Induction Chemotherapy followed by Consolidative Chemoradiation in patients with Locally Advanced, U

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Induction Chemotherapy followed by Consolidative
Chemoradiation in patients with Locally Advanced,
Unresectable Pancreatic Cancer

• By Abhilasha (Abby) Patel
• MS IV
• University of Texas Medical Branch
• OHSU clinical rotation

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Case Presentation

• Patient OA 61 y.o. Hispanic female
• Presented to OSH for 2 month hx of diarrhea,
  jaundice, weight loss and dehydration
• LFTs elevated and US showed abdominal mass.
• CT enlargement of head of pancreas, biliary tree
  dilatation ? stent placed biopsy
• Bx moderately differentiated adenocarcinoma of
  the pancreas
• Referred to your center for further evaluation

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HP

• PMHx HTN, dyslipidemia, obesity, PVD, DM2
• FHx Sister died of breast cancer, aunt died of
  lung cancer
• SHx widow, homemaker, no hx of smoking, OH, or
  drug use.
• ROS 12lb weight loss in one month and fatigue.
  Denied pain, diarrhea, change in stool or urine
  color, jaundice.
• PE unremarkable

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CT

• Confirmed mass (2.6 X 2.5 cm) in the uncinate
  process, abutting SMA, mass effect on SMV and
  portal confluence, regional lymphadenopathy
  (1.4-cm porta caval node and smaller suspicious
  nodes along the hepatic artery, left gastric
  artery, and gastro-epiploic vessels)

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Case Presentation

• Outside pathology specimen confirmed to be
  invasive, moderately differentiated pancreatic
  ductal adenocarcinoma
• CA 19-9 107, LFTs normal
• Staged T3N1M0

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Pancreatic Cancer

• 10th most common cancer.
• 4th leading cause of cancer death in men and
  women.
• Incidence peaks in 7th and 8th decade. Rare
  before age 40.
• 2008
• 37,680 new cases
• 34,290 deaths

Jemal et al. Cancer Statistics 2008. CA Cancer J
Clin 2008 5871-96
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Risk factors

• smoking
• age
• gender (MF)
• race
• family history
• b-naphthylamine, benzidine, pesticides, dyes

• chronic pancreatitis
• diabetes mellitus
• prior gastric surgery
• obesity
• high fat diet

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Detection

• No tests are recommended for screening the
  general population
• Often called the silent disease because it
  usually doesnt cause symptoms in early stages

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Sign Symptoms

• jaundice
• weight loss
• abdominal pain (epigastric and/or back pain)
• anorexia
• fatigue and weakness

• depression
• floating stools
• nausea and vomiting
• diabetes

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Work-Up

• Labs (LFTs, CBC, electrolytes, tumor markers)
• Spiral CT abdomen
• EGD and EUS with FNA biopsy
• Chest X-ray
• Others as indicated (ERCP, CT chest)

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The Pancreas
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Staging
Tram et al. Diagnosis, Staging, and Surveillance
of Pancreatic Cancer . Am. J. Roentgenol. May
2003 1801311-1323
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Classification

• Pancreas cancer is most commonly classified as
• Resectable (able to be surgically removed)
• Locally Advanced (cancer confined to the area
  around the pancreas, but may not be resectable
  because of extension/invasion into surrounding
  vessels and organs)
• Metastatic (cancer has spread to other organs)

• NCCN criteria for resectability
• Resectable - no distant mets, clear fat plane
  around celiac/SMA, patent SMV
• Borderline Resectable - severe unilateral
  SMV/portal impingement, abut SMA, gastroduodenal
  artery encasement up to hepatic artery, limited
  involvement of IVC, colonic invasion, SMV
  occlusion
• Unresectable - distant mets (including
  celiac/para-aortic), SMA/celiac encasement,
  SMV/portal occlusion, aortic/IVC invasion, SMV
  invasion below transverse mesocolon

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Prognosis

• Most patient have metastatic disease at time of
  diagnosis
• For those seemingly localized disease, high rates
  of occult metastasis
• Median survival with appropriate treatment
• 20 months - resectable
• 10 months - local advanced, unresectable
• 5 months - metastatic

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Therapeutic modalities used in Locally Advanced
Pancreatic Cancer

• Chemotherapy
• Radiation
• Pancreatic enzymes and diabetic medications
• Stents
• Palliative surgery
• Possibly curative surgery following neoadjuvent
  treatment

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Standard of Care

• No universally accepted, standard guidelines for
  treating patients with LAPC
• Use of radiation still controversial

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Background
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Early RT

• In 1960s, EBRT alone had survival 6 months

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RT alone vs. Chemo-RT

• Conclusion Chemo-RT superior to radiation alone.

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Chemo alone vs. Chemo-RT
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E4201 Schema
RANDOMIZE
ARM A CONSOLIDATION GEMCITABINE 1000mg/M2 Once
weekly x 3 weeks Followed by 1 week rest x 5
cycles 1 cycle 4 weeks
ARM A INDUCTION GEMCITABINE 1000mg/M2 Once
weekly x 6 weeks
1 week rest

• Stratify
• PS (0 vs 1)
• Weight loss
• ( 10 vs

ARM B INDUCTION GEMCITABINE 600 mg/M2 Once
weekly x 6 weeks CONCURRENT RT 180 cGy/day 5
days week x 6 weeks Total dose 50.40 Gy
ARM B CONSOLIDATION GEMCITABINE 1000mg/M2 Once
weekly x 3 weeks Followed by 1 week rest x 5
cycles 1 cycle 4 weeks
4 weeks rest
Loehrer et al.
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Endpoints

• Primary
• Overall Survival
• Secondary
• Response Rates
• Progression Free Survival

Loehrer et al.
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Overall Survival
Loehrer et al.
p-value 0.034 Two-Sided, stratified Log rank
GEM plus XRT
GEM
GEM Median Survival 9.2 Months (95 CI 7.8,
11.4) ----------------------- GEM
Radiation Median Survival 11.0 Months (95 CI
8.4, 15.5) -----------------------
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Survival
Loehrer et al.
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Conclusions

• Gemcitabine plus radiation therapy has superior
  survival compared to gemcitabine alone (11.0 mos
  vs. 9.2 mos p0.034)
• Similar PFS and overall response rates
• Toxicity was common but manageable in both arms

Loehrer et al.
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Article

• Induction Chemotherapy Selects Patients with
  Locally Advanced, Unresectable Pancreatic Cancer
  for Optimal Benefit From Consolidative
  Chemoradiation Therapy
• Krishnan et al.
• Cancer 2007 110(1)47-55

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Objective

• to determine whether there were differences in
  outcome for patients with unresectable locally
  advanced pancreatic cancer (LAPC) who received
  treatment with chemoradiation (CR) versus
  induction chemotherapy followed by CR (CCR).

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Methods

• Retrospective study from Dec 1993 to July 2005 -
  323 pts at MDACC
• Locally advanced and unresectable tumors that
  extended to the celiac axis or the SMA or tumors
  that occluded the SMV-portal vein confluence
  based on CT
• No evidence of metastasis
• 247 CR vs. 76 CCR

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Chemotherapy

• Induction chemotherapy consisted of gemcitabine
  based treatment
• Chemoradiation given on average 2.5 months after
  induction chemotherapy
• Chemotherapy with CMT consisted of either 5-FU
  (41), gemcitabine (39) or capecitabine (20)

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Radiation

• 276 pts (85) 30Gy/10fx over 2 wks using 4 field
  technique
• 34 pts (11) 45Gy/25fx with 5.4Gy boost to total
  of 50.4Gy over 5-6 wks

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Endpoints

• Overall Survival
• Progression Free Survival
• Local progression
• Distant progression
• Toxicity
• Predictors

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Results
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All Patients

• Median OS 9.1 months
• Median PFS 5 months
• 1 year estimated OS 28
• 1 year estimated PFS 13

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Overall Survival
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Progression Free Survival
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Local and Distant Progression
No significant difference in the patterns of
failure with the use of induction chemotherapy
Significant difference in the time to failure
with the use of induction chemotherapy (P.003
and P.007 respectively)
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Toxicity

• 1576 (20) developed severe acute toxicity in
  the CCR group
• 1 gemcitabine induced pneumonitis
• Intractable N/V and FTT
• 33247 (13) developed severe acute toxicity in
  the CR group
• 22 of 81 (27) gemcitabine
• 10 of 133 (8) 5-FU
• 1 of 33 capecitabine

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Significant Predictors for Survival Outcomes

• Age
• Sex
• Weight loss
• KPS
• Hgb
• Radiation fractionation
• Concurrent chemotherapy regimen
• Use of induction chemotherapy

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Resectablility

• 9 patients (7 CR, 2 CCR) were able to undergo
  margin-negative resection
• Median OS 29.4 months (5.6 - 63 months)
• Median PFS 20 months (5.6 63 months)

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Conclusion

• The improvement in survival is achieved by
  eliminating patients who have micrometastases
  that progress during the induction phase, thereby
  enriching the population of patients for
  treatment with localized therapy, such as CCR.

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Reasons for induction chemotherapy

• Potential screening tool to select for patients
  who would benefit from CCR
• Eradication of micrometastatic disease
• Shrinkage of tumors thus more likely to respond
  to chemo-RT
• Better drug delivery to untreated, well
  vascularized tumors
• Response to induction chemo may guide choice of
  chemotherapy used with RT
• Better patient compliance

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Limitations

• Retrospective incomplete information
• Inability to assess patients who progressed
  during induction chemo
• Selection biases for treatment
• Unknown confounders

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Strengths

• Large group of patients
• Multidisciplinary team
• Single center

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Future

• Prospective randomized trial
• More effective sequencing and dosing
• Use of new techniques and targeted agents

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Patient OA

• Started on induction chemotherapy
• Imaging showed tumor shrinkage from 2.6 to 2.1 cm
  in largest diameter and CA 19-9 initially
  decreased and has remained stable
• Followed by chemoradiation
• Will reassess with imaging for possible resection
  after CCR.

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Thank you