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Pancreatic Cancer.pptx

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Kiran Ramakrishna

This document summarizes the management of pancreatic carcinoma. It discusses the anatomy, epidemiology, risk factors, hereditary syndromes, pathophysiology including pre-cancerous lesions, types of pancreatic cancer, staging, prognostic factors, diagnostic techniques, treatment including surgery, chemotherapy, targeted therapy, radiotherapy and historical prospective studies. It provides a comprehensive overview of pancreatic carcinoma covering all relevant aspects of the disease.

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Management of Carcinoma Pancreas Dr Kiran Kumar BR
ANATOMY
Regional drainage Pancreatic head : peripancreatic, pancreaticoduodenal, porta hepatis, celiac, and superior mesenteric lymph nodes. Pancreatic body and tail : splenic artery, peripancreatic, celiac, superior mesenteric, paraaortic nodal basins.
EPIDEMIOLOGY • There were 460,000 new cases in 2018 worldwide. • In comparison to the West, India has a relatively lower incidence of pancreatic cancer. • The rates in India vary from 0.5 to 2.4/1lac persons per year among women to 0.2 to 1.8/1 lac persons per year among men. • The National Cancer Registry Programme has estimated that by 2020, there will be 8440 and 6090 new cases of pancreatic cancer afflicting Indian men and women, respectively.
Pancreatic Cancer.pptx
Risk Factors 1.Age 2.Sex. 3.Ethnicity. 4.Cigarette smoking. 5.Obesity. 1.Family history. 2.Chronic pancreatitis: almost triple risk. 3.Diabetes mellitus 4.Dietary factors. 5.Helicobacter pylori infections. Drinking alcohol excessively is a major cause of chronic pancreatitis
Hereditary syndromes • Peutz–Jeghers syndrome- due to mutations in the STK11 tumor suppressor gene. • Dysplastic nevus syndrome (or familial atypical multiple mole and melanoma syndrome, FAMMM-PC) due to mutations in the CDKN2A tumor suppressor gene. • Autosomal recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 gene and PALB2 gene. • Hereditary non-polyposis colon cancer (Lynch syndrome) and familial adenomatous polyposis. • PanNETs have been associated with multiple endocrine neoplasia type 1 (MEN1) and von Hippel Lindau syndromes.
Pancreatic intraepithelial neoplasia Intraductal papillary mucinous neoplasms Microscopic abnormalities in the pancreas May progress from low to high grade and then to a tumor. More than 90% of cases at all grades carry a faulty KRAS gene. Macroscopic lesions, which are found in about 2% of all adults. This rate rises to ~10% by age 70. Have about a 25% risk of developing into invasive cancer. May have KRAS gene mutations (~40–65% of cases) Pathophysiology Precancer
Pancreatic mucinous cystic neoplasms (MCNs) Intraductal tubulo-papillary neoplasm Mainly occur in women, May remain benign or progress to cancer. If these lesions become large, cause symptoms, or have suspicious features, they can usually be successfully removed by surgery. Recognized by the WHO in 2010 and constitutes about 1–3% of all pancreatic neoplasms. Mean age at diagnosis is 61 years. About 50% of these lesions become invasive. Diagnosis depends on histology as these lesions are very difficult to differentiate from other lesions. Pathophysiology Precancer
Invasive cancer Four genes have each been found to be mutated in the majority of adenocarcinomas:  KRAS (in 95% of cases).  CDKN2A (also in 95%).  TP53 (75%).  SMAD4 (55%). • SWI/SNF mutations/deletions occur in about 10–15% of the adenocarcinomas.
PanNETs • The genes often found mutated in PanNETs are different from those in exocrine pancreatic cancer. • MEN 1 gene mutation. • About 40–70% of people born with a MEN1 mutation eventually develop a PanNet. • Other genes that are frequently mutated include DAXX, mTOR and ATRX.
Exocrine component. Pancreatic neuroendocrine tumors 1. The vast majority of cases (about 95%) 2. Pancreatic adenocarcinoma 3. most common type, about 85% of all pancreatic cancers. 4. Nearly all these start in the ducts of the pancreas, as pancreatic ductal adenocarcinoma (PDAC). 5. About 60–70% of adenocarcinomas occur in the head of the pancreas. 6. Acinar cell carcinoma , Cystadenocarcinomas, Pancreatoblastoma. 1. Functioning' and ‘Non-functioning' types 2. The functioning types secrete hormones such as insulin, gastrin, and glucagon into the bloodstream, often in large quantities 3. Gives rise to serious symptoms such as low blood sugar, but also favors relatively early detection. 4. The most common functioning PanNETs are insulinomas and gastrinomas. Types: Both groups occur mainly (but not exclusively) in people over 40
Signs and symptoms • Pain in the upper abdomen or back, often spreading from around the stomach to the back. • Jaundice. • Unexplained weight loss, either from loss of appetite. • At least 50% of people with pancreatic adenocarcinoma have diabetes at the time of diagnosis. • Trousseau's syndrome: blood clots form spontaneously in the portal blood vessels, the deep veins of the extremities, or the superficial veins anywhere on the body, found in about 10% of cases.
Diagnosis • High-resolution pancreatic CT and EUS remain the current standard for diagnosis and staging of pancreatic malignancies. Multiphasic CT scan: This allows for adequate imaging • of the pancreas and assessment of metastatic deposits in other intra- abdominal organs such as the liver. • limited in detection of nodal involvement and peritoneal disease • useful in evaluating for metastatic disease.
• A Pancreatic protocol is used during the CT image acquisition. • Under this, iv contrast is administered and a triphasic scan is performed. The three phases are: • Early arterial phase - 15-20 sec. For delineating arterial structures like celiac artery and SMA. • Pancreatic (late arterial); - 35-40 sec. Maximal differentiation between the normal parenchyma and hypodense pancreatic tumors like adenocarcinoma. • Portal venous- 70-80 sec. Metastases in the liver are best detected at 70-80 sec when the liver parenchyma enhances optimally.
Endoscopic ultrasound MRI PET CT An endoscope with an ultrasound transducer at its tip is passed into the stomach and duodenum, where it provides high- resolution images of the pancreas and surrounding vessels. An advantage of EUS over CT is the ability to detect small lesions. Staging laparoscopy has been used preoperatively to assess for intraperitoneal metastases. Three-dimensional (3D) reconstruction, functional imaging, and MR cholangiopancreatography, have led to an improved ability of MRI to diagnose and stage pancreatic cancer. In patients with poor renal function to assess the primary tumor and determine resectability; Not as sensitive as EUS or CT in tumor detection. Integrated PET-CT had a higher sensitivity for malignancy detection than did either PET or CT alone (96% vs. 84% vs. 77%) but did not improve specificity (64%).
• Liver function tests can show a combination of results indicative of bile duct obstruction (raised conjugated bilirubin, γ-glutamyl transpeptidase and alkaline phosphatase levels). • CA19-9 (carbohydrate antigen 19-9) is a tumor marker that is frequently elevated in pancreatic cancer. However, it lacks sensitivity and specificity, because 5% of people lack the Lewis antigen and cannot produce CA19-9. • It has a sensitivity of 80% and specificity of 73% in detecting pancreatic adenocarcinoma, and is used for following known cases rather than diagnosis.
AJCC Staging
Pancreatic Cancer.pptx
To help decide treatment, the tumors are also divided into
Criteria for Resectability
Prognostic Factors: Positive operative margins, Poor histologic grade, Larger tumor size, Lymphovascular invasion, Lymph node involvement. CA19-9
Treatment • Surgery represents the only potentially curative treatment strategy. • Head or uncinate : pancreaticoduodenectomy or Whipple's procedure. • Pancreatic tail lesions, distal pancreatectomy is employed, frequently with splenectomy. • 12 to 15 lymph nodes constitute an adequate assessment
Pancreatic Cancer.pptx
Chemotherapeutic agents
Chemotherapy Regimen • Gemcitabine 100mg/m2 • Capecitabine 1200mg/m2. Targeted therapy: Erlotinib Cetuxiamb
Radiotherapy  Resectable/borderline resectable  Resected (adjuvant)  Locally advanced  Palliative  Recurrent
Dose and Fractionation Resectable/Borderline Resectable (Neoadjuvant): • 36Gy in 2.4Gy fractions to 45–54Gy in 1.8–2.0Gy fractions Resected (Adjuvant): • 45–46Gy in 1.8–2.0Gy fractions to the tumor bed, surgical anastomoses and adjacent lymph node basins, • Potentially followed by an additional 5–9Gy to the tumor bed and anastomoses, if clinically appropriate. • Escalation above 54Gy should ideally be avoided or used only in a clinical trial.
Locally Advanced (Definitive): 45–54Gy in 1.8–2.0Gy fractions. Doses higher than 54Gy may be considered on a clinical trial. There are limited data to support a specific RT dosing for SBRT; preferably be utilized as part of a clinical trial or at an experienced, high-volume center. SBRT doses of 3 fractions (total dose 30–45 Gy) or 5 fractions (total dose 25–45 Gy) have been reported.
SBRT • Involves the delivery of high dose per fraction radiation treatments over a small number of fractions (generally 1 to 5 treatments), utilizing techniques that allow very highly conformal dose delivery of external beam radiotherapy. • Potentially improving local control through the delivery of ablative doses of radiation, while minimizing associated side effects. • A report from these investigators described 77 patients who were treated with SBRT and found that freedom from local progression was 91% at 6 months and 84% at 12 months. • A meta-analysis of 19 studies encompassing over 1,000 patients treated with SBRT demonstrated a 1-year local control rate of 72%.
RADIATION THERAPY TECHNIQUES Position: Supine with arms up in an Alpha Cradle or equivalent immobilization device custom-made for each patient. Simulation: • Ideally, placement of 1–5 (preferably ≥3) gold fiducial markers. • Placement of fiducial markers directly into the tumor and/or periphery under EUS is preferred. • Stents can assist with targeting; however, they can shift and are therefore less reliable than fiducials. Scan range: • T4/T5 to L5/S1 (upper abdomen). • CT simulation (2- to 3-mm slices) should be performed with IV (assuming adequate kidney function) and oral contrast.
Motion Management: • Respiratory motion should be accounted for determining the internal target volume (ITV). • This may be accomplished utilizing a 4D-CT scan. • Motion management using respiratory gating or breath-hold, respiratory tracking, or abdominal compression may be used to reduce cranio-caudal tumor/fiducial marker motion, typically reducing from an 11- to 22-mm peak to ≤5 mm. Treatment Volumes and Fields: • Surgical clips should be placed to mark the extent of the lesion for postoperative irradiation. • Multiple field, fractionated, external beam techniques utilizing high- energy photons to deliver 45 to 50Gy in 1.8Gy fractions to tumor bed, unresected or residual tumor, and lymph node–bearing areas at risk.
Approximately two-thirds of the left kidney must be excluded from the AP/PA field because the right kidney is often in the field because of duodenal (bed) inclusion. The superior field extent : middle or upper portion of the T11 vertebral body for adequate margins on the celiac vessels (T12, L1) Inferior limit at the level L2–L3 to include the superior mesenteric lymph nodes and third portion of the duodenum. The upper field extent is sometimes more superior with body lesions to obtain adequate margin on the primary lesion.
Lateral fields, the anterior field margin is 1.5 to 2.0 cm beyond initial gross disease. The posterior margin is 1.5 cm behind the anterior portion of the vertebral body to allow adequate margins on paraaortic nodes The lateral contribution usually is limited to 15 to 18Gy because a moderate volume of kidney or liver may be in the irradiated volume
Pancreatic Cancer.pptx
Pancreatic Cancer.pptx
Contouring Guidelines Post-op case • CTV:  Post-operative bed • Based on location of initial tumor from pre-operative imaging and pathology  Anastomoses • Pancreaticojejunostomy(PJ) • Choledochal or hepaticojunostomy  Abdominal nodal regions • Peripancreatic • Celiac • Superior mesenteric • Porta hepatis • Para-aortic
Pancreatic Cancer.pptx
Organ at Risk (OAR) Neoadjuvant/Definitive/Palliati ve and Recurrent Recommendations Adjuvant Recommendationse Kidney (right and left) Not more than 30% of the total volume can receive ≥18 Gy. For 3D conformal plans in patients with two normally functioning kidneys, at least 50% of the right kidney and at least 65% of the left kidney must receive <18 Gy. For IMRT planning, mean dose to bilateral kidneys must be <18 Gy. If only one kidney is present, not more than 15% of the volume of that kidney can receive ≥18 Gy and not more than 30% can receive ≥14 Gy. Stomach , duodenu m, jejunum Max dose 55 Gy. <15% of the volume of each organ can receive between 45 and 49.99 Gy. Liver Mean dose cannot exceed 30 Gy. Mean liver dose must be ≤25 Gy. Spinal cord Max dose to a volume of at least 0.03 cc must be ≤45 Gy. Max dose ≤45 Gy. Organs at Risk
• The CONKO 001 trial demonstrated significant improvements in DFS and OS with use of postoperative gemcitabine as adjuvant chemotherapy versus observation in resectable pancreatic adenocarcinoma. • ESPAC-3 study results showed no significant difference in OS between 5-FU/leucovorin versus gemcitabine following surgery. When the groups receiving adjuvant 5-FU/leucovorin and adjuvant gemcitabine were compared, median survival was 23.0 months and 23.6 months, respectively. • Data from ESPAC-4 support the use of gemcitabine combined with capecitabine (1,660 mg/m2/day days 1–21 every 4 weeks) with superiority demonstrated compared to gemcitabine alone (HR, 0.82; 95% CI, 0.68, 0.98; P = .032).3 • No significant differences were observed in the RTOG 97-04 study comparing pre- and post-chemoradiation 5-FU with pre- and post- chemoradiation gemcitabine for postoperative adjuvant treatment.4
Historical Prospective Studies The gastrointestinal tumor study group (GITSG) • Multicenter prospective trial • Resected pancreatic cancer and negative surgical margins, • Forty-three patients • Randomized to observation or CRT to 40 gy delivered in split- course fashion with concurrent 5- fluorouracil (5-FU) (500 mg/m2) as an intravenous bolus on the first 3 and last 3 days of radiation, followed by maintenance weekly 5-FU for 2 years or until disease progression.
• European Organisation for Research and Treatment of Cancer (EORTC) • Two hundred eighteen patients with resected pancreas or periampullary cancers • Randomly assigned to observation or CRT to 40 Gy in a split-dose fashion with concurrent continuous infusional 5-FU (25 mg/kg) without further adjuvant chemotherapy
• European trial conducted by the European Study Group for Pancreatic Cancer (ESPAC) “Macroscopically” resected pancreatic cancers. • Treating physicians were allowed to enroll patients into one of three parallel randomized studies:  Chemoradiation versus no chemoradiation 20Gy over 2 weeks with 5-FU (500 mg/m2) on days 1 through 3, then repeated after a 2- week break.  Chemotherapy versus no chemotherapy bolus 5-FU(425 mg/m2) and leucovorin (20 mg/m2) given for 5 days every 28 days for 6 cycles.  A 2-by-2 factorial design of 285 patients enrolled on chemoradiotherapy, chemotherapy, chemoradiotherapy with maintenance chemotherapy, or observation.
• No survival difference between the patients who received adjuvant chemoradiation and the patients who did not receive therapy (median survival, 15.5 vs. 16.1 months; P=.24). • In the chemotherapy arm, however, a 35% reduction in death was seen in the group who received adjuvant chemotherapy compared with those who received no chemotherapy, with a difference in median survival of 19.7 versus 14 months (P = .0005). • On further follow-up of patients randomized using the 2-by-2 factorial design, the 5-year survival rate for the patients who received chemotherapy was 21% versus 8% for those who did not. • Additionally, adjuvant CTRT was associated with a deleterious effect on survival
• A common critique of the aforementioned trials: Lack of restaging to evaluate for the presence of persistent or metastatic disease after surgical resection and prior to the initiation of adjuvant therapy. The time between initial staging and the commencement of adjuvant treatment was sometimes as long as 3 to 4 months, during which a significant number of patients would be expected to develop radiographically apparent metastases. Without interval restaging, these patients may inappropriately receive CRT
Modern Studies Adjuvant Systemic Therapy • Conko Three hundred sixty-eight patients were enrolled on the charite onkologie (conko) trial Randomized to: • Observation or • Adjuvant gemcitabine (1,000 mg/m2 intravenous days 1, 8, and 15 every 4 weeks for 6 months). The primary end point was dfs, and patients treated with gemcitabine achieved a statistically significantly longer dfs (14.2 vs. 7.5 months) than those observed after surgery. • This improvement was seen in both the r0 and r1 subgroups.
Espac-3 Largest randomized controlled trial in pancreatic cancer to date, • Enrolled 1,088 patients with pancreatic adenocarcinoma who underwent R0 or R1 resection. Patients were randomly assigned to : • 6 cycles of adjuvant gemcitabine (3 weekly infusions of 1,000 mg/m2) or • 6 cycles of bolus 5-FU (425 mg/m2)/leucovorin (LV) (20 mg/m2). • Patients receiving 5-fu/lv experienced significantly higher rates of grade 3 or 4 gastrointestinal toxicity (stomatitis and diarrhea), whereas patients receiving gemcitabine experienced significantly higher rates of grade 3 or 4 hematologic toxicity. • At a median follow-up of 34.2 months, there was no difference between the two groups in the primary end point of OS
ESPAC-4 trial Randomized patients with resected pancreatic cancer to: • Gemcitabine alone versus • Gemcitabine/capecitabine. Primary end point of overall survival. The median survival for patients receiving adjuvant gemcitabine and capecitabine was 28 months compared to 25.5 months in the gemcitabine-alone arm. Estimated overall survival was Gemcitabine group: 80.5% at 12 months and 52.1% at 24 months Gemcitabine plus capecitabine group : 84.1% at 12 months and 53.8% at 24 months.
Modern Studies: Adjuvant Chemoradiation Rtog/gastrointestinal intergroup trial 9704 Phase iii randomized study Comparing adjuvant 5- fu–based chemotherapy to gemcitabine-based chemotherapy, with both regimens followed by CRT. Four hundred fifty-one patients with resected pancreatic cancer were randomized to • Continuous infusion 5-fu (250 mg/m2/d) • Or gemcitabine (1,000 mg/m2 weekly) for 3 weeks prior to CRT and 12 weeks after CRT. Crt in both groups consisted of 50.4 gy delivered with continuous Infusion 5-FU (250 mg/m2/d)
Median and 5-year OS rates Pancreatic head tumors of 20.5 months and 22% in those who received Gemcitabine, Compared with 17.2 months and 18% in those who received 5-FU. On multivariate analysis, in the subgroup of patients with pancreatic head lesions who received gemcitabine, there was a non significant trend toward improved os (p = .08). A secondary aim of rtog-9704 was to assess the ability of postresection CA19-9 levels to predict survival. When ca19-9 levels were analyzed in a cohort of 385 patients as a dichotomized variable (<180 iu/ml vs. ≥180 IU/ml, ≤90 IU/ml vs. >90 IU/ml), Significant survival difference favoring patients with CA19-9 levels of <180 IU/ml. This corresponded to a 72% reduction in the risk of death
Neoadjuvant Chemoradiation No phase III randomized trials of neoadjuvant CRT in resectable pancreatic lesions have been conducted vast majority of data come from phase II and retrospective studies A review of the Surveillance, Epidemiology, and End Results (SEER) database supports the use of neoadjuvant treatment. This analysis included 3,885 patients treated for resectable pancreatic cancer: • 70 patients (2%) received neoadjuvant EBRT, • 1,478 (38%) received adjuvant EBRT, • 2,337 (60%) weretreated with surgery alone. Median OS was • 23 months in patients receiving neoadjuvant EBRT, • 17 months with adjuvant EBRT, • 12 months in the surgery-alone cohort.
Pancreatic neuroendocrine tumor
• Some specific differences in treatment: In functioning PanNETs, • Octreotide is usually recommended prior to biopsy or surgery • but is generally avoided in insulinomas to avoid profound hypoglycemia PanNETs in Multiple endocrine neoplasia type 1 are often multiple, and thus require different treatment and surveillance strategies. Chemotherapy: Combinations of several medicines have been used, such as doxorubicin with streptozocin and fluorouracil (5-FU) and capecitabine with temozolomide. Targeted therapy : Everolimus and Sunitinib : for treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease.
• Thank you.

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Pancreatic Cancer.pptx

  • 1. Management of Carcinoma Pancreas Dr Kiran Kumar BR
  • 3. Regional drainage Pancreatic head : peripancreatic, pancreaticoduodenal, porta hepatis, celiac, and superior mesenteric lymph nodes. Pancreatic body and tail : splenic artery, peripancreatic, celiac, superior mesenteric, paraaortic nodal basins.
  • 4. EPIDEMIOLOGY • There were 460,000 new cases in 2018 worldwide. • In comparison to the West, India has a relatively lower incidence of pancreatic cancer. • The rates in India vary from 0.5 to 2.4/1lac persons per year among women to 0.2 to 1.8/1 lac persons per year among men. • The National Cancer Registry Programme has estimated that by 2020, there will be 8440 and 6090 new cases of pancreatic cancer afflicting Indian men and women, respectively.
  • 6. Risk Factors 1.Age 2.Sex. 3.Ethnicity. 4.Cigarette smoking. 5.Obesity. 1.Family history. 2.Chronic pancreatitis: almost triple risk. 3.Diabetes mellitus 4.Dietary factors. 5.Helicobacter pylori infections. Drinking alcohol excessively is a major cause of chronic pancreatitis
  • 7. Hereditary syndromes • Peutz–Jeghers syndrome- due to mutations in the STK11 tumor suppressor gene. • Dysplastic nevus syndrome (or familial atypical multiple mole and melanoma syndrome, FAMMM-PC) due to mutations in the CDKN2A tumor suppressor gene. • Autosomal recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 gene and PALB2 gene. • Hereditary non-polyposis colon cancer (Lynch syndrome) and familial adenomatous polyposis. • PanNETs have been associated with multiple endocrine neoplasia type 1 (MEN1) and von Hippel Lindau syndromes.
  • 8. Pancreatic intraepithelial neoplasia Intraductal papillary mucinous neoplasms Microscopic abnormalities in the pancreas May progress from low to high grade and then to a tumor. More than 90% of cases at all grades carry a faulty KRAS gene. Macroscopic lesions, which are found in about 2% of all adults. This rate rises to ~10% by age 70. Have about a 25% risk of developing into invasive cancer. May have KRAS gene mutations (~40–65% of cases) Pathophysiology Precancer
  • 9. Pancreatic mucinous cystic neoplasms (MCNs) Intraductal tubulo-papillary neoplasm Mainly occur in women, May remain benign or progress to cancer. If these lesions become large, cause symptoms, or have suspicious features, they can usually be successfully removed by surgery. Recognized by the WHO in 2010 and constitutes about 1–3% of all pancreatic neoplasms. Mean age at diagnosis is 61 years. About 50% of these lesions become invasive. Diagnosis depends on histology as these lesions are very difficult to differentiate from other lesions. Pathophysiology Precancer
  • 10. Invasive cancer Four genes have each been found to be mutated in the majority of adenocarcinomas:  KRAS (in 95% of cases).  CDKN2A (also in 95%).  TP53 (75%).  SMAD4 (55%). • SWI/SNF mutations/deletions occur in about 10–15% of the adenocarcinomas.
  • 11. PanNETs • The genes often found mutated in PanNETs are different from those in exocrine pancreatic cancer. • MEN 1 gene mutation. • About 40–70% of people born with a MEN1 mutation eventually develop a PanNet. • Other genes that are frequently mutated include DAXX, mTOR and ATRX.
  • 12. Exocrine component. Pancreatic neuroendocrine tumors 1. The vast majority of cases (about 95%) 2. Pancreatic adenocarcinoma 3. most common type, about 85% of all pancreatic cancers. 4. Nearly all these start in the ducts of the pancreas, as pancreatic ductal adenocarcinoma (PDAC). 5. About 60–70% of adenocarcinomas occur in the head of the pancreas. 6. Acinar cell carcinoma , Cystadenocarcinomas, Pancreatoblastoma. 1. Functioning' and ‘Non-functioning' types 2. The functioning types secrete hormones such as insulin, gastrin, and glucagon into the bloodstream, often in large quantities 3. Gives rise to serious symptoms such as low blood sugar, but also favors relatively early detection. 4. The most common functioning PanNETs are insulinomas and gastrinomas. Types: Both groups occur mainly (but not exclusively) in people over 40
  • 13. Signs and symptoms • Pain in the upper abdomen or back, often spreading from around the stomach to the back. • Jaundice. • Unexplained weight loss, either from loss of appetite. • At least 50% of people with pancreatic adenocarcinoma have diabetes at the time of diagnosis. • Trousseau's syndrome: blood clots form spontaneously in the portal blood vessels, the deep veins of the extremities, or the superficial veins anywhere on the body, found in about 10% of cases.
  • 14. Diagnosis • High-resolution pancreatic CT and EUS remain the current standard for diagnosis and staging of pancreatic malignancies. Multiphasic CT scan: This allows for adequate imaging • of the pancreas and assessment of metastatic deposits in other intra- abdominal organs such as the liver. • limited in detection of nodal involvement and peritoneal disease • useful in evaluating for metastatic disease.
  • 15. • A Pancreatic protocol is used during the CT image acquisition. • Under this, iv contrast is administered and a triphasic scan is performed. The three phases are: • Early arterial phase - 15-20 sec. For delineating arterial structures like celiac artery and SMA. • Pancreatic (late arterial); - 35-40 sec. Maximal differentiation between the normal parenchyma and hypodense pancreatic tumors like adenocarcinoma. • Portal venous- 70-80 sec. Metastases in the liver are best detected at 70-80 sec when the liver parenchyma enhances optimally.
  • 16. Endoscopic ultrasound MRI PET CT An endoscope with an ultrasound transducer at its tip is passed into the stomach and duodenum, where it provides high- resolution images of the pancreas and surrounding vessels. An advantage of EUS over CT is the ability to detect small lesions. Staging laparoscopy has been used preoperatively to assess for intraperitoneal metastases. Three-dimensional (3D) reconstruction, functional imaging, and MR cholangiopancreatography, have led to an improved ability of MRI to diagnose and stage pancreatic cancer. In patients with poor renal function to assess the primary tumor and determine resectability; Not as sensitive as EUS or CT in tumor detection. Integrated PET-CT had a higher sensitivity for malignancy detection than did either PET or CT alone (96% vs. 84% vs. 77%) but did not improve specificity (64%).
  • 17. • Liver function tests can show a combination of results indicative of bile duct obstruction (raised conjugated bilirubin, γ-glutamyl transpeptidase and alkaline phosphatase levels). • CA19-9 (carbohydrate antigen 19-9) is a tumor marker that is frequently elevated in pancreatic cancer. However, it lacks sensitivity and specificity, because 5% of people lack the Lewis antigen and cannot produce CA19-9. • It has a sensitivity of 80% and specificity of 73% in detecting pancreatic adenocarcinoma, and is used for following known cases rather than diagnosis.
  • 20. To help decide treatment, the tumors are also divided into
  • 22. Prognostic Factors: Positive operative margins, Poor histologic grade, Larger tumor size, Lymphovascular invasion, Lymph node involvement. CA19-9
  • 23. Treatment • Surgery represents the only potentially curative treatment strategy. • Head or uncinate : pancreaticoduodenectomy or Whipple's procedure. • Pancreatic tail lesions, distal pancreatectomy is employed, frequently with splenectomy. • 12 to 15 lymph nodes constitute an adequate assessment
  • 26. Chemotherapy Regimen • Gemcitabine 100mg/m2 • Capecitabine 1200mg/m2. Targeted therapy: Erlotinib Cetuxiamb
  • 27. Radiotherapy  Resectable/borderline resectable  Resected (adjuvant)  Locally advanced  Palliative  Recurrent
  • 28. Dose and Fractionation Resectable/Borderline Resectable (Neoadjuvant): • 36Gy in 2.4Gy fractions to 45–54Gy in 1.8–2.0Gy fractions Resected (Adjuvant): • 45–46Gy in 1.8–2.0Gy fractions to the tumor bed, surgical anastomoses and adjacent lymph node basins, • Potentially followed by an additional 5–9Gy to the tumor bed and anastomoses, if clinically appropriate. • Escalation above 54Gy should ideally be avoided or used only in a clinical trial.
  • 29. Locally Advanced (Definitive): 45–54Gy in 1.8–2.0Gy fractions. Doses higher than 54Gy may be considered on a clinical trial. There are limited data to support a specific RT dosing for SBRT; preferably be utilized as part of a clinical trial or at an experienced, high-volume center. SBRT doses of 3 fractions (total dose 30–45 Gy) or 5 fractions (total dose 25–45 Gy) have been reported.
  • 30. SBRT • Involves the delivery of high dose per fraction radiation treatments over a small number of fractions (generally 1 to 5 treatments), utilizing techniques that allow very highly conformal dose delivery of external beam radiotherapy. • Potentially improving local control through the delivery of ablative doses of radiation, while minimizing associated side effects. • A report from these investigators described 77 patients who were treated with SBRT and found that freedom from local progression was 91% at 6 months and 84% at 12 months. • A meta-analysis of 19 studies encompassing over 1,000 patients treated with SBRT demonstrated a 1-year local control rate of 72%.
  • 31. RADIATION THERAPY TECHNIQUES Position: Supine with arms up in an Alpha Cradle or equivalent immobilization device custom-made for each patient. Simulation: • Ideally, placement of 1–5 (preferably ≥3) gold fiducial markers. • Placement of fiducial markers directly into the tumor and/or periphery under EUS is preferred. • Stents can assist with targeting; however, they can shift and are therefore less reliable than fiducials. Scan range: • T4/T5 to L5/S1 (upper abdomen). • CT simulation (2- to 3-mm slices) should be performed with IV (assuming adequate kidney function) and oral contrast.
  • 32. Motion Management: • Respiratory motion should be accounted for determining the internal target volume (ITV). • This may be accomplished utilizing a 4D-CT scan. • Motion management using respiratory gating or breath-hold, respiratory tracking, or abdominal compression may be used to reduce cranio-caudal tumor/fiducial marker motion, typically reducing from an 11- to 22-mm peak to ≤5 mm. Treatment Volumes and Fields: • Surgical clips should be placed to mark the extent of the lesion for postoperative irradiation. • Multiple field, fractionated, external beam techniques utilizing high- energy photons to deliver 45 to 50Gy in 1.8Gy fractions to tumor bed, unresected or residual tumor, and lymph node–bearing areas at risk.
  • 33. Approximately two-thirds of the left kidney must be excluded from the AP/PA field because the right kidney is often in the field because of duodenal (bed) inclusion. The superior field extent : middle or upper portion of the T11 vertebral body for adequate margins on the celiac vessels (T12, L1) Inferior limit at the level L2–L3 to include the superior mesenteric lymph nodes and third portion of the duodenum. The upper field extent is sometimes more superior with body lesions to obtain adequate margin on the primary lesion.
  • 34. Lateral fields, the anterior field margin is 1.5 to 2.0 cm beyond initial gross disease. The posterior margin is 1.5 cm behind the anterior portion of the vertebral body to allow adequate margins on paraaortic nodes The lateral contribution usually is limited to 15 to 18Gy because a moderate volume of kidney or liver may be in the irradiated volume
  • 37. Contouring Guidelines Post-op case • CTV:  Post-operative bed • Based on location of initial tumor from pre-operative imaging and pathology  Anastomoses • Pancreaticojejunostomy(PJ) • Choledochal or hepaticojunostomy  Abdominal nodal regions • Peripancreatic • Celiac • Superior mesenteric • Porta hepatis • Para-aortic
  • 39. Organ at Risk (OAR) Neoadjuvant/Definitive/Palliati ve and Recurrent Recommendations Adjuvant Recommendationse Kidney (right and left) Not more than 30% of the total volume can receive ≥18 Gy. For 3D conformal plans in patients with two normally functioning kidneys, at least 50% of the right kidney and at least 65% of the left kidney must receive <18 Gy. For IMRT planning, mean dose to bilateral kidneys must be <18 Gy. If only one kidney is present, not more than 15% of the volume of that kidney can receive ≥18 Gy and not more than 30% can receive ≥14 Gy. Stomach , duodenu m, jejunum Max dose 55 Gy. <15% of the volume of each organ can receive between 45 and 49.99 Gy. Liver Mean dose cannot exceed 30 Gy. Mean liver dose must be ≤25 Gy. Spinal cord Max dose to a volume of at least 0.03 cc must be ≤45 Gy. Max dose ≤45 Gy. Organs at Risk
  • 40. • The CONKO 001 trial demonstrated significant improvements in DFS and OS with use of postoperative gemcitabine as adjuvant chemotherapy versus observation in resectable pancreatic adenocarcinoma. • ESPAC-3 study results showed no significant difference in OS between 5-FU/leucovorin versus gemcitabine following surgery. When the groups receiving adjuvant 5-FU/leucovorin and adjuvant gemcitabine were compared, median survival was 23.0 months and 23.6 months, respectively. • Data from ESPAC-4 support the use of gemcitabine combined with capecitabine (1,660 mg/m2/day days 1–21 every 4 weeks) with superiority demonstrated compared to gemcitabine alone (HR, 0.82; 95% CI, 0.68, 0.98; P = .032).3 • No significant differences were observed in the RTOG 97-04 study comparing pre- and post-chemoradiation 5-FU with pre- and post- chemoradiation gemcitabine for postoperative adjuvant treatment.4
  • 41. Historical Prospective Studies The gastrointestinal tumor study group (GITSG) • Multicenter prospective trial • Resected pancreatic cancer and negative surgical margins, • Forty-three patients • Randomized to observation or CRT to 40 gy delivered in split- course fashion with concurrent 5- fluorouracil (5-FU) (500 mg/m2) as an intravenous bolus on the first 3 and last 3 days of radiation, followed by maintenance weekly 5-FU for 2 years or until disease progression.
  • 42. • European Organisation for Research and Treatment of Cancer (EORTC) • Two hundred eighteen patients with resected pancreas or periampullary cancers • Randomly assigned to observation or CRT to 40 Gy in a split-dose fashion with concurrent continuous infusional 5-FU (25 mg/kg) without further adjuvant chemotherapy
  • 43. • European trial conducted by the European Study Group for Pancreatic Cancer (ESPAC) “Macroscopically” resected pancreatic cancers. • Treating physicians were allowed to enroll patients into one of three parallel randomized studies:  Chemoradiation versus no chemoradiation 20Gy over 2 weeks with 5-FU (500 mg/m2) on days 1 through 3, then repeated after a 2- week break.  Chemotherapy versus no chemotherapy bolus 5-FU(425 mg/m2) and leucovorin (20 mg/m2) given for 5 days every 28 days for 6 cycles.  A 2-by-2 factorial design of 285 patients enrolled on chemoradiotherapy, chemotherapy, chemoradiotherapy with maintenance chemotherapy, or observation.
  • 44. • No survival difference between the patients who received adjuvant chemoradiation and the patients who did not receive therapy (median survival, 15.5 vs. 16.1 months; P=.24). • In the chemotherapy arm, however, a 35% reduction in death was seen in the group who received adjuvant chemotherapy compared with those who received no chemotherapy, with a difference in median survival of 19.7 versus 14 months (P = .0005). • On further follow-up of patients randomized using the 2-by-2 factorial design, the 5-year survival rate for the patients who received chemotherapy was 21% versus 8% for those who did not. • Additionally, adjuvant CTRT was associated with a deleterious effect on survival
  • 45. • A common critique of the aforementioned trials: Lack of restaging to evaluate for the presence of persistent or metastatic disease after surgical resection and prior to the initiation of adjuvant therapy. The time between initial staging and the commencement of adjuvant treatment was sometimes as long as 3 to 4 months, during which a significant number of patients would be expected to develop radiographically apparent metastases. Without interval restaging, these patients may inappropriately receive CRT
  • 46. Modern Studies Adjuvant Systemic Therapy • Conko Three hundred sixty-eight patients were enrolled on the charite onkologie (conko) trial Randomized to: • Observation or • Adjuvant gemcitabine (1,000 mg/m2 intravenous days 1, 8, and 15 every 4 weeks for 6 months). The primary end point was dfs, and patients treated with gemcitabine achieved a statistically significantly longer dfs (14.2 vs. 7.5 months) than those observed after surgery. • This improvement was seen in both the r0 and r1 subgroups.
  • 47. Espac-3 Largest randomized controlled trial in pancreatic cancer to date, • Enrolled 1,088 patients with pancreatic adenocarcinoma who underwent R0 or R1 resection. Patients were randomly assigned to : • 6 cycles of adjuvant gemcitabine (3 weekly infusions of 1,000 mg/m2) or • 6 cycles of bolus 5-FU (425 mg/m2)/leucovorin (LV) (20 mg/m2). • Patients receiving 5-fu/lv experienced significantly higher rates of grade 3 or 4 gastrointestinal toxicity (stomatitis and diarrhea), whereas patients receiving gemcitabine experienced significantly higher rates of grade 3 or 4 hematologic toxicity. • At a median follow-up of 34.2 months, there was no difference between the two groups in the primary end point of OS
  • 48. ESPAC-4 trial Randomized patients with resected pancreatic cancer to: • Gemcitabine alone versus • Gemcitabine/capecitabine. Primary end point of overall survival. The median survival for patients receiving adjuvant gemcitabine and capecitabine was 28 months compared to 25.5 months in the gemcitabine-alone arm. Estimated overall survival was Gemcitabine group: 80.5% at 12 months and 52.1% at 24 months Gemcitabine plus capecitabine group : 84.1% at 12 months and 53.8% at 24 months.
  • 49. Modern Studies: Adjuvant Chemoradiation Rtog/gastrointestinal intergroup trial 9704 Phase iii randomized study Comparing adjuvant 5- fu–based chemotherapy to gemcitabine-based chemotherapy, with both regimens followed by CRT. Four hundred fifty-one patients with resected pancreatic cancer were randomized to • Continuous infusion 5-fu (250 mg/m2/d) • Or gemcitabine (1,000 mg/m2 weekly) for 3 weeks prior to CRT and 12 weeks after CRT. Crt in both groups consisted of 50.4 gy delivered with continuous Infusion 5-FU (250 mg/m2/d)
  • 50. Median and 5-year OS rates Pancreatic head tumors of 20.5 months and 22% in those who received Gemcitabine, Compared with 17.2 months and 18% in those who received 5-FU. On multivariate analysis, in the subgroup of patients with pancreatic head lesions who received gemcitabine, there was a non significant trend toward improved os (p = .08). A secondary aim of rtog-9704 was to assess the ability of postresection CA19-9 levels to predict survival. When ca19-9 levels were analyzed in a cohort of 385 patients as a dichotomized variable (<180 iu/ml vs. ≥180 IU/ml, ≤90 IU/ml vs. >90 IU/ml), Significant survival difference favoring patients with CA19-9 levels of <180 IU/ml. This corresponded to a 72% reduction in the risk of death
  • 51. Neoadjuvant Chemoradiation No phase III randomized trials of neoadjuvant CRT in resectable pancreatic lesions have been conducted vast majority of data come from phase II and retrospective studies A review of the Surveillance, Epidemiology, and End Results (SEER) database supports the use of neoadjuvant treatment. This analysis included 3,885 patients treated for resectable pancreatic cancer: • 70 patients (2%) received neoadjuvant EBRT, • 1,478 (38%) received adjuvant EBRT, • 2,337 (60%) weretreated with surgery alone. Median OS was • 23 months in patients receiving neoadjuvant EBRT, • 17 months with adjuvant EBRT, • 12 months in the surgery-alone cohort.
  • 53. • Some specific differences in treatment: In functioning PanNETs, • Octreotide is usually recommended prior to biopsy or surgery • but is generally avoided in insulinomas to avoid profound hypoglycemia PanNETs in Multiple endocrine neoplasia type 1 are often multiple, and thus require different treatment and surveillance strategies. Chemotherapy: Combinations of several medicines have been used, such as doxorubicin with streptozocin and fluorouracil (5-FU) and capecitabine with temozolomide. Targeted therapy : Everolimus and Sunitinib : for treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease.