ChemoRadiotherapy after Induction

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ChemoRadiotherapy after Induction ChemoTherapy
in Cancer of the Stomach CRITICS study A
multicenter randomized phase III trial of
neo-adjuvant chemotherapy followed by surgery and
chemotherapy or by surgery and chemoradiotherapy
in resectable gastric cancer
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Topics

• Epidemiology
• Surgery
• Postoperative chemo or radiotherapy
• Preoperative radiotherapy
• Postoperative chemoradiotherapy
• NKI-AVL Phase I-II studies
• Perioperative chemotherapy
• CRITICS

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Epidemiology of Gastric Cancer

• USA gt25.000 cases/year 16.000 deaths
• The Netherlands gt2000 cases/yr 1000 deaths
• 2nd cause of cancer death worldwide
• 3rd cause (after lung and colorectal) of cancer
  death in Europe (138.000/yr)
• Distal cancers decreasing tumors of cardia or
  esophago-gastric junction increasing
• 65 T3-T4 85 N 30 liver metastases

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Topics

• Epidemiology
• Surgery
• Postoperative chemo or radiotherapy
• Preoperative radiotherapy
• Postoperative chemoradiotherapy
• NKI-AVL Phase I-II studies
• Perioperative chemotherapy
• CRITICS

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Gastric Cancer SurgerySurvival US vs. Japanese
Centers
Maruyama et al., World J Surg 198711418-25
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Sites of Failure after Curative Resection
Local Regional (total) 88 Distant
(only) 25 Local / Regional (only) 54
Adapted from Gunderson et al. 1981 Smalley et
al, IJROBP 2002
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How extensive should surgery be?

• Goal of gastric cancer treatment is a R0
  resection
• D1 resection involved part of stomach lesser
  and greater omenta (incl. nodes along lesser and
  greater curvature)
• D2 resection D1 plus transverse mesocolon,
  spleen, tail of pancreas and nodes along left
  gastric artery, common hepatic artery, celiac
  artery and splenic artery

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Lymphatic drainage of the stomach
N1
N2
Hartgrink et al. JCO 2004
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D1 vs D2 Updated results
Lancet 1995, N Eng J Med 1999, J Clin Oncol 2004
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D1 vs D2 Survival
Lancet 1995, N Eng J Med 1999, J Clin Oncol 2004
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D1 vs D2 Relapse Risk
Hartgrink et al. JCO 2004
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D1 vs D2 Prognostic FactorsAge (n711)
Hartgrink et al. JCO 2004
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Survival after splenec-/pancreatectomy Median FUP
11 years
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D1 vs D2 Results without splenectomy
D1 D2 p-value Morbidity
() 23 35 0.001 Mortality () 3.8 6.3 NS
Survival mean (yrs) 5.77 6.67 0.018 5
year () 47 56 7 year () 42 52 11 year
() 33 47
Courtesy C.J.H. van de Velde
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D1 vs D2 Lymph node dissection Survival
according to N-stage
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Comparison Dutch and MRC trial
Bonenkamp JJ et al. Lancet 1995, Cushieri A
et al. Lancet 1996
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Summary 1/3

• Surgery is the primary curative treatment of
  gastric cancer
• Total gastrectomy shows no survival benefit over
  partial gastrectomy (unless proximal
  location/diffuse subtype)
• Following curative resection the incidence of
  locoregional recurrences is high

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Summary 2/3

• Extended lymph node dissection provides no
  survival advantage over D1 dissection
• D2 lymph node dissection is associated with
  higher morbidity and mortality
• Morbidity and mortality are greatly influenced by
  the extent of lymph node dissection,
  pancreatectomy/splenectomy, age, gender and
  experience/volume of surgical department
• For N2 disease, an extended lymph node dissection
  may offer cure females may benefit from D2
  resection

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Summary 3/3

• AJCC and UICC recommend analysis of ?15 lymph
  nodes for accurate staging (18 of US patients
  have ?15 lymph nodes analyzed)

Hundahl, Cancer 2000
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Conclusions Type of Surgery

• The treatment of choice for resectable gastric
  cancer anno 2005 is D1 surgery
• Subtotal gastrectomy without pancreatico-splenecto
  my
• Dissection of ?15 lymph nodes (D1 plus) for
  accurate staging
• Whether/which adjuvant therapy offers a benefit
  after adequate surgery should be tested in
  randomized trials with standardized surgery and
  pathology, optimal chemotherapy and
  state-of-the-art radiotherapy
• New predictive tests should identify patients
  that would benefit from tailored adjuvant therapy

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Adjuvant strategies in gastric cancer

• postoperative chemotherapy
• postoperative radiotherapy
• postoperative chemoradiotherapy
• preoperative radiotherapy
• preoperative chemotherapy
• preoperative chemoradiotherapy

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Topics

• Epidemiology
• Surgery
• Postoperative chemo or radiotherapy
• Preoperative radiotherapy
• Postoperative chemoradiotherapy
• NKI-AVL Phase I-II studies
• Perioperative chemotherapy
• CRITICS

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British Stomach Cancer Group Trial Adjuvant
radiotherapy / chemotherapy in resectable gastric
cancer
Hallissey et al, Lancet 1994
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Adjuvant Chemotherapy vs SurgeryOdds ratios for
13 chemotherapy regimens (n2096)
Hermans et al, JCO 1993
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Adjuvant chemotherapy for resectable gastric
cancer

• 5 published meta-analyses (Hermans 1993, Earle
  1999, Mari 2000, Janunger 2002, Panzini 2002)
• Combined data indicate a small, non- or
  borderline statistically significant survival
  benefit 3-5
• No large phase III trials
• Modern chemotherapeutic regimens are lacking

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Topics

• Epidemiology
• Surgery
• Postoperative chemo or radiotherapy
• Preoperative radiotherapy
• Postoperative chemoradiotherapy
• NKI-AVL Phase I-II studies
• Perioperative chemotherapy
• CRITICS

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Preoperative Radiotherapy40 Gy surgery vs
surgery alone (n370)
5 yr OS 19.8 vs. 30.1 plt0.01
Zhang et al (IJROBP, 1998)
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SWOG Intergroup 0116 Gastric Surgical Adjuvant
Trial

• Inclusion criteria
• stage Ib-IVM0
• adenocarcinoma of stomach or gastro-esophageal
  junction
• (macroscopic) complete resection of tumor
• WHO ? 2
• caloric intake gt 1500 kcal (oral or enterostomal)
• Surgery D2 recommended 54 D0 resection
• Randomization
• surgery only (n275)
• surgery chemoradiotherapy (n281)

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SWOG Intergroup 0116 Trial Design

• Chemotherapy
• 5-FU(425 mg/m2)/LV (20 mg/m2) d1-5
• Chemo-radiotherapy
• d28 start
• 45 Gy/25 fx
• plus 5-FU (400 mg/m2) / LV (20 mg/m2)
• first 4 days and last 3 days
• Chemotherapy
• 2 cycles 5-FU (425 mg/m2)/LV (20 mg/m2) 5d
• 1 and 2 months after chemo-radiotherapy

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SWOG Intergroup 0116 TrialRadiotherapy

• Target volume consisted of tumor bed, regional
  nodes and 2 cm beyond proximal and distal margins
  of resection
• Tumor bed based on pre-op CT, barium X-rays,
  surgical clips
• Proximal T3 tumors left hemidiaphragm included
• Perigastric, celiac, local para-aortic, splenic,
  hepatoduodenal and pancreatico-duodenal nodes
  were included
• At least 2/3 of one kidney was spared

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SWOG Intergroup 0116 TrialResults 1
Overall survival Relapse-free survival
p0.005
plt0.001
Median 27 vs. 36 19 vs. 30 (months) NEJM
26 vs. 35 19 vs. 30 (months) update 3-yr 41
vs. 50 31 vs. 48 ()
Mcdonald et al, NEJM 2001, ASCO GI 2004
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SWOG Intergroup 0116 TrialResults 2
Mcdonald et al, NEJM 2001
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SWOG Intergroup 0116 TrialConclusions

• Only 10 underwent the advised D2 dissection
• Randomization was after surgery
• 34 had major radiation treatment plan deviation
• According to present standard, chemotherapy was
  suboptimal and the interaction with radiation
  limited
• 64 completed postoperative therapy
• No data on late toxicity provided

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Effect of postoperative chemoradiation

• 54 D0 effect
• 36 D1 effect
• 10 D2 no effect

John S. Macdonald. World Congress on
Gastro-Intestinal Cancer, 16-19 June 2004,
Barcelona, Spain
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Role of adjuvant chemoradiotherapy in D2-resected
gastric cancer patients

• Observational study
• n544 postoperative CRT (INT-0116) after
  curative D2 resection
• n446 surgery only
• Median duration of
• OS 95.3 vs. 62.6 months (p0.02)
• DFS 75.6 vs. 52.7 months (plt0.02)

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Role of adjuvant chemoradiotherapy in D2-resected
gastric cancer patients
Kim et al.(IJROBP, 2005)
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Topics

• Epidemiology
• Surgery
• Postoperative chemo or radiotherapy
• Preoperative radiotherapy
• Postoperative chemoradiotherapy
• NKI-AVL Phase I-II studies
• Perioperative chemotherapy
• CRITICS

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Protocol I N02RCA

• Postoperative chemo-radiotherapy after surgical
  resection of gastric and esophageal cancer
• A single institution phase I-II dose-finding
  study of a fixed radiotherapy regimen with
  dose-escalation of a chemotherapy regimen of
  cisplatin and capecitabine

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Protocol II M02PCR

• Postoperative chemo-radiotherapy after surgical
  resection of gastric and esophageal cancer
• A multicenter phase I-II study of a fixed
  radiotherapy regimen with concurrent chemotherapy
  with escalating doses of capecitabine

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Local Recurrence
Oppedijk et al ASTRO 2006
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Topics

• Epidemiology
• Surgery
• Postoperative chemo or radiotherapy
• Preoperative radiotherapy
• Postoperative chemoradiotherapy
• NKI-AVL Phase I-II studies
• Perioperative chemotherapy
• CRITICS

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Magic Trial
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Magic TrialDesign

• Median FU survivors gt 3 yrs
• 90 or gt 2 yrs FU

Cunningham ASCO 2005
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Magic TrialPathologic staging following surgery
Cunningham NEJM 2006
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Magic TrialOverall survival
Cunningham NEJM 2006
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Magic TrialConclusions

• Perioperative chemotherapy in resectable
  carcinoma of the stomach and distal esophagus
  results in
• Tumor downsizing and downstaging
• Increased PFS
• Increased OS

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Topics

• Epidemiology
• Surgery
• Postoperative chemo or radiotherapy
• Preoperative radiotherapy
• Postoperative chemoradiotherapy
• NKI-AVL Phase I-II studies
• Perioperative chemotherapy
• CRITICS

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REAL-2Design

• UK NCRI cooperative group study
• 63 centres mostly UK, 2 Australian

Epirubicin Cisplatin 5FU
Locally advanced or metastatic oesophago gastric
cancer (chemonaive)
Epirubicin Cisplatin Capecitabine
Epirubicin Oxaliplatin 5FU
Epirubicin Oxaliplatin Capecitabine

• Stratified for
• Centre
• Locally advanced vs metastatic
• PS 0/1 vs 2

Cunningham ASCO 2006
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Fluoropyrimidine comparisionOverall survival
(per-protocol)
HR for ITT population 0.88 (0.77 1.00) p
0.058
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Platinum comparisionOverall survival
(per-protocol)
HR for ITT population 0.91 (0.79-1.04) p0.159
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REAL-2 Conclusions

• The primary objective of the trial was met
• Capecitabine is not inferior to 5-FU
• Oxaliplatin is not inferior to Cisplatin
• In these triplet regimens
• Capecitabine could replace PVI 5-FU
• Oxaliplatin could replace Cisplatin
• The use of EOX is associated with improved
  efficacy over ECF

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XP vs. FP in advanced gastric cancerDesign
Kang, ASCO 2006
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XP vs. FP in advanced gastric cancerPrimary
endpoint met progression-free survival HR 0.81
Per protocol analysis
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XP vs. FP in advanced gastric cancerSuperior
response rate with XP vs. FP
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XP vs. FP in advanced gastric cancerConclusion

• XP can be a new standard chemotherapy in AGC
• Primary objective met (non-inferiority of XP vs.
  FP for PFS)
• OS results support primary analysis
• Independent review confirmed the results
• XP curve clearly above FP
• Response rate superior with XP vs. FP
• Multivariate and subgroup analyses confirm
  results
• Similar favorable safety of XP vs. FP
• XP avoids inconvenience and complications
  associated with infusional 5-FU

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CRITICS Protocol and Trial Logistics

• Protocol
• Participating hospitals
• Local approval
• Local initiation
• Randomisation procedure
• Case Report Forms
• Tissue collection
• Financial support

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CRITICSDesign
Preoperative chemotherapy 3x ECC q 3 wks
3x ECC q 3 wks
D1 surgery
QoL
R
Preoperative chemotherapy 3x ECC q 3 wks
D1 surgery
Chemoradiation
Tissue banking
³
MAGIC(3xECC)
15
Lymph nodes
45 Gy/25
fx

no
splenectomy
capecitabine bid
Epirubicine
/
Cisplatin
/Capecitabine
cisplatin weekly
3D
-
CRT/IMRT

• Stratified for
• Centre
• Histological type
• Localisation of tumour

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Chemotherapy (ECC)

• Epirubicine 50 mg/m2 i.v. (3 weekly x3) on day 1
• Cisplatin 60 mg/m2 i.v. (3 weekly x3) on day 1
• Capecitabine 1000 mg/m2 orally bid on day 1-14
  (3 weekly x3)

Chemotherapy (CRT)

• Cisplatin 20 mg/m2 i.v. on day 1 (weekly x5)
• Capecitabine 575 mg/m2 bid orally on each day
  of RT

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CRITICSDesign
Preoperative chemotherapy 3x ECC q 3 wks
3x ECC q 3 wks
D1 surgery
QoL
R
Preoperative chemotherapy 3x ECC q 3 wks
D1 surgery
Chemoradiation
Tissue banking
³
MAGIC(3xECC)
15
Lymph nodes
45 Gy/25
fx

no
splenectomy
capecitabine bid
Epirubicine
/
Cisplatin
/Capecitabine
cisplatin weekly
3D
-
CRT/IMRT

• Stratified for
• Centre
• Histological type
• Localisation of tumour

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CRITICS Radiotherapy

• Clinical Target Volume (CTV) is based on
• type of surgery (partial or total gastrectomy)
• anastomosis and stumps
• gastric remnant
• regional lymph nodes

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CRITICS Anastomosis and stumpsRoux-en-Y
oesphagojejunal anastomosis
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CRITICS Anastomosis and stumpsRoux-en-Y
oesphagojejunal anastomosis

• Duodenal stump has to be treated in tumors of the
  distal stomach
• For tumors of the proximal stomach or
  GE-junction, the oesophagojejunal anastomosis has
  to be treated
• Cave for GE-junction tumors a margin of 4cm (!)
  of oesophagus (paraoesophageal nodes) has to be
  included in the CTV

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CRITICS Gastric remnant and tumor bed

• GE and proximal tumors at least medial
  hemidiaphragm
• T1-2 tumors tumor bed not necessarily
• Hepatogastric ligament (i.e. part of lesser
  omentum between liver and lesser curvature, which
  contains peri-gastric nodes)
• Anterior abdominal wall (?) (only T3-4 tumors)

HGL
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CRITICS Regional lymph nodesJapanese
classification

• right cardial nodes
• left cardial nodes
• nodes along the lesser curvature
• nodes along the greater curvature
• suprapyloric nodes
• infrapyloric nodes
• nodes along the left gastric artery
• nodes along the common hepatic artery
• nodes around the celiac axis
• nodes at the splenic hilus
• nodes along the splenic artery
• nodes in the hepatoduodenale ligament
• nodes at the posterior aspect of the pancreas
  head
• nodes at the root of the mesenterium
• nodes in the mesocolon of the transverse colon
• para-aortic nodes

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CRITICS Regional lymph nodesWhich lymph nodes
have to be included in the CTV?
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CRITICS Regional lymph nodesWhich lymph nodes
have to be included in the CTV?

• pN0 after adequate (gt15 lnn) D1/D2 dissection ??
• Individualize for GE, cardia, fundus and antrum
  tumors
• GE-junction paraoesophageal, perigastric,
  hepatogastro lig, celiac stations 1-67-911-12
• Cardia/proximal 1/3 perigastric, celiac, splenic
  hilum, supra-pancreatic (if extensive nodal
  involvement also porta hepatis,
  pancreaticoduodenal and paraoesophageal)
  stations 3-11
• Body/middle 1/3 perigastric, celiac, splenic
  hilum, supra-pancreatic, porta hepatis,
  pancreaticoduodenal stations 1-13
• Antrum/distal 1/3 perigastric,
  pancreaticoduodenal, porta hepatis, celiac,
  suprapancreatic (if extensive nodal involvement
  also splenic hilum) stations 3-912-13
• all combinations

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CRITICS Pathology

• Diagnostic protocol
• According to NVVP guidelines
• Correlation of histopathological characteristics
  with clinical data
• Biobanking
• Correlation of molecular characteristics with
  clinical data

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CRITICS Macroscopy

• Description of specimen
• Partial or complete gastrectomy
• Other organs present
• Length greater curvature
• Length lesser curvature
• Size of omentum major / minus
• Open specimen along greater curvature

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CRITICS Macroscopy

• Tumor
• Localisation
• Aspect
• Size
• Surgical margins
• Depth of invasion
• Serosa at site of tumor
• Mucosa

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Intestinal Type (1)
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Intestinal Type (2)
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Intestinal Type (3)
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Diffuse Type (1)
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Diffuse Type (2)
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Diffuse Type (3)
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CRITICS Macroscopy

• Lymph nodes
• Number of lymph nodes (greater and lesser
  curvature, marked by surgeon)
• Number of positive lymph nodes

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CRITICS Blocks

• Diagnostic purposes
• At least 2x tumor (deepest invasion, junction
  tumor-normal mucosa)
• Both surgical margins
• Junction esophagus/stomoch for diagnosis of
  Barrett carcinoma (in case of proximal tumor)
• At least 1x omentum
• All lymph nodes
• Frozen tissue (tumor and normal mucosa)

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CRITICS Biobanking

• When tumor size allows
• Fresh
• 1 container with vital tumor in liquid nitrogen
• 1 container with normal mucosa in liquid nitrogen
• After fixation
• 1 paraffin block with vital tumor tissue
• 1 paraffin block with normal gastric wall (incl.
  musc. propria)
• Register duration of fixation

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CRITICS Microscopy

• Tumor type (WHO)
• Depth of invasion
• Angioinvasion
• Surgical margins
• Serosal surface
• Other mucosal abnormalities
• Regional lymph nodes
• Marked lymh nodes

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CRITICS Pathology conclusion

• Tumor type
• Grade of differentiation
• Localisation
• Size
• Depth of invasion
• Surgical mucosal margins

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CRITICS Pathology Summary

• Diagnostic protocol
• According to NVVP guidelines
• Correlation of histopathological characteristics
  with clinical data
• Biobanking
• Correlation of molecular characteristics with
  clinical data

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CRITICS Kidney functionRenography
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CRITICS Kidney function Worsening of (left)
kidney function after AP-PA RT
Pre RT
T7m
T12m
L
T18m
T29m
T36m
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IMRT Gastric Cancer
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CRITICS Kidney and Liver functions

• In order to preserve kidney and liver function,
  IMRT or at least 3-D CT-based conformal RT is
  mandatory
• Pre- and postop CT-scanning
• Pre RT renography
• At least 2/3 of one kidney should receive lt 18 Gy
  (40)
• Mean liver dose lt 30 Gy
• Epid or conebeam verification

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CRITICS ObjectivesPrimary
To assess whether postoperative chemoradiotherapy
prolongs overall survival compared to
postoperative chemotherapy in patients that have
had adequate stomach surgery following
preoperative chemotherapy
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CRITICS ObjectivesSecondary

• To assess whether postoperative chemoradiotherapy
  prolongs disease free survival compared to
  postoperative chemotherapy in patients that have
  had adequate stomach surgery following
  preoperative chemotherapy
• To assess the toxicity profile of both
  preoperative and postoperative chemotherapy and
  postoperative chemoradiotherapy
• To collect tissue and serum before treatment for
  genomic profiling and proteomics to detect tumor
  recurrence risk patterns in gastric cancer
• To determine a genomic profile and classifier to
  predict response to therapy
• To assess the value of Maruyama-index and
  predictive nomograms for disease recurrence
  (3940)
• To compare health-related quality of life (HRQL)
  of both treatment regimens

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CRITICS Inclusion criteria 1/2

• Ib-IVa (no distant metastases) gastric cancer
  (histologically proven) tumor bulk has to be in
  the stomach but may involve gastro-esophageal
  junction
• WHO lt 2
• Age 18 yrs
• Operable gastric cancer
• No prior abdominal radiotherapy or chemotherapy
• Hematology Hb ? 5.0 mmol/l leukocytes ?
  3.0x109/l, neutrophils ? 1.5x109/l, thrombocytes
  ? 100 x 109/l
• Renal function serum creatinine 1.25 ULN,
  creatinine clearance ? 60 ml/min (measured, or
  calculated by Cockcroft and Gault formula) and
  urinary excretion of ? 1.0 gram protein/24
  hours

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CRITICS Inclusion criteria 2/2

• Liver function total bilirubin ?1.5x ULN,
  Alkaline phosphatase and ASAT/ALAT 3x ULN
• Left ventricular ejection fraction gt 50
• Tumornegative laparoscopy when CT suggests
  peritoneal carcinomatosis
• Start treatment within 10 working days after
  registration
• Written informed consent
• Expected adequacy of follow-up

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CRITICS Exclusion criteria 1/2

• T1N0 disease (endoscopic ultrasound)
• Distant metastases
• Inoperable patients (due to technical
  surgery-related factors or general condition)
• Previous malignancy (except adequately treated
  non-melanoma skin cancer or in-situ cancer of the
  cervix uteri)
• Solitary functioning kidney that will be within
  the radiation field
• Major surgery within 4 weeks prior to study
  treatment start, or lack of complete recovery
  from the effects of major surgery
• Uncontrolled (bacterial) infections

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CRITICS Exclusion criteria 1/2

• Significant concomitant diseases preventing the
  safe administration of study drugs or likely to
  interfere with study assessments
• Uncontrolled angina pectoris, cardiac failure or
  clinically significant arrhytmias
• Continuous use of immunosuppressive agents
• Concurrent use of the antiviral agent sorivudine
  or chemically related analogues, such as
  brivudine
• Hearing loss gt CTC grade 1
• Neurotoxicity gt CTC grade 1
• Pregnancy or breast feeding
• Patients (M/F) with reproductive potential not
  implementing adequate contraceptive measures

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CRITICS Statistics

• Assumptions
• 5 year overall survival 40 in standard arm and
  50 in experimental arm
• 10 drop out due to progressive disease
• 10 loss to follow-up
• 4 year accrual
• 3 year follow-up
• 80 power, significance level 5 (2-tailed)
• 430 events required, HR experimental arm 0.76
• 788 patients needed
• 197 yearly accrual

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CRITICS Interim analysis

• After 215 events
• First analysis, alpha level 0.003
• Second analysis, alpha level 0.047
• Overall alpha 0.05

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Requirements Treatment and Follow-up
chemotherapy-surgery-chemotherapy arm
Q 6 months until 5 years, yearly
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Requirements Treatment and Follow-up
chemotherapy-surgery-chemoradiotherapy arm
Q 6 months until 5 years, yearly
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Local approvalInsurance

• Central insurance Gerling Allgemeine
  Versicherungs AG
• Amsterdam
• ? 020 - 54 92 213

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Local approvalSupport

• Raymond Schmidt Consultancy
• Dr. A. Ariensstraat 45
• 7221 CB Steenderen
• ? 0575 441 001
• ? 0575 441 045
• ? rsc_at_rsconsultancy.nl
• After receipt of the FAX form RSC will contact
  you

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Randomisation procedure

• Via Datacenter of the Dept. of Surgery, LUMC
• ? 071 526 3500
• Monday-Friday, 900 1700 uur

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Randomisation procedure
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Serious Adverse Event reports

• Directly to AvL
• Within 24 hours

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Tissue Collection

• Optional
• Patient gives separate informed consent
• Approved by central METC
• Special pathology handbook /sheet

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Financial Support
No investigator fee..
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Organization

• Principal investigators
• Professor M. Verheij, radiation oncologist, AvL
• E.P.M. Jansen, radiation oncologist, AvL
• Professor C.J.H. van de Velde, surgeon, LUMC
• H. Boot, gastroenterologist, AvL
• A. Cats, gastroenterologist/medical oncologist,
  AvL
• Professor G.A. Meijer, pathologist, VUMC
• Professor N.K. Aaronson, quality of life, AvL
• H. Putter, statistician, LUMC
• E. Meershoek Klein Kranenbarg, datacenter, LUMC