Initial chemotherapy and radiation for pancreatic cancer

1. INITIAL CHEMOTHERAPY AND RADIATION
FOR
1. NONMETASTATIC LOCALLY ADVANCED UNRESECTABLE
2. BORDERLINE RESECTABLE, AND
3.POTENTIALLY RESECTABLE
EXOCRINE PANCREATIC CANCER
Dr Touqeer A Siddiqui
MBBS MD FICM (MRCP) (UK)
Fellow medical oncology
Prince sultan military medical city
Source up to date
NCCN/’ESMO
guidelines

2. INTRODUCTION
 Approximately 46,420 people develop exocrine pancreatic cancer
each year in the United States.
 It is of aggressive character and the fact that most patients present
with relatively advanced disease, most die from the disease.
 The majority of these tumors (85 percent) are adenocarcinomas
arising from the ductal epithelium.
 Surgical resection offers the only chance of cure.

3. INTRODUCTION
 Surgical resection offers the only chance of cure for nonmetastatic
exocrine pancreatic cancer. –
 disease at diagnosis
 only 15 to 20 ---potentially resectable;
 approximately 40 percent have distant metastases,
 another 30 to 40 percent have locally advanced unresectable tumors.
 Therapeutic options include radiation therapy (RT) alone,
chemoradiotherapy, and chemotherapy alone.
 Rarely, a response to initial therapy will be sufficient to permit an
attempt at subsequent resection.

4. TREATMENT ALGORITHEM NONMETASTATIC
PANCREATIC CANCER

5. DEFINITIONS
 Criteria for unresectability
 Consensus-based guidelines from the National Comprehensive
Cancer Network (NCCN) define the following characteristics as
indicating unresectability:
 ●Head of pancreas lesions
 •Greater than 180 degrees SMA encasement, any celiac abutment
 •Unreconstructable SMV/portal vein occlusion
 •Aortic invasion or encasement
 ●Body
 •SMA or celiac encasement greater than 180 degrees
 •Unreconstructable SMV/portal vein occlusion
 •Aortic invasion

6. CRITERIA FOR UNRESECTABILITY
 ●Tail
 •SMA or celiac encasement greater than 180 degrees
 ●For all sites
 •Distant metastases
 •Metastases to lymph nodes beyond the field of resection
 also been adopted by the European Society of Medical Oncology
(ESMO) .

7. CRITERIA FOR UNRESECTABILITY
 categorically unresectable if any of the following are present:
 ●The presence of metastases in the liver, peritoneum, omentum, or
any extraabdominal site, or nodal involvement beyond the
peripancreatic tissues.
 ●Encasement (more than one-half of the vessel circumference)
or occlusion/thrombus of the superior mesenteric artery (SMA),
unreconstructable superior mesenteric vein (SMV) or SMV-portal
vein confluence occlusion, or direct involvement of the inferior vena
cava, aorta, or celiac axis, as defined by the absence of a fat plane
between the low density tumor and these structures on CT or EUS.

8. BORDERLINE RESECTABLE
 A consensus statement from a conference sponsored by the American
Hepato-Pancreato-Biliary Association and cosponsored by the Society of
Surgical Oncology and the Society for Surgery of the Alimentary Tract
recommended that tumors considered borderline resectable include the
following .
 ●No distant metastases.
 ●Venous involvement of the SMV/portal vein demonstrating tumor
abutment with or without impingement and narrowing of the lumen,
encasement of the SMV/portal vein but without encasement of the
nearby arteries, or short segment venous occlusion resulting from either
tumor thrombus or encasement, but with suitable vessel proximal and
distal to the area of vessel involvement, allowing for safe resection and
reconstruction.

9. BORDERLINE RESECTABLE
 ●Gastroduodenal artery encasement up to the hepatic artery with either
short segment encasement or direct tumor abutment of the hepatic
artery, but without extension to the celiac axis.
 ●Tumor abutment of the SMA not to exceed >180 degrees of the
circumference of the vessel wall.
 These criteria have also been adopted as definitions of borderline
resectable disease in the consensus-based guidelines of the NCCN. We
agree with these definitions, which have also been adopted by ESMO [4

10. TREATMENT
 The treatment of nonmetastatic pancreatic cancer, particularly for
locally advanced unresectable and borderline resectable tumors, is in
evolution.
 Traditionally, the standard approach for potentially resectable
disease has been surgery followed by adjuvant therapy.

11. NEOADJUVANT CHEMOTHERAPY
 The rationale for neoadjuvant chemotherapy is as follows:
 ●Improve the selection of patients for whom resection will not offer a
survival benefit (ie, those who rapidly progress to metastatic disease
during preoperative therapy).
 ●Increase rates of margin-negative resections, which is the major
goal of surgery.
 ●Early treatment of micrometastatic disease.

12. NEOADJUVANT CHEMOTHERAPY
 Two important considerations for patients who will be treated initially
with chemotherapy with or without radiation therapy (RT) prior to
surgery are:
 ●A tissue diagnosis should be established before initiation of therapy.
 This differs from a surgery-first strategy in which preoperative tissue
diagnosis may not be needed.
 ●For patients who present with obstructive jaundice, delivery of
neoadjuvant therapy necessitates durable biliary decompression for
as many as six months.
 This can usually be accomplished through placement of a biliary
stent

13. LOCALLY ADVANCED UNRESECTABLE
DISEASE
 For most patients with locally advanced categorically unresectable
disease,
 An initial period of chemotherapy rather than immediate radiation
therapy (RT) or chemoradiotherapy.
 This recommendation is consistent with consensus-based guidelines
from the National Comprehensive Cancer Network (NCCN) and the
European Society of Medical Oncology (ESMO)

14. LOCALLY ADVANCED UNRESECTABLE
DISEASE
 optimal regimen has not been established, and enrollment of these
patients on clinical trials is preferred.
 If trials are unavailable, or patients are ineligible,
 gemcitabine monotherapy or a
 gemcitabine-based combination regimen represents a standard
approach.
 excellent performance status,
 total bilirubin level that is FOLFIRINOX
 below 1.5 times the upper limit of normal
 able to tolerate it,
 combination chemotherapy with (short-term infusional fluorouracil
[FU] plus leucovorin, irinotecan, and oxaliplatin) is an option.

15. do not progress following initial
chemotherapy
combined treatment with external beam RT
(EBRT) plus concomitant low-dose infusional
FU (eg, 200 mg/m2 daily) rather than
conventional fractionation EBRT alone
NCCN//ESMO
alternative acceptable
approach is continued
chemotherapy alone

16. INITIAL CHEMOTHERAPY
 Initial chemotherapy is an increasingly utilized treatment option for
patients with locally advanced unresectable exocrine pancreatic
cancer.
 The data to support the use of gemcitabine in this setting come mainly from
two sources:
 Gemcitabine alone

17.  ●In a global phase III trial comparing gemcitabine with and without tipifarnib in
688 patients with locally advanced (n = 164) or metastatic pancreatic cancer,
the median survival of patients with locally advanced disease in both groups
was 10.5 months [14].
 ●A randomized comparison between gemcitabine with or without irinotecan in
360 patients (51 with locally advanced disease) reported a median survival
duration of 11.7 and 9.8 months in the patients with locally advanced disease
in the gemcitabine alone and gemcitabine/irinotecan arms, respectively [15].
 ●A longer median survival duration (15 months) was reported in a Japanese
phase II trial of single agent gemcitabine that was limited to 50 patients with
locally advanced, nonmetastatic pancreatic cancer [16].
SOURCE UP TODATE
Ishii H, Furuse J, Boku N, et al. Phase II study of gemcitabine chemotherapy alone for locally advanced pancreatic carcinoma: JCOG0506.
Jpn J Clin Oncol 2010; 40:573

18. INITIAL CHEMOTHERAPY
 Combination regimens
 Whether better outcomes could be achieved using more effective
chemotherapy combinations is unclear.
 there are no randomized trials comparing this approach to gemcitabine
monotherapy alone in patients with locally advanced disease.
 In particular, in the metastatic setting, many clinicians are now using
short-term infusional FU plus leucovorin, irinotecan, and oxaliplatin
(FOLFIRINOX ) and gemcitabine combinations such as gemcitabine plus
nab-paclitaxel based on the improved activity and survival when these
regimens are compared with gemcitabine monotherapy.
 However, these regimens are also associated with enhanced toxicity,
and appropriate patient selection is critically important.

20. FOLFIRINOX
 While many institutions have embraced neoadjuvant FOLFIRINOX
for patients with locally advanced pancreatic cancer.
 excellent performance status,
 a normal total bilirubin,
 the available data on the safety and efficacy of this approach for
locally advanced unresectable disease are scant.
 Although it appears that objective response rates in the primary
tumor are at least as good as they are in metastatic disease,
 there are few data on rates of resectability, perioperative morbidity,
and mortality in patients who undergo surgery after receiving
FOLFIRINOX for locally advanced unresectable disease, and no
data on long-term outcomes.
Conroy T, Gavoille C, Samalin E, et al. The role of the FOLFIRINOX regimen for advanced pancreatic cancer. Curr Oncol Rep 2013; 15:182.
Faris JE, Blaszkowsky LS, McDermott S, et al. FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital Cancer Center experience.
Oncologist 2013; 18:543.
Boone BA, Steve J, Krasinskas AM, et al. Outcomes with FOLFIRINOX for borderline resectable and locally unresectable pancreatic cancer. J Surg Oncol 2013;
108:236.

22.  Despite the paucity of evidence from prospective trials, the
 FOLFIRINOX regimen is being increasingly used in this setting as it is an
active regimen, and some patients will have sufficient downstaging to permit a
later R0 resection.
 As such, it represents a reasonable approach for robust patients with a good
performance status and a near normal total bilirubin level who wish to pursue
an aggressive approach.

23. GEMCITABINE COMBINATIONS
There are even fewer data on gemcitabine combinations and no
published data for gemcitabine plus nab-paclitaxel .
One phase II trial evaluating neoadjuvant gemcitabine plus oxaliplatin in
patients with initially unresectable (n = 18) or borderline resectable (n =
15) nonmetastatic pancreatic cancer showed that 40 percent had
sufficient tumor regression to undergo operative resection, which was
complete (R0) in 69 percent
Sahora K, Kuehrer I, Eisenhut A, et al. NeoGemOx: Gemcitabine and oxaliplatin as neoadjuvant treatment for locally advanced,
nonmetastasized pancreatic cancer. Surgery 2011; 149:311.
Motoi F, Ishida K, Fujishima F, et al. Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal
adenocarcinoma: results from a prospective multi-institutional phase 2 trial. Ann Surg Oncol 2013; 20:3794.

24. CONCOMITANT CHEMORADIOTHERAPY

25. CONCOMITANT CHEMORADIOTHERAPY
 For most patients, guidelines suggest ,an initial period of
chemotherapy rather than chemoradiotherapy;
 for patients who do not progress after initial chemotherapy,
 The suggested therapy is ,combined treatment with conventionally
fractionated EBRT plus concomitant low-dose infusional FU (eg, 200
mg/m2 daily) rather than conventionally fractionated RT alone.
 As has been seen in a variety of tumors arising in the gastrointestinal
tract, the addition of concurrent chemotherapy to EBRT improves
outcomes compared to EBRT alone in patients with locally advanced
pancreatic cancer.

26. FU-BASED APPROACHES
 Most studies have evaluated combined FU and EBRT, which are
synergistic in other gastrointestinal malignancies.
 While the majority compare chemoradiotherapy versus EBRT alone,
the control arm in a few studies was supportive care only or
chemotherapy alone.

27. 5FU VERSUS RT ALONE
 A survival benefit for the addition of concomitant FU to RT has been
difficult to demonstrate;
 Two early randomized trials directly comparing EBRT with and
without concomitant FU-based chemotherapy came to opposite
conclusions:

28. GITSG
trial
EBRT (60 Gy) alone
concurrent EBRT
(either 40 or 60 Gy)
plus bolus FU
Enrollment to the EBRT alone arm was
discontinued when interim analysis
demonstrated clearly superior median
time to progression (TTP) and overall
survival in both combined modality
groups
The one-year survival was
11 %---EBRT alone,
compared with
38% 40Gy
36% 60 Gy
EBRT plus FU,
respectively.
After an additional 88 patients were enrolled in the combined modality
arms, there was a trend toward improved survival with 60 Gy EBRT
plus FU, but the difference in TTP and overall survival was not
statistically significant when compared to the 40 Gy arm.

29.  ●Largely based upon the experience in other
gastrointestinal malignancies such as rectal cancer,
infusional rather than bolus FU has become the
most commonly used approach for radiation
sensitization.

30. 5FU VS EBRT

Infusional FU was used in a trial from the Eastern Cooperative
Oncology Group (ECOG), which randomly assigned 114 patients to
RT (59.4 Gy) alone or with concurrent infusional FU (1000 mg/m2
daily on days 2 through 5 and 28 to 31) plus mitomycin (10 mg/m2
on day 2) .
 In contrast to the GITSG trial, the addition of chemotherapy to RT
increased toxicity without providing any benefit in terms of response
rate (9 versus 6 percent), median disease-free survival (5 versus 5.1
months), or overall survival (7.1 versus 8.4 months, respectively).

31. 5FU VS EBRT
 The method of FU administration (intermittent high-dose rather than
the more contemporary method of continuous infusions of lower
doses such as 200 mg/m2 daily during EBRT) as well as the
inclusion of mitomycin C might have contributed to the relatively poor
outcomes in the experimental group.

32. 5FU VS EBRT
 ●A pooled analysis of both trials concluded that the length of survival
with chemoradiotherapy was significantly increased relative to
radiotherapy alone (hazard ration [HR] for death 0.69, 95% CI 0.51 to
0.94) .
 ●A qualitative meta-analysis of 21 studies also concluded that FU-
based chemoradiotherapy improved overall survival when compared
to RT alone or best supportive care.
 However, chemoradiotherapy was not superior to chemotherapy
alone

33. MEDICARE/SEER REPORT
 support for the benefit for chemoradiotherapy as compared to RT
alone was provided by a retrospective but large series of 1700
elderly patients with locally advanced pancreatic cancer derived from
a linked Medicare/Surveillance, Epidemiology and End Results
(SEER) database
 Although not derived from a randomized trial, these data support the
view that chemoradiotherapy provides benefit over either modality
alone and that treatment appears to be better than supportive care

34. ORAL FLUOROPYRIMIDINES AS A SUBSTITUTE
FOR INFUSIONAL FU
 Accumulating data from uncontrolled trials support the view that oral
capecitabine can safely replace infusional FU as a radiation
sensitizer in patients treated for locally advanced pancreatic cancer .
 Based upon the results of phase III studies comparing capecitabine
versus infusional FU during chemoradiotherapy for rectal cancer,
 many investigators feel that substituting capecitabine for infusional
FU as a radiation sensitizer is reasonable

35. GEMCITABINE-BASED CHEMORADIOTHERAPY
 (CALGB)
 conducted a phase II trial of low-dose twice weekly gemcitabine (40
mg/m2 twice weekly) plus concurrent RT (50.4 Gy) in 43 patients
with locally unresectable nonmetastatic pancreatic cancer .
 Treatment was still relatively toxic: grade 3 or 4 hematologic toxicity
in 60 percent, grade 3 or 4 gastrointestinal toxicity in 42 percent, and
one treatment-related death attributed to sepsis.
 Although median overall survival was a disappointing 8.2 months,
two patients were still alive at 35 and 41 months of posttreatment
follow-up

36. GEMCITABINE-BASED CHEMORADIOTHERAPY
 prospective phase II study conducted in Italy
 tested weekly gemcitabine (100 mg/m2 over 24 hours) plus
concurrent three-dimensional conformal RT (50.4 Gy), followed by
five cycles of standard-dose gemcitabine alone in 40 patients with
locally advanced pancreatic cancer [48].
 Grade 3 to 4 acute toxicity was observed in 21 (53 percent), but the
median survival was 15.5 months, and 25 percent were still alive at
two years

37. GEMCITABINE-BASED CHEMORADIOTHERAPY
 An alternative strategy is being pursued by other investigators using
standard doses of gemcitabine (1000 mg/m2 weekly) plus small field
RT .
 Early results are encouraging, particularly in the setting of locally
advanced but potentially resectable disease.

38. GEMCITABINE VERSUS FLUOROPYRIMIDINES
 There is little evidence to support better outcomes .
 guidelines suggest not using gemcitabine as a radiation sensitizer
during chemoradiotherapy.
 A 2009 qualitative systematic review concluded that FU is still the
reference chemotherapy for use with concurrent radiotherapy

39. COMBINING GEMCITABINE AND FU
 The ECOG attempted a trial in which FU, gemcitabine, and RT were
combined in the treatment of locally unresectable pancreatic cancer;
however, excess toxicity forced early closure after only seven
patients were treated .
 On the other hand, a subsequent phase II trial of this approach
conducted by the CALGB suggested acceptable toxicity and a
median survival of 12.2 months .
 Further experience with this approach is needed.

40. PACLITAXEL PLUS EBRT
 Paclitaxel is a potent radiation sensitizer and may be particularly
beneficial for the many pancreatic cancers that harbor p53 mutations
.
 ●In an initial report, 11 of 42 assessable patients with locally
advanced disease who were treated with paclitaxel 50 mg/m2 per
week and concurrent EBRT (50.4 Gy) obtained a partial response .
 Fourteen patients with initially unresectable disease then underwent
surgical reexploration, and four could be completely resected.

41. PACLITAXEL PLUS EBRT
 ●A subsequent Radiation Therapy Oncology Group (RTOG)
study applied this same regimen to 122 patients with locally
advanced unresectable disease, 109 of whom were assessable
for response .
 There were 7 clinically complete and 28 partial responses
(overall response rate 32 percent); median survival was 11.2
months.
 Chemoradiotherapy was complicated by a grade 3 or 4
hypersensitivity reaction in seven, myelosuppression in 16, and
one patient had a fatal neutropenic infection.
 these data are too preliminary to support a recommendation for
the use of paclitaxel as a radiation sensitizer off-protocol.

42. CHEMORADIOTHERAPY VERSUS
CHEMOTHERAPY
 few trials have directly compared initial chemoradiotherapy
versus chemotherapy .
 none of which provide a definitive answer as to which approach
is better.
 One hypothesis for the inability to detect a survival advantage
from the addition of RT to chemotherapy is that
 up to 1/3 of patients ,harbor occult micrometastatic disease at
the time of initial presentation.
 This has led to attempts to introduce chemoradiotherapy
sequentially after a period of chemotherapy.

43. FU-BASED CHEMOTHERAPY
 The results of early trials comparing chemoradiotherapy to FU-based
chemotherapy conducted in the 1980s were mixed .
 However, RT doses and chemotherapy combinations were often
suboptimal.

44. GEMCITABINE-BASED CHEMOTHERAPY
 A survival benefit for chemoradiotherapy followed by gemcitabine
could not be shown compared to gemcitabine alone in the French
FFCD-SFRO trial.
 A second randomized trial (ECOG 4201) of gemcitabine with or
without RT (50.4 Gy in 28 fractions) in patients with localized
unresectable pancreatic cancer was prematurely terminated (with
only 74 of 316 patients enrolled) due to poor accrual .
 In the final publication, there was a significantly better median
overall survival with chemoradiotherapy (11.1 versus 9.2 months),
but there was also a significantly higher rate of grade 4 and 5 (fatal)
toxicity (41 versus 9 percent).

45. CHEMORADIOTHERAPY VERSUS
CHEMOTHERAPY
 Meta-analysis — Two separate meta-analyses of trials comparing
chemoradiotherapy (with or without subsequent chemotherapy)
versus chemotherapy alone concluded that there was no survival
benefit (and greater toxicity) for chemoradiotherapy as compared to
chemotherapy alone .
 However, the obvious heterogeneity in the trials in terms of
chemotherapy regimen and RT dose, as well as their small size,
limits the confidence in this conclusion.

46. CHEMORADIOTHERAPY AFTER INITIAL
CHEMOTHERAPY
 For patients with locally advanced unresectable disease who begin
therapy with chemotherapy, an increasingly used alternative to FU-
based chemoradiotherapy is continued chemotherapy alone.
 No trial has shown that chemotherapy alone is superior to
conventionally-dosed RT using concomitant infusional FU in patients
with locally advanced unresectable disease,
 Hence ,prefer FU-based concurrent chemoradiotherapy to
chemotherapy alone.

47. CHEMORADIOTHERAPY AFTER INITIAL
CHEMOTHERAPY
 this strategy was evaluated in a retrospective series of 181 patients
with locally advanced, unresectable but nonmetastatic pancreatic
cancer who had been treated with gemcitabine-based chemotherapy
alone as part of phase II and III trials conducted by the European
Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR).
 chemoradiotherapy was associated with significant improvement in
median progression-free survival (10.8 versus 7.4 months with
chemotherapy) and overall survival (15 versus 11.7 months).

48. CHEMORADIOTHERAPY AFTER INITIAL
CHEMOTHERAPY
 Efficacy of this approach could not be confirmed in the international LAP
07 trial,
 In a preliminary report presented at the 2013 American Society of Clinical
Oncology (ASCO) annual meeting, at a median follow-up of 36 months,
chemoradiotherapy was not superior to continuing chemotherapy
(median overall survival 15.3 versus 16.5 months)
 there were some issues with RT compliance.
 interpretation of these data requires more complete analysis and
publication of the final results in a peer-reviewed journal.

49. CHEMORADIOTHERAPY AFTER INITIAL
CHEMOTHERAPY
 Until then, suggestion is for chemoradiotherapy for patients who do
not progress with metastatic disease after an initial period of
chemotherapy.
 In the studies evaluating sequential chemotherapy followed by
chemoradiotherapy, no patient has received a combination
chemotherapy regimen such as FOLFIRINOX.
 Thus, the contribution of chemoradiotherapy to outcomes after
FOLFIRINOX (or gemcitabine plus nab-paclitaxel) remains uncertain.

50. STEREOTACTIC BODY RADIOTHERAPY
 SBRT has been explored in an increasing number of clinical studies
as an alternative approach to conventionally fractionated EBRT with
concurrent chemotherapy for the management of locally advanced
disease.
 However, the benefit of SBRT remains uncertain, since it is not clear
that median survival is better than would be expected with other
forms of therapy, and toxicity has been worse in some studies

51. ROLE OF SURGERY
 It is reasonable to restage and reevaluate the potential for
resectability after chemotherapy with or without chemoradiotherapy;
 however, the frequency of a complete resection and long-term
survival is low for patients who initially have categorically
unresectable tumors.
 Nevertheless, all such patients should be assessed for surgery after
initial medical therapy.

52. ROLE OF SURGERY
 Imaging is imperfect in this setting and laparoscopic or open
evaluation of the abdomen may be necessary in order to determine
the potential for resection.
 Even tumors that appear to be resectable at open evaluation may
have positive posterior margins as that margin cannot be assessed
until the resection is completed.

53. EXTERNAL BEAM RT ALONE
 Locally advanced pancreatic tumors can usually be encompassed in a
conventional EBRT portal.
 However, in most settings, EBRT alone does not provide optimal tumor
control; local failure rates are as high as 72 percent [89].
 These dismal results have spawned efforts to improve outcomes by the
concurrent administration of drugs that act as radiation sensitizers,
including FU,gemcitabine, and paclitaxel

54. SUMMERY

55. BORDERLINE RESECTABLE DISEASE
 Some of these patients will prove to be resectable with initial surgery,
the likelihood of an incomplete resection is high.
 For fit patients who are willing to accept the uncertainty of benefit
from this approach,
 we suggest an initial attempt at neoadjuvant therapy followed by
restaging and surgical exploration in the absence of metastatic
disease rather than upfront surgery.
 This approach is consistent with guidelines from the National
Comprehensive Cancer Network (NCCN) and European Society of
Medical Oncology (ESMO) [4].

56. BORDERLINE RESECTABLE DISEASE
 The best form of induction therapy to use in this setting is unclear.
 Whenever possible, such patients should be encouraged to enroll on
clinical trials testing new approaches.
 If clinical trials are unavailable, or patients are ineligible, our
suggested initial approach is similar to that used for locally advanced
unresectable pancreatic .

57.  There are no randomized trials comparing this approach versus upfront
surgery alone.
 The available data consist of small single institution like MD Anderson
and small phase II (uncontrolled) trials that enrolled a mixture of patients
with initially resectable, unresectable, and borderline resectable disease .

58. ROLE OF INTRAOPERATIVE RT
 A number of reports from both single institutions and cooperative groups
have explored IORT, usually in conjunction with preoperative
chemoradiotherapy .
 while local control rates may be higher with
 rapid development of metastatic disease in most reports,
 The benefits of IORT have been marginal or absent in other reports .
 In the absence of randomized trials demonstrating benefit, IORT cannot
be considered a standard approach, and it should be reserved for
carefully selected patients

59. POTENTIALLY RESECTABLE TUMORS

60. POTENTIALLY RESECTABLE TUMORS
 neoadjuvant therapy can be safely delivered ---without adversely
influencing perioperative morbidity or mortality,
 no study -------improved resectability or survival --- surgery
alone,
 unclear whether this approach provides benefit compared to
adjuvant (postoperative) therapy.
 Suggestion, not administering neoadjuvant chemotherapy or
chemoradiotherapy outside of the context of a clinical trial, which
is consistent with guidelines from the National Comprehensive
Cancer Network (NCCN) and European Society of Medical
Oncology (ESMO) [4].
 The first United States national trial of neoadjuvant therapy for
potentially resectable pancreatic cancer (ACOSOG Z5041) is
open, and eligible patients should be encouraged to enroll.

61. POTENTIALLY RESECTABLE TUMORS
 FU-based therapy
 Although initial reports of preoperative RT with or without concurrent
fluorouracil (FU) demonstrated that this approach did not worsen
perioperative morbidity and mortality, there was no obvious improvement
in either resectability or overall survival .
 Gemcitabine-based chemoradiotherapy — Gemcitabine-based
chemoradiotherapy may provide an enhanced local effect, although with
the potential for more toxicity than FU-based regimens.
 Several early reports are promising, but complete pathologic response
rates are not higher than has been seen with FU-based regimens .

62. POTENTIALLY RESECTABLE TUMORS
 Meta-analyses
 three meta-analyses have addressed the benefit of neoadjuvant therapy in
patients with initially potentially resectable pancreatic cancer:
 14 phase II trials concluded the rate of potentially curative resection after
neoadjuvant therapy was 66 percent and median survival in the resected
patients was 23 months .
 ●A second meta-analysis of 7 prospective but uncontrolled trials of
gemcitabine-based neoadjuvant therapy in this setting concluded that 89
percent of initially resectable patients were able to undergo potentially
curative resection, with a median survival in the resected patients of 31
months [79].
 .

63. POTENTIALLY RESECTABLE TUMORS
 A third analysis of 111 studies,
 including 56 phase I/II trials,
 96 percent of the patients receiving chemotherapy and
 94 percent RT,
 concluded that among patients with initially resectable disease,
 35 percent had an objective response to neoadjuvant therapy while
21 percent had progressive disease .
 Resectability rates were 74 percent.

64. POTENTIALLY RESECTABLE TUMORS
 whether these results represent an improvement in outcomes in
patients who undergo resection without neoadjuvant therapy is
unclear, given the lack of a surgery alone control arm in any of the
trials included in any of the analyses.
 Thus, at present, neoadjuvant therapy cannot be considered a
standard approach for potentially resectable disease.

65. POTENTIALLY RESECTABLE TUMORS
 ??????? ------improvement in outcomes in patients who undergo
resection without neoadjuvant therapy is unclear,
 given the lack of a surgery alone control arm in any of the trials
included in any of the analyses.
 Thus, at present, neoadjuvant therapy cannot be considered a
standard approach for potentially resectable disease.

66. SUMMERY