Download PMH CLINICAL PRACTICE GUIDELINES TEMPLATE

PRINCESS MARGARET CANCER CENTRE
CLINICAL PRACTICE GUIDELINES
GASTROINTESTINAL
PANCREATIC CANCER
GI Site Group – Pancreatic Cancer
Authors: Dr. Jennifer Knox, Dr. Mairead McNamara
1. INTRODUCTION
3
2. SCREENING AND EARLY DETECTION
3
3. DIAGNOSIS
3
4. PATHOLOGY
4
5. MANAGEMENT
4
5.1 SURGERY
5.2 THERAPY: ADJUVANT, LOCALLY ADVANCED, METASTATIC
5.3 ONCOLOGY NURSING PRACTICE
4
5
8
6. SUPPORTIVE CARE
8
6.1
6.2
6.3
6.4
6.5
8
8
8
8
8
PATIENT EDUCATION
PSYCHOSOCIAL CARE
SYMPTOM MANAGEMENT
CLINICAL NUTRITION
PALLIATIVE CARE
7. FOLLOW-UP CARE
8. REFERENCES
8
10
These guidelines are evidence-based and thus subject to change. Some recommendations
are currently funded in this jurisdiction, while others are in negotiation.
2
Last Revision Date – August 2015
1. Introduction
Pancreatic cancer is one of the most highly fatal cancers, with >95% of those affected
dying of their disease. The high mortality rate is due primarily to the high incidence of
metastatic disease at diagnosis. It is also noted that a significant minority progress by
local invasion from unresectable primary. It is estimated that more than 200,000 patients
die of pancreatic cancer each year worldwide.
2. Screening and Early detection
The risk factors for pancreatic cancer are largely unknown. Data regarding coffee and
excess alcohol consumption are conflicting and therefore can not be considered true
etiologic factors. There is an association between pancreatic cancer and diabetes,
however it is more likely that diabetes is an early manifestation of cancer and not
necessarily a predisposing factor. Chronic pancreatitis and smoking may also be a
predisposing factor. Asthma and allergies are protective (Eppel et al., 2007).
There are no current screening programmes that can be recommended in the general
population. However, some patients are at greater risk of developing a pancreatic cancer.
Pancreatic cancer is associated with several genetic syndromes including hereditary
pancreatitis syndrome, Lynch Syndrome, hereditary atypical multiple mole melanoma
syndrome, hereditary Breast Cancer gene 2 (BRCA2)-related breast and ovarian cancer
and to a lesser degree, selective mutations of BRCA1 have been associated with familial
pancreatic cancer, p16 mutations, Peutz-Jeghers syndrome and ataxia telangiectasia. For
these patients, specific research programmes have been established in order to recognize
pre-cancerous lesions. Screening is not evidenced based.
3. Diagnosis
CT in addition to the assessment of the primary tumour location and size, is utilized to
evaluate major vessels adjacent to the pancreas for neoplastic invasion or thrombosis, as
well as to evaluate hepatic or distant metastases, enlargement of peripancreatic regional
lymph nodes, invasion of retroperitoneal structures and intraperitoneal dissemination.
Selected cases may benefit from MRI and laparoscopy. The role of endoscopic
retrograde cholangiopancreatography (ERCP) may only be therapeutic. For small
tumours, EUS may be utilized and may help to more accurately stage the disease. PET
scanning may be used to adequately stage the disease.
Pathological proof of malignancy is mandatory in unresectable cases or when
preoperative treatment is planned. For patients expected to undergo surgery with radical
intent, a previous biopsy is not necessary.
3
Last Revision Date – August 2015
4. Pathology
Infiltrating ductal adenocarcinomas account for 90% of pancreatic neoplasms, the
remaining 10% being represented by acinar cell carcinoma, accounting for <1% of
pancreatic cancers (in this type, overproduction of lipase may lead to metastatic fat
necrosis syndrome, which includes peripheral fat necrosis, eosinophilia and
polyarthralgias) and pancreatoblastoma (a tumour occurring mainly in children).
More than 90% of pancreatic cancers carry mutations in the K-ras oncogene. In addition,
most pancreatic cancers show mutations in several tumour suppressor genes such as p53,
DPC4, p16 and BRCA2.
Pancreatic adenocarcinomas arise from ductal epithelial cells. Intraductal proliferative
epithelial lesions (pancreatic intraepithelial neoplasms (PanINs) are thought to be
precursors of invasive ductal adenocarcinomas.
The American Joint Committee on Cancer (AJCC) TNM and Union for International
Cancer Control (UICC) staging system (pancreatic cancer) is available online at
www.nccn.org
5. Management
5.1 Surgery
Surgery remains the only potentially curative treatment option for patients with a
diagnosis of pancreatic cancer and only approximately 20% to 25% of all pancreatic
cancers appear resectable at diagnosis. Radical surgery is recommended for patients with
early stage disease (stage I and some stage II).
For stage I disease, the standard treatment option is radical pancreatic resection.
For pancreatic head tumours, pancreaticoduodenectomy is the procedure of choice.
Resection of the portal vein, superior mesenteric vein or their confluence during
pancreaticoduodenectomy is performed when the tumor cannot be safely separated from
these structures to achieve a negative margin. This approach has been shown to result in
a survival similar to that of a standard pancreaticoduodenectomy (i.e. without venous
resection) (Tseng et al., 2004). In general, we do not offer neoadjuvant therapy before a
Whipple’s procedure with major vein resection at UHN. Proceeding straight to surgery
with post-operative adjuvant therapy is recommended.
Highly selected patients with limited arterial vascular involvement and with regression or
no evidence of disease progression after neoadjuvant chemoradiotherapy are considered
for a complete en-bloc pancreaticoduodenectomy with segmental arterial resection and
reconstruction, on an in-house clinical protocol.
The most common surgical approach for tumours of the pancreatic body and tail is a
distal pancreatectomy which also routinely includes splenectomy.
4
Last Revision Date – August 2015
5.2 Treatment
5.2.1 Adjuvant therapy
Systemic chemotherapy, radiation therapy, and a combination of chemotherapy and
radiotherapy have all been applied following surgery in an effort to improve cure rates.
The optimal choice of treatment modality remains intensely controversial.
Eligible patients should be encouraged to enrol in clinical trials, if available, evaluating
the potential benefits of chemotherapy and/or chemoradiotherapy as well as new
therapies.
It is our current policy to offer approximately 5-6 months of adjuvant
chemotherapy to both R0 and R1 resections of pancreas cancer. Both adjuvant
gemcitabine or bolus 5-FU/leucovorin can be considered as appropriate adjuvant
chemotherapy for resected pancreatic cancer based on a German phase III trial
(CONKO-1) and the European Study Group for Pancreatic Cancer (ESPAC)-3
trial.
The CONKO-1 trial demonstrated the superiority of adjuvant chemotherapy with
gemcitabine compared with surgery alone for patients with resected pancreatic cancer,
regardless of whether a tumour-free resection margin could be obtained (Oettle et al.,
2007).
The ESPAC-3 trial compared weekly gemcitabine to bolus 5-FU/LV (Mayo clinic
regimen) as adjuvant therapy in patients with resected pancreatic cancer, and compared
with the use of 5-FU/LV, gemcitabine did not result in improved overall survival in
patients with completely resected pancreatic cancer (Neoptolemos et al., 2010).
Adjuvant chemoradiation:
It is our current policy to consider additional chemoradiation in select patients with
R1 (microscopic positive) margins.
The American approach more often includes chemoradiotherapy as well as adjuvant
chemotherapy in the absence of level I data and the NCCN guidelines support either
approach. There is greater emphasis on local control (in addition to consideration of
survival rates) in many North American protocols. The risk of local failure after surgery
alone is >50%; after adjuvant chemotherapy >25 – 30%; and after modern radiation
treatment and chemotherapy from 10 to 30%. In a phase 2 trial, the rates of local failure
after gemcitabine alone versus after radiation plus gemcitabine were 24% and 11%
respectively (Van Laethem et al., 2010). The optimal way to sequence 5-FU-based
chemoradiotherapy and gemcitabine chemotherapy is unclear but an acceptable regimen
is that used in RTOG 9704 (Regine et al., 2008). Alternatively, the protocol of combined
Gemcitabine and radiation used by EORTC (Van Laethem et al., 2010) may be used.
5
Last Revision Date – August 2015
More intense combination regimens to date have not demonstrated benefit to patients and
we do not support their use outside of clinical trials. Recently, an open-label,
multicentre, randomized phase III trial of adjuvant 5-FU, cisplatin and interferon α-2b
plus radiotherapy for patients with resected pancreatic adenocarcinoma did not improve
survival compared with fluorouracil/leucovorin monotherapy and was associated with
considerable acute toxicity (Schmidt et al., 2012).
Patients with positive surgical margins may also be treated in a similar manner to that
described in next section for unresectable tumours (i.e. radiotherapy and concurrent
gemcitabine).
Periampullary cancer:
These are treated similar to pancreas in the adjuvant setting. The ESPAC-3
periampullary cancer randomized trial studied the effect of adjuvant chemotherapy with
fluorouracil plus folinic acid or gemcitabine versus observation on survival in patients
with resected periampullary adenocarcinoma.
Among patients with resected
periampullary adenocarcinoma, adjuvant chemotherapy compared with observation was
not associated with a significant survival benefit in the primary analysis. However,
multivariable analysis adjusting for prognostic variables demonstrated a statistically
significant survival benefit associated with adjuvant chemotherapy (Neoptolemos et al.,
2012).
5.2.2 Locally advanced pancreatic cancers
Although neoadjuvant chemoradiotherapy can be safely delivered to patients with
localized pancreatic cancer, no study clearly demonstrates improved resectability or
survival, and it remains unclear whether this approach provides comparable benefit to
adjuvant (post-operative) therapy, but can be considered in patients with borderline
resectable tumours.
Most patients in North America with locally advanced, unresectable disease are treated
with a combination of radiation therapy and chemotherapy. At PMCC, Gemcitabine is
given weekly for 7 weeks. The patient is then restaged and if there is still no evidence of
distant metastatic disease, concurrent gemcitabine at a dose of 40 mg/m2 is given twice
weekly with radiotherapy (5250 cGy in 30 fractions over 6 weeks).
Highly selected patients with limited arterial vascular involvement and with regression or
no evidence of disease progression after neoadjuvant chemoradiotherapy are considered
for a complete en-bloc pancreaticoduodenectomy with segmental arterial resection and
reconstruction.
Other regimens may include infusion fluorouracil and radiation therapy. The role of
contemporary chemotherapy agents, including capecitabine and targeted agents in
combination with radiation therapy is being explored in this setting.
6
Last Revision Date – August 2015
5.2.3. Treatment of metastatic pancreatic cancer
First-line therapy
For patients with metastatic pancreatic cancer who have a good performance status (0 or
1) and a serum total bilirubin level that is <1.5 times the upper limit of normal,
combination of 5-FU/irinotecan/oxaliplatin (FOLFIRINOX) is suggested rather than
gemcitabine alone following reports of the ACCORD 11 trial (median survival 11.1
months vs 6.8 months) (Conroy et al., 2011).
For patients who are willing to sacrifice possible survival benefit for a less toxic regimen,
gemcitabine alone or gemcitabine plus capecitabine is a reasonable option.
For patients with a performance status worse than 1, gemcitabine monotherapy rather
than FOLFIRINOX is suggested.
For patients with serum bilirubin >1.5 x upper limit of normal despite placement of a
stent, FOLFOX could be considered over a gemcitabine-containing regimen as
gemcitabine is metabolized by the liver, although funding issues may apply.
Another therapeutic possibility is a combination of gemcitabine and erlotinib (Moore et
al., 2007). Although the gain in survival in this study was statistically significant, it is
unclear whether the modest improvement in survival is clinically meaningful in a nonselected population. Erlotinib is not funded in Ontario.
Data from the phase III Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT)
has reported that the study of Abraxane ® (paclitaxel protein-bound particles for
injectable suspension [albumin bound]) in combination with gemcitabine in treatmentnaïve patients with advanced pancreatic cancer met its primary endpoint of overall
survival, 8.5 months versus 6.7 months in gemcitabine alone group and may be
considered as an option in first line therapy (Von Hoff et al., 2012). Funding issues for
Abraxane may apply in Ontario.
In rare cases with known familial BRCA1/2 mutations, there is growing evidence to
support more durable responses with a cisplatin-based regimen such as
cisplatin/gemcitabine (Tran et al., 2012).
Second-line therapy
There is no standard chemotherapy for patients who have progressed following
first-line treatment. Enrolment in clinical trials should be considered.
For patients who retain a good performance status after failing initial gemcitabine
therapy, second-line therapy is suggested rather than best supportive care. The optimal
regimen is unknown, but an oxaliplatin/fluoropyrimidine combination such as FOLFOX
appears to be better than a fluoropyrimidine alone.
7
Last Revision Date – August 2015
The optimal management strategy for patients who fail initial FOLFIRINOX is
undefined. For patients who retain a good performance status, a reasonable option is
gemcitabine monotherapy.
At the moment, there is no evidence supporting the use of either cetuximab or
bevacizumab in the overall setting of pancreatic cancer.
5.3 Oncology Nursing
Refer to general oncology nursing practices
6. Supportive Care
6.1 Patient Education
Refer to general patient education practices
6.2 Psychosocial Care
Refer to general psychosocial oncology care guidelines
6.3 Symptom Management
Refer to general symptom management care guidelines
6.4 Clinical Nutrition
Refer to general clinical nutrition care guidelines
6.5 Palliative Care
Jaundice is common (70%-80%) in cancers involving the pancreatic head. For
unresectable patients, endoscopic stent placement should be considered. Metal
prostheses are preferred for patients with a life expectancy of greater than 3 months since
they present fewer complications (occlusions) than plastic endoprostheses.
Patients who present with severe pain may respond to local radiation therapy and should
be referred to palliative care specialists for appropriate management of symptoms.
7. Follow-up care
7.1 For patients who have had potentially curative surgery, in the case of elevated
preoperative serum CA 19-9 levels, the assessment of this marker could be performed
every 3 months for 2 years and an abdominal CT scan every 6 months. However, there is
no advantage in an earlier detection of recurrence.
8
Last Revision Date – August 2015
7.2 Patients should be followed at each cycle of chemotherapy for toxicity and evaluated
radiologically by CT scan for response to chemotherapy every 2 to 3 months.
Data is insufficient to recommend the use of serum CA 19-9 levels alone for monitoring
response to treatment. If elevated prior to treatment for advanced pancreatic cancer, it
could be measured every one to three months during therapy and suspected disease
progression based upon rising CA19-9 levels should be confirmed radiologically.
9
Last Revision Date – August 2015
8. References
Eppel A, Cotterchio M, Gallinger S. Allergies are associated with reduced pancreas
cancer risk: A population-based case-control study in Ontario, Canada. Int J Cancer 121:
2241-2245, 2007.
Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic
pancreatic cancer. N Engl J Med 364: 1817-1825, 2011.
Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with
gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the
National Cancer Institute of Canada Clinical Trials group. J Clin Oncol 25: 1960-1966,
2007.
Neoptolemos JP, Moore MJ, Cox TF et al. Effect of adjuvant chemotherapy with
fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with
resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized
trial. JAMA 308: 147-156, 2012.
Neoptolemos JP, Stocken DD, Bassi C et al. Adjuvant chemotherapy with fluorouracil
plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized
controlled trial. JAMA 304: 1073-1081, 2010.
Oettle H, Post S, Neuhaus P et al. Adjuvant chemotherapy with gemcitabine vs
observation in patients undergoing curative-intent resection of pancreatic cancer: a
randomized controlled trial. JAMA 297: 267-277, 2007.
Regine WF, Winter KA, Abrams R et al. Fluorouracil vs gemcitabine chemotherapy
before and after fluorouracil-based chemoradiation following resection of pancreatic
adenocarcinoma: a randomized controlled trial. JAMA 299: 1019-1026, 2008.
Schmidt J, Abel U, Debus J et al. Open-label, multicenter, randomized phase III trial of
adjuvant chemoradiation plus interferon alfa-2b versus fluorouracil and folinic acid for
patients with resected pancreatic adenocarcinoma. J Clin Oncol 30: 4077-4083, 2012.
Tran B, Moore S, Zogopoulos G et al. Platinum-based chemotherapy (Pt-chemo) in
pancreatic adenocarcinoma (PC) associated with BRCA mutations : A translational case
series. J Clin Oncol 30: (supplement 4; abstract 217), 2012.
Tseng JF et al. Pancreaticoduodenectomy with vascular resection: margin status and
survival duration. J Gastrointest Surg 8(8): p. 935-49; discussion 949-50, 2004.
Van Laethem JL, Hammel P, Mornex F et al. Adjuvant gemcitabine alone versus
gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a
randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study. J Clin Oncol
28: 4450-4456, 2010.
10
Last Revision Date – August 2015
Von Hoff DD, Ervin TJ, Arena FP et al. Randomized phase III study of weekly nabpaclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic
adenocarcinoma of the pancreas (MPACT). J Clin Oncol 30: (supplement 34; late
breaking abstract 148), 2012.
11
Last Revision Date – August 2015