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

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.

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.  

TREATMENT ALGORITHEM NONMETASTATIC PANCREATIC CANCER

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

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) .

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.

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.

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

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.

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.

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

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)

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.

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

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

●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

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.

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.

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.

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.

CONCOMITANT CHEMORADIOTHERAPY

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.

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.

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:

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% 40Gy36% 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.

●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.

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).

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.

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

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

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

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

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

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.

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

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.

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.

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.

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.

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.

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).

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.

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.

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).

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.

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.

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

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.

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.

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

SUMMERY

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].

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 .

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 .

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

POTENTIALLY RESECTABLE TUMORS

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.

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 .

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].

.

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.

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.

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.

SUMMERY