Landmark trials in chemorthrapy in pancreatic cancer

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Pancreatic cancer
trial's – chemo/rt
related
Department of Surgical Oncology
Centre for Oncology
GRH,Royapettah

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staging
T4 tumour involves celiac axis, superior
mesenteric axis and/or common hepatic
artery, regardless of size

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resectability

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Neoadjuvant Therapy for Resectable
Pancreatic Ductal Adenocarcinoma
• Median survival when resection is performed first is just 18 months.
ARGUMENTS IN FAVOUR OF NEOADJUVANT THERAPY:
1. PDA is a systemic disease in the majority of cases, 80% of patients recur at a distant
site after resection.
2. The most active, multiagent regimens for PDA are best tolerated prior to resection.
3. Roughly 15% to 30% of resected patients experience a significant complication, have a
protracted recovery, or are too frail to receive adjuvant chemotherapy.
4. neoadjuvant therapy allows observance of antitumor response to selected agents, so
ineffective therapies can be abandoned rather than completed as a full treatment course

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SURGERY ( UNITED STATES)
2016

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• n = 69 patients
• Operative resection was in 60 (87%) of the 69 patients.
• A complete pathologic response was observed in 2 (3%)
patients
• 20 (33%) had positive lymph nodes, and the median number of
positive lymph nodes was 2 (IQR 3).
• R0 resections were achieved in 58 (97%) of the 60 patients

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• Additional postoperative adjuvant therapy was administered to
37 (62%) of the 60 patients.
• Median survival of 44.9 months for the 60 patients who
completed all Neo TX and resection compared with 8.1 months
for the 9 patients who were not resected (log rank P < .001).

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ANNALS OF SURGERY-2014

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• Thirty-five of 38 (92%) patients completed neoadjuvant therapy.
• 27 patients underwent tumor resection (resectability rate 71%)
of which 26 initiated adjuvant therapy for a total of 23 patients
(60.5%) who completed all planned therapy.
• The 18-month survival was 63% (24 patients alive).
• The median overall survival for all 38 patients was 27.2 months
(95% CI 17- NA) and the median disease-specific survival was
30.6 months (95% CI 19 - NA).

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Adjuvant triAls – biomarker that
predicts recurrence
• A local predominant pattern was associated with intact SMAD4
expression (7 of 9 cases),
• Whereas a disseminated pattern was associated with absent
SMAD4 expression (16 of 22 cases)
2013

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• Intact SMAD4 may indicate appropriateness for adjuvant
radiation, whereas those patients with absent SMAD4 should
only receive systemic therapy
• Further studies are needed to support this correlation

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Adjuvant triAls

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Gastrointestinal tumor study
group

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• The Gastrointestinal Tumor Study Group (GITSG) trial was the first of the
adjuvant trials and was a small phase III trial
• n = 49
• between 1974 and 1982 (United States).
• Patients in the experimental arm received 40 Gy and Bolus 5-FU was
administered weekly for 2 years as maintenance therapy (500 mg/m2) but
was given daily for the first 3 days of each radiation course.
• chemoradiation conferred superior survival (20 versus 11 months, P = .04).

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European study group for
pancreatic cancer-1 (2004)

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• N=289
• patients were randomized to a complex 2 × 2 study design, with
one of the four groups receiving no treatment.
• Treatment groups included (1) chemoradiation (40 Gy split-
course radiation with bolus 5-FU at 500 mg/m2 on days 1 to 3 of
radiation, followed by chemotherapy (bolus leucovorin at 20
mg/m2 and 5-FU at 425 mg/m2 daily for 5 days, every 28 days for
six cycles)

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• (2) adjuvant chemotherapy only (without
• chemoradiation)
• (3) chemoradiation only (without chemotherapy) and
• (4) no treatment.
• The two groups receiving chemotherapy (groups 1 and 2) had
superior survival as compared to those who did not (20.1 versus
15.5 months, P = .009).

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• When chemoradiation was analyzed separately, the overall
survival rates were 15.9 months with the two chemoradiation
groups (groups 1 and 3) and 17.9 months without
chemoradiation (groups 2 and 4, P = .05; worse with
chemoradiation).
• When patients who received chemotherapy only were excluded
from the no chemoradiation group (leaving just patients in the
observation group), there was still a strong trend toward
improved survival without chemoradiation.

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• This study established chemotherapy alone as an acceptable
standard of care in Europe and other parts of the world
• The results have been widely questioned because of the
challenging study design and because patients received
suboptimal radiation therapy

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Charité Onkologie (CONKO-001)
trial – A german trial

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Ongoing trials
• RTOG0848 – chemotherapy vs chemo + chemoradiation
• GEMCITABINE + nab paclitaxel vs FOLFIRINOX

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Locally advanced pda

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UNIVERSITY OF MICHIGAN–
JOURNAL OF RADIATION
ONCOLOGY 2012

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• The maximal tolerated dose was 55 Gy (2.2 Gy per fraction) in
combination with fixed dose rate gemcitabine (1,000 mg/m).
• Patients had a median survival of 14.8 months, and 24% (12 of
50 patients, a very high rate compared to previous studies)
underwent resection (10 R0 and 2 R1).
• Among resected patients, the median survival was 32 months.

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• A meta-analysis of 182 patients from 10 prospective trials of
borderline resectable patients included 7 studies reporting on
the impact of chemoradiation (with or without chemotherapy)
and 3 on chemotherapy alone
• At restaging following neoadjuvant therapy, 16% of patients
responded to treatment, 69% had stable disease, and 19%
showed progression.

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• The median survival for the cohort was 22.0 months
• Surgical exploration was performed in 69% of patients, and
80% of surgically explored patients were resected. Moreover,
83% of resected specimens had microscopically negative
resection margins.
• Among resected patients, 61% were alive at 1 year and 44%
were alive at 2 years.
• The median survival in this highly selected and favorable group
was 22.0 months.

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Metastatic PDA

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• 861 patients with advanced PDA to receive either gemcitabine/nab-
paclitaxel or gemcitabine alone.
• median overall survival of 8.5 months in the gemcitabine/nab-
paclitaxel arm and 6.7 months in the gemcitabine group (P < .001).
• Progression-free survival rates were 5.5 and 3.7 months,
respectively (P < .001).
• The 1-year overall survival rates were 35% versus 22%,
• and the 2-year overall survival rates were 9% versus 4%,
respectively.

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• Grade 3 or higher toxicities that were more common in the nab-
paclitaxel arm included neutropenia (38% versus 27%), fatigue
(17% versus 7%), and neuropathy (17% versus 1%). Alopecia is
common (50%).
• Given the results of this trial, gemcitabine combined with nab-
paclitaxel has eclipsed gemcitabine plus erlotinib as a standard
of care in the first-line treatment of advanced, unresectable, or
metastatic pancreatic adenocarcinoma.

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The PRODIGE 4/ACCORD 11
study
• Randomized 342 patients with a performance status of ECOG 0 to 1 to
receive FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2,
leucovorin 400 mg/m2, and 5-FU 400 mg/m2 IV bolus followed by 5-FU
2,400 mg/m2 as a 46-hour continuous infusion every 2 weeks) versus
gemcitabine 1,000 mg/m2 weekly for 7 weeks followed by 1 week of rest
and then weekly × 3 every 4 weeks.

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• The FOLFIRINOX group had a median overall survival of 11.1
months compared to 6.8 months in the gemcitabine alone arm
(P < .001).
• Median progression-free survival rates were 6.4 months and 3.3
months (P < .001), respectively.

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• The FOLFIRINOX regimen resulted in substantially more toxicity,
including higher grade 3 and 4 neutropenia (45% versus 21%),
febrile neutropenia (5.4% versus 1.2%), thrombocytopenia
(9.1% versus 3.6%), diarrhea (12.7% versus 1.8%), and sensory
neuropathy (9% versus 0%).
• Despite these significant side effects, only 31% of patients in the
FOLFIRINOX group had a definitive degradation in quality of life,
as compared to 66% in the gemcitabine group. The time to
definitive deterioration was also significantly longer for the
FOLFIRINOX.

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Take home message
• RCT’s are needed to confer benefit of neoadjuvant approach over surgery
1st approach in resectable PDA.
• 6m of adjuvant therapy clearly supported as standard of care for patients
with resectable PDA, but whether chemoradiation is important ? Is an un
answered question, needed further research
• Chemo radiation as neoadjuvant therapy definitely has role in locally
advanced PDA
• Borderline resectable patients favor neoadjuvant therapy over direct
surgery
• Gemcitabine + Nab-paclitaxel or FOLFIRINOX has good results in
metastatic PDA

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