Gastric & Rectal CancerGastric & Rectal CancerD. Genovesi

Radiation Oncology Department CHIETIwww.radioterapia.unich.it

GASTRIC CANCER

GASTRIC CANCER

GASTRIC CANCERTNM Classifications

AJCC

Gastric Cancer: Clinical Case Presentation

PS: 100% (Karnofsky); 68 yrs old; male;

Cardiac stroke 8yrs ago, no other diseases and no drugs at the moment. Endoscopy (17/12/2008): ulcer with free bottom and infiltrated margins at antropyloric region, increased thickness with non crossing stenosis. Contrast CT Thorax+abdomen (01/’09): negative lungs, liver and bones. Increased wall thikcness of gastric antrum (thickness of 2 cm) compatible with Eteroplasy. Concomitant small perivisceral nodes (0.5 cm) Bigger nodes at celiac region (2.1 cm); interaortocaval region (2.1 cm), paraortic region (1 cm). 05/01/’09: Sub-total gastrectomy+limphoadenectomy D2.Histology: Macroscopic: vegetant lesion of 4. 5 cm of antropyloric region at 1 cmfrom distal marginMicroscopic: Carcinoma G3 (70%) and Adenocarcinoma G2 (30%) with entire gastric wall invasion. Free duodenal stump. Free proximal marginM+ of Carcinoma G3 in 1/14 lesser curvature nodes. No M+ in 22 greater curvature. No omental tumour. No M+ in retrocoledocus, retropancreatic, celiac, and left gastric artery nodes. PATHOLOGIC STAGE: p T2 p N1 M0 STAGE II

Key Points

Diagnostic Work-up for Staging

Prognostic Factors

Surgical Treatment

Adjuvant Treatments

Neoadjuvant Treatments

Key Points

Diagnostic Work-up for Staging

Double Contrast Upper G.I.

Barium Radiological Studies

Endoscopy: procedure of choice (8-10 biopsies)

Chest-Abdomen-Pelvic enhanced CT sensitivity 23-56% Early Gastric Cancer; 92-95% in advanced tumors metastatic lymph node: size criterion > 10 mm

Endoscopic Ultrasonography (EUS)

MRI has not achieved clinical importance

CT-PET: investigational procedure

Key Points

Prognostic Factors

Tumor Grading ++

R0; R1; R2 resection (operating procedure) +++

T stage +++

Lymphadenectomy ++++ at least 15 lymph nodes removed and analyzed Japanese Classification: 16 node stations in 3 groups depending on T

T location +++ proximal cancer poorer SVV vs distal cancer

Lymphatic, Venous or Perieneural invasion +++

High CEA levels preop +

Key PointsSurgical Treatment

Total Gastrectomy: proximal or middle third or diffuse T

Total Gastrectomy vs Subtotal Gastrectomy no advantage for distal (antral) Stomach

5 cm free is required for resection margins D1: perigastric LFN along lesser and greater curvatures (1-6)

D2: plus LFN along left gastric artery (7), common hepatic artery (8),

celiac trunk (9), splenic hilus and splenic artery (10, 11)

D3: plus LFN along hepatoduodenal ligament (12), posterior surface

of head of the pancreas (13) and the root of the mesentery (14)

D4: plus LFN paracolic region and abdominal aorta (15, 16)

Key PointsNeoadjuvant Treatments

Preop Chemo: high risk pts (T3-T4; N0-2 M0); feasibility in

Phase II studies (increase R0 rate); improve SVV in 4 Random Trials (ECF schedule); Type 2 Level of Evidence for Stages II-IV

Preop Radiotherapy (RT): benefit in only one random trial

40 Gy+S vs S Further Randomised Trials are required

Key PointsAdjuvant Treatments

Postop Chemo: results often disappointing; poor compliance with multidrugs schedules; small-moderate benefit Type 2 Level of Evidence for Stages II-IV

Postop Radiotherapy (RT): No Benefit Postop ChemoRadiotherapy:

SWOG-INT 116, Stage I-IV, M0; Surgery + Obs vs CT-RT 5FU/L 5yrs OS: 40% vs 28.4% (p<0.001) 5yrs DFS: 31% vs 25% (p<0.001) 36% D1; only 10% D2 Kim et al: IJROBP 63, 2005: clinical benefit in D2 (SVV & DFS) Type 2 Level of Evidence for Stages II-IV

Type II Level of Evidence

Macdonald JS et Al – New Eng J Med -2001Macdonald JS et Al – New Eng J Med -2001

RESULTS

41%41% 48%48%

3 yr OS:3 yr OS:

41%41%

Type III Level of Evidence

OS DFS

Results

Kim IJROBP, 2005

GASTRIC CANCER: EBM for Radiotherapy

Gastric Cancer: Clinical Case Presentation

PS: 100% (Karnofsky); 68 yrs old; male;

Cardiac stroke 8yrs ago, no other diseases and no drugs at the moment. Endoscopy (17/12/2008): ulcer with free bottom and infiltrated margins at antropyloric region, increased thickness with non crossing stenosis. Contrast CT Thorax+abdomen (01/’09): negative lungs, liver and bones. Increased wall thikcness of gastric antrum (thickness of 2 cm) compatible with Eteroplasy. Concomitant small perivisceral nodes (0.5 cm) Bigger nodes at celiac region (2.1 cm); interaortocaval region (2.1 cm), paraortic region (1 cm). 05/01/’09: Sub-total gastrectomy+limphoadenectomy D2.Histology: Macroscopic: vegetant lesion of 4. 5 cm of antropyloric region at 1 cmfrom distal marginMicroscopic: Carcinoma G3 (70%) and Adenocarcinoma G2 (30%) with entire gastric wall invasion. Free duodenal stump. Free proximal marginM+ of Carcinoma G3 in 1/14 lesser curvature nodes. No M+ in 22 greater curvature. No omental tumour. No M+ in retrocoledocus, retropancreatic, celiac, and left gastric artery nodes. PATHOLOGIC STAGE: p T2 p N1 M0 STAGE II

FU-FA(5 gg)

FU-FA(5 gg)

FU-FA(5 gg)

FU-FA(5 gg)

FU-FA(3 gg)

FU-FA(3 gg)

FU-FA(4 gg)

FU-FA(4 gg)

RadiotherapyRadiotherapy

Day 1- Day 28-31 Day 56-58 Day 84-98 Day 112-6

FU-FA(5 gg)

FU-FA(5 gg)

Macdonald JS et Al – New Eng J Med -2001INT-0116

GASTRIC CANCER: Management of our Clinical Case

Ajani JA et Al – JCO - 2005 Ajani JA et Al – JCO - 2005

R0 vs R+ R0 vs R+

pCR pCR

Why preoperative treatments ?Why preoperative treatments ?

RECTAL CANCER

De Carli A., La Vecchia C. – 2002Verdecchia A., Micheli A., Gatta G. – 2002

11.000 – 12.000 new cases/year in Italy

RECTAL CANCER

RECTAL CANCER

RECTAL CANCER

Rectal Cancer: Clinical Case Presentation

PS: 100% (Karnofsky); 62 yrs old; male; no other diseases.

Endoscopy (13/01/2006): ulcerated and vegetant lesion of 6 cm very near to internal anal sphincter

HISTOLOGY: Adenocarcinoma G2. Contrast CT Thorax+abdomen (20/01/’06): negative lungs and liver. Neoplastic lesion which makes the lumen substenotic, presence of some lesions in perirectal adipous tissue.Two nodes of 1 cm in perirectal adipous tissue.

CLINICAL STAGE: c T3 c N1 M0 IIIB STAGE

Key Points

Diagnostic Work-up for Staging

Pathology

Surgical Treatment

Ongoing Research

Radiotherapy and Chemotherapy

Key Points

Diagnostic Work-up for Staging

Endoscopy with biopsies

Endorectal ultrasound: T1 vs T2 tumors vs borderline T3

Multislice-CT is not sufficiently accurate for low tumors CT cannot accurately distinguish LFN+ vs LFN-

Phased Array MRI is highly accurate in StagingDifficulty in differentiation T1 vs T2 vs borderline T3

Circumferential Resection Margin (CRM): MRI is highly accurate for the prediction of CRM

MRI with specific contrast enhanced (USPIO):promising

FDG-PET:disappointing results on N; role in response evaluation

The Circumferential Resection Margin predictivityMRI

Sensitivity: 60-80%; Specificity: 73-100%

T3 with involved mesorectal fascia

Beets-Tan et al. Lancet 2001 357 (9255) 497 - 504Beets-Tan et al. Lancet 2001 357 (9255) 497 - 504

The Value of CRM

Macroscopic assessment of Mesorectal excision

CRM ( cm ) % incomplete < 0.1 43.9 % 0.1 - 0.2 27.8 % 0.2 - 0.5 27.8 % 0.5 - 1.0 12.9 % > 1.0 11.1 %

Criterion for detection of node metastases

No choice but to use the size of lymph nodes as the most reliable criterion In most cases, 5mm or larger,

or 10mm or larger is regarded as criterion for lymph node metastases.

Metastatic nodes: less than Ø 5mm in > 50%

Dworak et al. Surg Endos 1989;3:96-9Brown et al. Radiology 2003;227:371-7

USPIO MRI for nodal staging

Key Points

Pathology

Guideline and experience significantly improve the quality:www.rcpath.org/resources/pdf/colorectalcancer.pdf

Careful Macroscopic and Microscopic examination

Tumor Regression Grade (TRG) scales

Tumor-Regression-Grading: TRG

Complete Regression (100%) Good Regression (> 50%) Moderate Regression (25-50%) Minimal Regression (< 25) No Regression (0%)

Key Points

Surgical Treatment

The standard surgery: Total Mesorectal Excision (TME)

Preop Radio-chemoterapy + S: increase sphincter preservation (with good sphincter function) for downsizing

Pathological studies of CRM in anorectal junction and anal canal sphincter show higher rates of CRM involvement

Key PointsRadiotherapy and Chemotherapy

Early T: local excision (adverse prognostic factors evaluation);

endoluminal radiotherapy c T3-4/N0 or plus: 15 Random Trials & 3 Meta-analysis:

increase LC; conflicting results in SVV for preop Radiotherapy

Short-Course preop (5Gyx5) vs RT-CT: not seem effective for pts with predictive positive CRM e low tumor location

2 Random Trials (EORTC 22921 & FFCD 9203) on role of chemo with preop-Radiotherapy: in RT-CT preop group increase of LC, increase rate of p T0, G3+ tox, no benefit of 5 yrs OS

Key PointsRadiotherapy and Chemotherapy

Polish Trial in c T3-4: 5 Gy x 5 vs preop RT-CT: no difference in sphincter preservation, LC, OS but LATE TOXICITY

NCI Consensus Conference 1990: post-op CT-RT 5FU-based Standard treatment in post-op p T3/ p N1-2 rectal tumors

Preop RT-CT vs Post-op RT-CT 5FU-based: 4 Random Trials. The most important closed Trial is German Study CAO/ARO/AIO ‘94

50.4 Gy BolusCI 5-FU Surgery 5-FU x 4wks 1,5

T3

50.4 Gy BolusSurgery CI 5-FU 5-FU x 4

wks 1,5

PHASE

III

CAO/ARO/AIO 94Trial

Sauer et al NEJM 2004

Post-op Pre-op PEvaluable # 394 405 -5-Yr LF % 15 6 0.0065-Yr Survival % 76 74 nsAcute toxicity 40 27 0.001Chronic toxicity 24 14 0.0125-Yr DF % 38 36 ns

SphincterPreservation 15/78 (20%) 45/116 (39%) 0.004

CAO/ARO/AIO 94

PHASE

TrialIII

C. Rödel et al., J Clin Oncol 2005; 23:8688-96

CAO/ARO/AIO 94

The Value of Downstaging !!!Trial

PHASE

III

PatientspT0-2/TOT

LC 5 aa

% pT0-2

OS 5 aa

% pT0-2

DFS 5 aa

% pT0-2

Berger ’97

Hosp Bretonneau19/167 - 92 87

Kaminsky-F ’98

Alexis Vautrin Cent.21/98 94 100 94

Janjan ’99

M.D.Anderson68/117 - 93-100 75-83

Mohiuddin ’00

Kentucky Univer.22/77 100 100 100

Valentini ’02

Catholic Univer76/165 96 90 80-83

Theodoropoulos ’02

Grant Med Center 16/88 100 100 100Aguilar ’03

Univ of Minnesota

21/168 100 95 95

Meaning of Downstaging Meaning of Downstaging

Key PointsRadiotherapy and Chemotherapy

No data with level 1 evidence for adjuvant post-op chemo after preoperative RT-CT: it seems an effect of adjuvant chemo in responder pts

Unresectable rectal cancer: pre-op RT-CT 5FU-based to enhance R0 resectability (50-54 Gy Radiation dose) IORT: single institutions studies support a favourable effect

Local Recurrence: pre-op RT-CT +/- IORT (conflicting results); Re-irradiation is under clinical evaluation

Key Points Ongoing Research

Topic for surgical research: enhance organ preservation

Intensification of pre-op RT-CT and post-op chemo: - New Drugs (Oxaliplatin; Capecitabine) - Altered fractionation RT dose

EGFR and VEGF: promising targets of antitumor treatment

Individualised therapies based on clinical-pathological features and molecular and genetic markers

New Imaging for response evaluation

Rectal Cancer: Clinical Case Presentation

PS: 100% (Karnofsky); 62 yrs old; male; no other diseases.

Endoscopy (13/01/2006): ulcerated and vegetant lesion of 6 cm very near to internal anal sphincter

HISTOLOGY: Adenocarcinoma G2. Contrast CT Thorax+abdomen (20/01/’06): negative lungs and liver. Neoplastic lesion which makes the lumen substenotic, presence of some lesions in perirectal adipous tissue.Two nodes of 1 cm in perirectal adipous tissue.

CLINICAL STAGE: c T3 c N1 M0 IIIB STAGE

Rectal Cancer: management of our clinical case

PLAFUR Schedule

50.4 Gy S

Follow-upFollow-up

CDDP 60 mg/mq 1° gg

5-FU 1000 mg/mq 1-5 gg

8 ws

Chemo: N+Chemo: N+

Pre CRTPre CRT Post CRTPost CRT

Ulcer

y p T0

Diffusion MRIDiffusion MRIPreCRTPreCRT

ypT0ypT0

PostCRTPostCRT