion, and psychological/social support was allowed. Type of Outcome Measures The primary outcome assessments were the resection rate after preoperative chemoradiotherapy on an intention-to-treat analysis and duration of survival of resected patients measured by median survival time and 3-year survival rate. Secondary outcomes of interest included the following end points: duration of survival of unresected patients and in the overall population measured by the median survival time and 3-year survival rate; clinical response, resectability rate, and rate of radically (R0) resected tumors assessed on an intention-to-treat analysis; rate of radically (R0) resected tumors evaluated among all performed resections; perioperative mortality computed among all surgical explorations performed after the preoperative treatment.

196

A. G. Morganti et al.

Search Methods for Identification of Studies The authors targeted broad searches that would identify all relevant published clinical trials. Articles published in any language were eligible for inclusion. Literature searches were made in the PubMed, Cochrane Central register of Controlled Trials, National Cancer Institute and Clinical Trial Registry electronic database (2000 to March 2009). Published abstracts from the following conference proceedings also were searched: • •

American Society of Clinical Oncology (ASCO) annual meeting (2000–2008) American Society for Therapeutic Radiology and Oncology (ASTRO) annual meeting (2000–2008)

The search strategy was based on the following search terms: ‘‘unresectable’’ or ‘‘loco-regionally advanced’’ or ‘‘locally advanced’’ in combination with ‘‘pancreatic cancer’’ or ‘‘pancreas,’’ and with ‘‘radiotherapy,’’ or ‘‘chemotherapy,’’ or ‘‘chemoradiation,’’ or ‘‘chemoradiotherapy.’’ Trial Selection and Quality Assessment Trials were selected for inclusion by two independent authors (MM and AP), with disagreements resolved by a third author (AGM). Data were extracted from published reports by pairs of reviewers using standardized forms, with disagreements resolved by discussion with the additional reviewer (AGM). The quality of evidence provided was classified according to the criteria of the Scottish Intercollegiate Guidelines Network (SIGN).25 Briefly, SIGN level of evidence 1 is provided by meta-analyses, 2 by case control or cohort studies, 3 by nonanalytic studies like case report and case series, and 4 by expert opinion. Level of evidence 1 and 2 are subgraded according to the risk of bias or confounding selected studies. Statistical Analysis For the selected outcomes, central tendency (median and weighted average of the medians) and dispersion (range) measures were calculated, for all studies and for selected groups. Differences between groups for qualitative and quantitative variables were assessed with the chi-square and Mann–Whitney tests, respectively. The statistical significance was set at P B 0.05. RESULTS Description of Studies Through the step of screening the title and the abstract, 30 papers were identified.14–24,26–44 Four series

were excluded due to use of rapid-fractionated radiotherapy.22,24,32,37 Three papers were excluded because of low total radiation doses used.16,23,30 Seven other papers were excluded due to lack of systematic evaluation for surgery after chemoradiation.21,33,40–44 Two studies were excluded because they were part of a much wider study.20,34 One study was excluded because the type of neoadjuvant treatment was not clearly specified.38 Therefore, 13 papers fulfilled the inclusion criteria and were included in our review (Table 1), amounting to 510 patients.14,15,17–19,26–29,31,35,36,39 No meta-analysis, systematic reviews of randomized controlled trial, randomized controlled trials, or case control studies were retrieved. Most papers were case series.14,17–19,27–29,36,39 Most studies had a prospective design.14,15,17,27–29,31,35,36,39 Three series were retrospective.18,19,27 Three cohort studies comparing outcome of primarily resected patient versus outcome of those undergoing secondary surgery were identified.15,31,35 These cohort studies, because of substantial heterogeneity among groups of enrolled patients and thus high risk of confusion or bias, were classified to provide a level of evidence graded as 2, according to SIGN classification.25 Therefore, the highest level of evidence provided was 2, according to SIGN classification.25 Type of Interventions Radiotherapy Megavoltage external-beam radiotherapy, based on standard fractionation (1.8 or 2 Gy daily fraction) was delivered up to a total dose ranging from 45 to 55.8 (median, 50.2) Gy to the Gross Tumor Volume. Elective irradiation of regional lymph nodes was invariably performed up to a total dose of 45 Gy except in the study by Crane and coworkers, in which treatment was delivered to the gross tumor only.39 A split course regimen was adopted in all 68 patients of the series by Snady and coworkers 15 and in 6 of 33 patients of the series by Adhoute and colleagues.19 A three-dimensional conformal technique was used in almost all series.17–19,27–29,31,35,36,39 Radiotherapy technique was not specified in three trials.14,15,26 Chemotherapy Chemotherapy mostly consisted of multidrug schedules.14,15,17–19,27–29,31,35,36,39 Only White and coworkers used 5-fluorouracil alone.26 5-fluorouracil-based regimens were used in five trials.14,15,18,19,27 5-fluorouracil was mostly combined with cisplatin or oxaliplatin.14,15,18,19 Gemcitabine-based combinations were used in four trials.28,29,35,36 5-fluorouracil and gemcitabine were both administered concurrently with radiotherapy in one study.29 In the series by Aristu and colleagues, various regimens, including 5-fluorouracil and gemcitabine, were delivered concomitantly to radiotherapy.17 Sequential chemotherapy (in adjunction to concurrent chemotherapy) was administered before surgery in five series.28,29,31,35,36

Group Hospitalier Sud, Bordeaux, Pessac

Sa Cunha (2005)

Retrospective case series

Prospective case series

University Hospital Grosshadern, Munich, Germany

University of Navarra, Pamplona, Spain

Duke University Medical Center, Durham, NC, USA

Mt. Sinai Medical Center, New York, NY, USA

Wilkowski (2004)


Aristu (2003)


White (2001)

Prospective cohort study

Snady (2000)


Wanebo (2000)

Boston University School of Medicine, Roger Williams Medical Center, Providence, RI, USA

University Erlangen, Germany

Brunner (2000)


Medical center

Authors (year) Type of study

TABLE 1

18

28

17

26

15

14

27

3

3

3

3

2-

3

3

Reference Level of evidence (SIGN)

61

47

49

58

68

14

29

45–50 Gy, 1.8–2 Gy/ day

45 Gy, 1.8 Gy/day

5-FU/CDDP

Gem/CDDP ? Subsequent two cycles of induction Gem/ CDDP

CDDP/5FU±Paclitx or CDDP/5-FU (protracted infusion); or Gem/Docetx

5-FU

NA NA NA NA

Metastatic Not evaluable

62

23 38

Not responding

38 0

4 Responding

2

NA NA


13

27

68 27

0

4

55

41 12

3

19

Not responding

32

0 Responding

2 Not evaluable

27

20 Metastatic

Not responding

Responding

2

11


NA NA

NA NA 6

0

10 0

7

Not responding

Responding

Not evaluable

NA

67 22

10

10

22

3

Not evaluable Not performed

46

3

Metastatic

24

55 NA

0

57

24

10

32

NA

NA

Resectable %

15

7

16

No. %

Not responding

Responding

Response

Clinical reevaluation

54 Gy, 2 Gy/ 5-FU/CDDP/ Strept Responding day in 3 Not responding split courses Metastatic

Arterial encasement of CA 45 Gy, or SMA or PV 1.8 Gy/day thrombosis

PV, SMA, SMA or CA involvement

CA or SMA involvement, or occlusion of the SMV–PV confluence

5-FU/Mito

Concurrent chemotherapy

45 Gy, 1.8 Gy/ 5-FU/CDDP day

55.8 Gy, 1.8 Gy/day

Radiotherapy: dose, fractionation

Presence of soft tissue 45 Gy abutting or encircling the ±5.4 Gy SMA or CA or occlusion boost, 1.8 of the SMV or PV Gy/day

Vascular invasion

Not clearly defined

Semicircular encasement, stenosis or occlusion of peripancreatic vessels

No. Unresectability criteria

Preoperative Chemoradiation in Unresectable Pancreatic Cancer 197


Crane (2006)


Marti (2008)


Lind (2007)


MD Anderson Cancer Center, Houston, TX, USA

NYU Cancer Institute, New York University school of Medicine, New York, NY, USA

Dept. of Oncology, Karolinska-Stockholm Soder Hospital, Stockholm, Sweden

Institute for Research and Cure of Cancer, Candiolo, Italy

Massucco (2006)


University Hospital Grosshadern, Munich, Germany

Wilkowski (2006)

39

36

31

35

29

3

3

2-

2-

3

3

19

Hoˆpital Haut-Le´veˆque, CHU de Bordeaux, Pessac.

Adhoute (2006)


Reference Level of evidence (SIGN)

Medical center


TABLE 1 continued

48

26

17

28

32

33

Radiotherapy: dose, fractionation

50.4 Gy, 1.8 Gy/day

Bevacizumab ?Capecit

CDDP/Gem ? two cycles of induction CDDP/Gem

Capecit/Oxa ? two cycles of induction Capecit/Oxa

45 Gy; 1.8 Gy/ Gem ? two day cycles of induction Oxa/ Gem (5 patients)

Tumor extension to the CA 50.4 Gy, or SMA or evidence of 1.8 Gy/day occlusion of the SMV or PV-SMV confluence

Involvement of SMA, SMV, CA, PV-SMV confluence.

5-FU/CDDP

Concurrent chemotherapy

45–50 Gy, 1.8– Gem/5-FU ? 2 Gy/day subsequent two cycles of induction Gem/CDDP

Regional vascular 50.4 Gy, invasiveness in the form 1.8 Gy/day of encasement of C 50% of the circumference for a distance C2 cm

Borderline resectable: CA or SMA abutment, stenosis of SMV or PV; Unresectable: CA or SMA encasement or thrombosis of SMV or PV

PV, SMA, SMA or CA involvement

Vascular extension 45–50.4 Gy, invading or encasing the 1.8–2 Gy/ celiomesenteric arterial die; split trunk and/or the course in 6 mesentericoportal patients junction circumscribing tumor [180, venous contact [2 cm, and/or nodal extension reaching the second or third nodal relay

No. Unresectability criteria

0

Not evaluable

0

Not evaluable

62 12

8

2

4

NA NA Not evaluable

Metastatic

77

19 4 37

9

2 Not responding

Responding

Not evaluable

77

20

NA NA

Metastatic

15 4

0

29

0

69 NA

18

11

64

18 NA

0

0

37

Not responding

4

5

Metastatic Responding

0

Not responding

11

5

Not evaluable

Responding

3

18 Metastatic

Not responding

5

0

Metastatic

20 12

Not responding

Responding

27

8

15

NA

NA

37

3

Resectable %

30 1 42

NA NA

9

14

10

No. %

Responding

Not evaluable

Metastatic

Not responding

Responding

Response

Clinical reevaluation

198 A. G. Morganti et al.

10

Brunner (2000)


8

50

8

50

NA

NA

0

NA

3

0

0/11

1/8

NA/9

0/10

0/23

0

13

nr

0

0

21

13.6

All Resected

13

Not resected

16.4

16

All Resected

NA

Not resected

NA

All Resected

NA NA

Not resected

28

All Resected

7.4 10.7

Not resected

NA NA

Not resected All

Lind (2007)

0

NA

1

0

0

15.4 29

25

12

21

18

0/25

All Resected

7

4

7

11

NA

23

All Resected

NA NA

Not resected

10

29

22

24

21

NA

6

Not reached after 16 month follow-up

23.6

All Resected

21.2

Not resected

32.3

NA

All Resected

19 9

9

All Resected Not resected

NA

NA

Median survival (mo)

Not resected

Resected

Status

Survival

Not resected

8

7

8

13

28

2/33

0

6

9

0

%


Massucco (2006)


Wilkowski (2006)


Adhoute (2006)


Sa Cunha (2005)


13

4

0/28

2/30

1/11

0/16

Perioperative deaths/ No. of surgical interventions

11 24.2

42

2

9

7

3

NA

%

All Resected

20

nr

NA

6

1

1

Pathological CR

Wilkowski (2004)

NA

14

28

58

34

%

10

18

8

19

8

10

Resected (R0)

Not resected

9

19

29

64

34

%


Aristu (2003)


White (2001)

11

20

Snady (2000)


9

Wanebo (2000) Prospective case series


Resected


TABLE 1 continued

NA

NA

NA NA

NA

NA

8

NA

NA

NA

0

73

NA

NA

37

NA

NA

NA NA

NA

48

NA

NA

NA

21

13

32

NA

NA NA

NA

NA

NA

3-year survival(%)

Preoperative Chemoradiation in Unresectable Pancreatic Cancer 199

NA not available, 5-FU 5-fluorouracil, Gem gemcitabine, CDDP cisplatin, Strept streptozocina, Paclitx paclitaxel, Docetx docetaxel, Capecit capecitabine, Oxa oxaliplatino, SIGN Scottish Intercollegiate Guidelines Network, SMA superior mesenteric artery, SMV superior mesenteric vein, PV portal vein, CA celiac axis

NA NA All

NA

NA NA NA NA

13

Resected Not resected 0 8

15

4 Crane (2006) Prospective case series


Marti (2008)

4

3

4

11

8

0

0

0/4

All

NA NA

NA

Resected 0 0

0

0/4

Not resected

Median survival (mo) Status

Survival %

Perioperative deaths/ No. of surgical interventions % Pathological CR % Resected (R0) % Resected Authors (year) Type of study

TABLE 1 continued

NA


3-year survival(%)

200

Resection Rate Data about resection rate after preoperative chemoradiotherapy were provided by all series. A resection rate of 8.3–64.2% was reported (median, 26.5%; weighted average, 27%), with 8.3–57.1% of enrolled patients (median, 23.1%; weighted average, 22.1%) having R0 tumor resection.14,15,17–19,26–29,31,35,36,39 R0/total resections rate ranged from 57.1 to 100% (median, 87.5).14,15,19,26–29,31,35,36,39 Several papers reported that some patients had complete pathological response (3.0– 8.8%).14,15,17,19,27 In 188 of 510 patients treated with radiation doses C50 Gy resection rate was 24.4%; in 322 of 510 patients who received radiation doses \50 Gy resection rate was 26.3% (P = not significant). Gemcitabine-based treatment resulted in a median resection rate of 25.5% (weighted average, 29.3%) vs. 26.5% (weighted average, 25.3%) for gemcitabine-free treatment.14,15,18,19,26–29,31,35,36,39 Induction chemotherapy in addition to chemoradiotherapy resulted in a median resection rate of 29% (weighted average, 31.3%) vs. 22.5% (weighted average, 23.3%) for chemoradiotherapy alone.14,15,17–19,26–29,31,35,36,39 Survival When considering outcome in all patients group, the median survival ranged from 9.0 to 23.6 months (median, 13.3 months; weighted average, 14.9 months).15,17,19,27,28,29,31,35,36 Median survival ranged from 16.4 to 32.3 months (median, 23.6 months; weighted average, 25.4 months) in resected patients and from 7.4 to 21.2 months (median, 10.0 months; weighted average, 13 months) in unresected patients.14,15,17,18,28,29,31,35 Three-year survival of resected patients varied from 32 to 73% (median, 42.5%; weighted average, 44%). Considering only studies with level 2 evidence, median survival ranged from 21 to 32.3 months (median, 29 months; weighted average, 29 months) in resected patients, and from 10 to 21.2 months (weighted average, 17.9 months) in unresected patients.14,31,35 In the group of resected patients, gemcitabine-based treatment resulted in a median survival time of 21 months (weighted average, 21) vs. 28 months (weighted average, 27.7) for gemcitabine-free treatment (P = 0.18); in unresected patients, 10 months (weighted average, 9.76) vs. 10 months (weighted average, 15.7; P = 0.658); in the whole group, 13.3 months (weighted average 12.8) vs. 13.5 months (weighted average, 16.4; P = 0.886). DISCUSSION Patients with unresectable pancreatic carcinoma have a dismal prognosis. Using standard chemoradiation, a median survival of 8–12 months may be predicted.10–13 Combined modality treatment based on neoadjuvant


chemoradiation followed by surgical resection is a theoretically promising strategy. However, several studies published in the 1980s and 1990s showed a poor clinical response rate (overall response rate, 0–36%; complete response rate, 0–10%), based on imaging reevaluation after chemoradiation.45–47 Therefore, radiochemotherapy was considered to be relatively uneffective for resectability improvement. However, some experiences questioned the sensitivity of imaging studies in tumor response evaluation.48,49,50 Hoffman and colleagues measured by CT scan the clinical response after concurrent chemoradiation in a group of 62 patients.49 Clinical response rate was only 7%. However, all patients underwent surgical resection, and pathological examination of the specimen revealed a significant tumor response in 71% of cases. Other reports showed not only a poor response rate, but also a poor rate of patients treated with resection after chemoradiation. Kim et al. reported only 1% of patients undergoing a potentially curative pancreaticoduodenectomy.22 However, it should be noted that in this series not all patients underwent reevaluation for surgery after chemoradiation. Kornek and colleagues, despite an encouraging 47% response rate recorded after concurrent chemoradiation based on cisplatin and 5-fluorouracil, reported only 8% of patients treated with an R0 resection.21 However, as stated by the authors, the potential rate of technically feasible resections could have been underestimated because of an a priori exclusion from surgery of those patients who showed major vessels invasion at presentation. Finally, Crane and colleagues and Zimmermann and coworkers reported 5–10% of patients with complete tumor removal after concurrent chemoradiation.23,24 However, both studies were based on low-dose (30–33 Gy) nonstandard (accelerated) fractionated radiotherapy. In this report only recent studies, based on radiotherapy with standard dose and fractionation, have been analyzed. Resection Rate A resection rate of 8.3–64.2% was reported (median, 26.5%), including 8.3–57.1% of enrolled patients (median, 23.1%) with R0 tumor resection.14,15,17–19,27–29,31,35,36,39 It should be noted that there was a wide range of results in terms of tumor resection rate. These data may be due to the different resectability criteria used (Table 1) or even to the lack in any specific criteria. Particularly, portal vein or superior mesenteric vein involvement was once considered a contraindication to pancreaticoduodenectomy, and thus, many series included this subset of lesions among those classified as unresectable.15,18,28,29,31 However, venous resection and reconstruction is now increasingly performed, with morbidity, mortality, and survival similar to pancreaticoduodenectomy without vascular reconstruction.42

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Obviously, such different resectability criteria might have caused some heterogeneity in patient accrual, with series including only more locoregionally advanced tumors or only less extended ones deemed as potentially resectable after a therapeutic downsizing effect.16,31 Current NCCN guidelines clearly define resectability criteria while making a distinction between borderline resectable and locally advanced unresectable disease.51 Varadhachary and coworkers from MD Anderson Cancer Center, recently also proposed an objectively defined, CT-based classification for tumors of the pancreatic head, neck, and proximal body, system, which clearly distinguishes borderline resectable from both resectable and locally advanced primary tumors.52 Another confounding factor relates to different staging procedures used. In many series local unresectability was defined on the basis of radiographic findings at CT or MRI scan and endoscopic ultrasonography (EUS), whereas others confirmed the suspect of vascular invasion by surgical exploration.15,17,19,29,31,35 At CT scan, Lu and colleagues reported that tumor contiguity with more than 50% of the perimeter of a vessel is the optimal threshold for predicting vascular invasion.53 This system has been widely adopted.27,31 However, it should be noted that, using this optimal threshold, approximately 10% of patients classified as unresectable at CT scan, conversely, will be resectable at surgical exploration.54 Therefore, tumor downstaging after preoperative treatment could have been overestimated in some cases because of an overestimation of the true extent of disease at diagnosis. Criteria used to select patients who are eligible for surgical exploration after preoperative treatment also differ among series. The proportion of patient submitted to surgical restaging varies from 25 to 67% of enrolled patients. Most investigators reserved surgery for patients who showed at least a tumor downsizing or were deemed to have resectable disease at revaluation CT or EUS.15,18,19,27–29,31,35 In the series by Sa Cunha and colleagues, all 61 treated tumors were deemed to remain unresectable after neoadjuvant therapy because of persistent arterial encasement at CT restaging.18 However, 13 patients (21%), who were selected for laparotomy on the basis of a radiographical tumor downsizing, underwent a Whipple procedure, after biopsies of arterial encasement were negative. On the contrary, in the study by Aristu and coworkers, surgical restaging was performed in 33 of 49 patients (67%), although only 12 of them were deemed to have a resectable tumor at radiographic revaluation.17 All 21 remaining tumors classified as unresectable at CT restaging were shown to have an unresectable tumor at surgical restaging. Given the extreme heterogeneity of selection of patients for inclusion in studies of locally advanced pancreatic

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cancer and the general lack of stated criteria for resection in most studies, it would seem impossible to make sense of the data. However, the high proportion of pR0 resections observed among total resections performed is probably less than the resection rate affected by confounding factors. It should be noted that procedures of vessels reconstruction, aiming to achieve R0 tumor resection during secondary surgery, were performed in some series while not in others. Obviously, differences in surgical procedures weaken the comparability of R0 resection rates among the different series. Wanebo and colleagues, in locally advanced pancreatic cancer, achieved a brilliant 57% R0 resection rate after neoadjuvant chemoradiation.14 However, among the 8 of 14 patients who underwent potentially curative resection, only 1 had a standard Whipple procedure, and 6 had an extended resection that required portal vein and/or major arterial resection and reconstruction. Considering this limitation, in reported series including only patients with primarily unresectable pancreatic cancer, R0/total resections rate ranged from 57.1 to 100% (median, 87.5%).15,18,19,27–29,31 This proportion is remarkable compared with the rate of pR0 resection recently reported in the literature, varying from 25 to 84% in patients with primarily resected pancreatic adenocarcinoma.55–57 Survival When outcome in all patient groups was considered, median survival ranged from 9 to 23 (median, 12.3) months, which compared favorably with literature data: 8.6–13 (median, 9.6) months.10–13,15,17,19,28,29 Surprisingly enough, in these patients with unresectable tumor at presentation, median survival after surgery ranged from 16.4 to 32 (median, 23.6) months.14,15,17,18,28,29,31,35 These results appear to be at least comparable to those reported with surgery alone in resectable patients (12.5– 20 months).58–62 More interestingly, these results appear almost similar if not even better than those reported with surgery plus postoperative adjuvant treatment in resectable tumors (15.8–24.5 months).59–62 The results of the study by Snady and coworkers are particularly interesting and paradoxical.15 The authors compared the survival of secondary surgery after neoadjuvant radiochemotherapy in 68 patients with locally advanced disease versus the outcome of primary resection in 91 patients with early-stage pancreatic adenocarcinoma. Survival curves of operated patients of the two groups were compared. A reversal of the expected trend—that patients with earlier stage resectable carcinoma survive longer than patients with more advanced regional disease—was observed. The median survival for patients with secondarily resected locally advanced pancreatic cancer was 23.6 months compared with 14 months for patients with primarily resected early-stage pancreatic


adenocarcinoma (P = 0.006) despite more advanced cases in the first group. It should be noted that in this series 12 of 68 patients (17%) were shown to have metastases during or immediately after chemoradiation. Similarly in the other analyzed series a 4.0–29.4% occurrence of these ‘‘early’’ metastases is reported.17,19,26,27,31,35 In a series of resected early-stage pancreatic tumors approximately 19% of hepatic recurrences occurred within 3 months after surgery and the median survival time after detection of metastases was only 3 months.63 The exclusion of patients with such an unfavorable prognosis from the analysis of survival in the group of patients with locally advanced pancreatic cancer could have played a role and should be considered when interpreting the results. These ‘‘early’’ metastases, occurring more or less within 3 months after diagnosis, are more likely to reflect an underestimation of the true spread of cancer at presentation than a real disease progression. Therefore, the finding of Snady and coworkers might more reveal a defect in selecting correctly those patients who will eventually benefit from radical surgery rather than a definite activity of the neoadjuvant regimen. However, it also should be noted that in the same series only 66% of primary resected patients underwent adjuvant therapy, whereas all secondary resected patients obviously completed the planned multimodality therapy. This could have further increased the difference in survival between the two patient populations. Findings similar to those reported by Snady and colleagues were described by Massucco and coworkers. These investigators reported that patients resected after chemoradiation for locally advanced tumor had the same survival as those primarily resected for a localized tumor treated with adjuvant chemotherapy. On the contrary, primarily resected patients who had no adjuvant therapy had the same median survival as unresectable patients treated with chemoradiotherapy alone.35 One potential disadvantage of preoperative radiochemotherapy would be increased perioperative morbidity and mortality. After chemoradiotherapy, perioperative mortality rate ranged from 0.0 to 12.5% with most series reporting no perioperative deaths.18,19,26,28,31,36 This finding is comparable to that reported in series of primarily resected pancreatic cancer (0.0–7.1%).64,65 Although interventions were found to be more technically demanding,31,35 no significant difference in operative mortality and morbidity was observed.15,31,35

CONCLUSIONS To date, a low level of evidence exists about efficacy of neoadjuvant chemoradiotherapy for patients with locally advanced pancreatic cancer. The extreme heterogeneity of selection of patients for inclusion in studies of locally


advanced pancreatic cancer and the general lack of stated criteria for resection in most studies, make it challenging to draw meaningful conclusions. Available data suggest that after neoadjuvant chemoradiation, complete tumor removal is achievable in almost a quarter of patients, with nearly a third of them surviving for more than 3 years. In our opinion, if no disease progression occurs after chemoradiotherapy, patients should be reevaluated by a skilled surgical team. Prospective high-quality trials are required for patients with locally advanced unresectable pancreatic cancer to determine whether this provides sustained benefits and to identify the best approach to downstaging tumors for resection. Homogeneous and well-defined resectability criteria, such as dose proposed by the NCCN or MD Anderson Cancer Center, should be used in these trials.51,52 Downstaging to resectable of a primarily unresectable tumor and long-term survival in secondarily resected pancreatic cancer could reflect the limitation of current staging procedures rather than the real benefit of neoadjuvant chemoradiotherapy in primary unresectable pancreatic cancer. However, the finding of a high proportion of R0 resection among all performed resections confirms the activity of neoadjuvant radiochemotherapy and should not be neglected. Such finding supports further investigations about preoperative chemoradiotherapy, even in patients with primarily resectable pancreatic cancer, considering the poor benefit achievable with available adjuvant therapies. These studies could be of particular interest in patients with ‘‘borderline resectable’’ tumors who are at high risk of undergoing an incomplete (R1-R2) resection.

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