Concurrent chemoradiotherapy in pancreatic cancer and ... · mesenteric LNs and third portion of the duodenum Upper: occasionally more superior with body lesions to obtain adequate

คณะแพทยศาสตรศ์ิรริาชพยาบาล มหาวทิยาลยัมหดิล

Concurrent chemoradiotherapy in pancreatic cancer and cholangiocarcinoma

Pawinee Mahasittiwat, MD.

12 Feb 2012

Outlines

Pancreatic cancer

– Adjuvant Postoperative Radiotherapy

– Borderline pancreatic carcinoma

– Unresectable pancreatic carcinoma

Cholangiocarcinoma

– Extrahepatic cholangiocarcinoma

– Intrahepatic cholangiocarcinoma

Pancreatic

carcinoma

20% of patients

present with

a resectable

tumor

50% present with

a metastatic

disease

30% present with

a locally

advanced

tumor

(borderline,

unresectable)

Imaging

CECT

– Arterial phase (performed 20-40 sec)

optimal visualization of tumor and peripancreatic arteries

Maximal contrast between hypovascular tumor and normal pancreas

Most tumor – hypoattenuating, mean size 3 cm., (range head 1.5-10 cm., body 2.5-3 cm and tail 5-7 cm.)

– Portal phase (performed 50-70 sec)

Optimal for detecting metastatic disease to liver and assesing peripancreatic veins

Imaging CT- Technique Pancreas Protocol

Encasement of SMA

Outlines

Pancreatic cancer




Cholangiocarcinoma



Patterns of Failure after Resection of Pancreatic Cancer without Adjuvant Radiation Therapy or Chemotherapy

Perez and Brady's Principles and Practice of Radiation

Oncology, 5th Edition, p 1338

Authors Design study Results Remarks

Mayo series Corsini et al. JCO 2008

180-observation 274-adj CRT

Med OS 19.2 mo vs 25.2 mo

Benefit seen in T3 tumors, any N stage and high grade tumors

Johns Hopkins sereies Herman et al. JCO 2008

345-observation 271-adj CRT

Med OS 14.4 mo vs 21.2 mo 5 yr sur 15% vs 20%, p<.001

No benefit for N0 patients

GITSG 1985

Total 43, observation CRT (40 Gy split course)

OS 10.9 mo vs 21 mo, p <0.05

EORTC Total 114, Observation CRT (40 Gy split course)

OS 17.1 mo vs 12.6 mo, p =0.099

ESPAC-1 289, obs/ CRT/ C/ CRT+ C (40 Gy split course)

Med sur 16.9/ 13.9/ 21.6/ 19.9 mo

Many criticisms; split course RT, no detail of RT, only 62% CRT received protocol, no. of C cycles

794 from Johns Hopkins Hospital

478 from Mayo Clinic

Obs (509) vs adj 5-FU based CRT (median dose 50.4 Gy, n=583)

Matched-pair analysis by treatment group (1:1) based on institution, age, sex, tumor size/stage, differentiation, margin, and node positivity with N = 496 (248 per treatment arm)

Results from The Johns Hopkins Hospital-Mayo Clinic Collaborative Study

Matched-pair analysis 14.3 vs

21.9 mo

2 yr OS: 31.4% vs 45.5%

5 yr OS: 12.2% vs 25.4%, p <.001

Results from The Johns Hopkins Hospital-Mayo Clinic Collaborative Study

RT Technique

Baseline CT scans and CA 19-9 concentrations should be obtained before initiation of adjuvant treatment.

Set up

– Supine, arms above head

– IV contrast

– Breath hold CT and 4D CT

RT dose: 45-46 Gy in 1.8-2 Gy/F to the tumor bed, surgical anastomoses, and adjacent LN, boost to tumor bed and anastomoses 5-9 Gy

RT technique

The dose-limiting organs for irradiation of upper-abdominal cancers are the small intestine, stomach, liver, kidneys, and spinal cord.

Head of the pancreas

LNs: pancreaticoduodenal, porta hepatis, celiac, and suprapancreatic

The entire duodenal loop with margin

Sup: the middle or upper portion of the T11 for adequate margins on the celiac vessels (T12, L1)

Inf: the level L2-3 to include the superior

mesenteric LNs and third portion of the duodenum

Upper: occasionally more superior with body lesions to obtain adequate margin on the primary lesion

Lat: ant-1.5-2.0 cm beyond gross dis, post- 1.5 cm behind the anterior portion of the vertebral body

Int J Radiat Oncol Biol Phys 2005: 62(4), 1021-1029

Distribution of LN involvement in head of

the PC CA (133 of 175 pts with positive

nodes)

•Celiac trunk 5%

•Splenic hilus 0%

•Hepatoduodenal ligament 18%

•Posterior pancreaticoduodenal 37%

•Superior mesenteric artery 10%

•Upper para-aortic 2%

•Juxtaregional lower para-aortic 1%

•Anterior pancreaticoduodenal 23%

•Infrapancreatic body 2%

•Suprapancreatic head 25%

•Suprapancreatic body 11%

•Infrapancreatic head 24%

Int J Radiat Oncol Biol Phys 2005: 62(4), 1021-1029

Example Case

Outlines

Pancreatic cancer




Cholangiocarcinoma



Neoadjuvant therapy for ‘borderline’ tumors

Available data is mixed bag:

– Definition of „borderline‟ imprecise

– Variety of chemo & chemoXRT regimens

About 40% of pts in most series come to surgery

Survival among resected pts compares very favorably to pts who are resectable at outset

Katz et al, JACS; 206, 2008

Brown et al, am J Surg: 195, 2008

Massucco et al, Ann Surg Onc:13(9), 2006

5–74% of pts undergoing a margin-negative resection

Numerous reports have demonstrated an R0 resection as the most important determinant of overall survival in pts with PDA, illustrating the importance of accurate preoperative staging.

The use of neoadjuvant therapy in pts with locally advanced pancreatic cancer appears to provide a higher rate of R0 resections (85–94%) compared with pts treated with surgery alone.

if a patient’s radiographic and

clinical findings warranted

inclusion in more than one

borderline subgroup, he or she

was classified in priority of C

>B > A

MD Anderson Cancer Center (MDACC) classification scheme

Katz et al. J Am Coll Surg 2008


A- abutment of SMV and SMA

B-mass abutting the celiac axis

C- mass encasement of the common hepatic artery

D-short-segment occlusion of the SMV/PV

EBRT = 50.4Gy in 28 fractions or 30 Gy in 10 fractions.

Concomitant chemotherapy consisted of 5-fluorouracil, paclitaxel,

gemcitabine, or capecitabine at radiosensitizing doses.



•Only 66 (41%) of 160 total pts had their tumors removed.

•When dealing with such complex surgery, which carries a risk of perioperative death (2

[3%] of 66 in this report), it is critically important to reserve operation for pts most likely

to benefit.


•The 66 pts who

completed all therapy

including resection had a

median survival of 40 mo

and a 5-yr overall

survival rate of 36%

(type A, 40 months/40%;

type

B, 29 mo/46%; type C,

39 mo/19%).

•In contrast, the 94 pts

who did not undergo

resection of the primary

tumor had a median

survival of only 13

months (type

A, 15 mo; type B, 12 mo;

type C, 13 mo; p 0.001).

Type A Type B

Type C

All

Solid line = Sx

Dot line = no Sx

•Retrospective study

MD Anderson Cancer Center (MDACC) classification scheme

GTV = primary tumor and the immediate draining LNs (not the para-aortic

or porta-hepatis regions)

PTV = 0.5–1.5-cm radial and 1–2-cm craniocaudal expansions of the GTV to

account for setup error.

Dose = 50.4 Gy/ 28F or 50 Gy/ 20F

•40 pts with borderline

resectable PDA

•22 (55%) completed

neoadjuvant CMT-RT

and demonstrated lack of

progression of disease on

restaging imaging.

•Of these, 16 pts (40%)

went on to resection and

the remaining 6 (15%)

had occult metastatic

disease discovered at

exploration.

44% vs

13%

alive,

p=.0002

34% alive

in PR

(Potential

resectable

cancer) ,

p=.67

p=.195

Current Strategy for Borderline Resectable pancreas cancer: selecting patients for XRT on the basis of Tumor Biology

Restage Induction

chemotherapy

Localized

Metastatic

Chemo XRT

2nd Line Rx or

Best supportive

care

Consider

surgery

Outlines

Pancreatic cancer




Cholangiocarcinoma



21 studies: 2 meta-analyses, 13 randomized trials, and 6 nonrandomized trials.

Recent data favor limited irradiation to the tumor volume (level C).

Fluorouracil is still the reference chemotherapy in association with radiotherapy (level B1).

Induction chemotherapy before chemoradiotherapy improves survival (level C).

Huguet et al JCO 2009

CRT vs best supportive care

•Chemoradiotherapy increases overall survival when compared

with best supportive care (level of evidence C) or with exclusive

radiotherapy (level B1), but is more toxic (level B1).

CRT vs RT

2 meta-analyses concluded that there was a significant benefit of chemo-radiotherapy on

overall survival, with, in the Sutana et al. study, a 31 % decrease in tumor-related deaths

after chemoradiotherapy compared with RT Huguet et al JCO 2009

ECOG

CRT vs CT Chemoradiotherapy is

not superior to

chemotherapy in terms of

survival (level B1) and

increases toxicity (level

A).

ECOG: E4201

Pts with locally unresectable pancreatic cancer

Randomized chemoradiotherapy with concurrent gemcitabine followed by gemcitabine versus gemcitabine alone.

RT dose = 50.4 Gy with concurrent gemcitabine (600 mg/m2/wk).

The study closed after the inclusion of 74 pts because of low accrual rate.

Median overall survival was better in the chemoradiotherapy arm (11 months versus 9.2 months, P .034).

Grade 4 toxicity was more common in chemoradiotherapy arm compared with the chemotherapy arm (41.2% v 5.7%, respectively; P.0001).

These results should be considered cautiously because of the limited number of patients included.

Loehrer et al., ASCO 2008

•using capecitabine and delivering RT to a limited radiation field that excluded non-involved

regional LNs from the CTV.

•EBRT 50.4 Gy/ 28 F to PTV which expanded from the primary tumor and involved nodes

only.

•Capecitabine (500-600 mg/m2) was given twice daily continuously during RT .

•One pt developed grade 3 nausea.

•The median time to progression was 8.8 mo, with 20% remaining progression free at 1 yr.

•The median overall survival was 9.7 months with a 1 year survival of 30%.

•Of 21 pts with imaged progression, 13 (62%) progressed systemically, three (14%) had

local progression, two (10%) had locoregional progression and three (14%) progressed

with both local/locoregional and systemic disease.

•Four pts (8.3%) did not complete the intended treatment due to CRT-related

toxicities.

•A multi-centre retrospective analysis of 48 pts with biopsy-proven LAPC

treated with CRT in four regional oncology centres in the UK between March

2000 and October 2007.

•The prescribed RT dose was 45-50.4 Gy/ 25-28 F and was given concurrent

with gemcitabine (n =37), gemcitabine/cisplatin (n= 9), 5-fluorouracil (n = 1)

or capecitabine (n = 1).

•The disease control rate (Objective response rate (ORR), stable disease (SD))

= 81.3%.

•The median overall survival was 17 mo (range 5-66 mo).

•In subgroup analysis, a trend towards improved survival was seen in pts who

completed the intended treatment (17.1 months vs 11.0 months, P < 0.06) and

in pts undergoing Sx (27 mo vs 16 mo, p < 0.023).

Emerging Strategy for Locally advanced pancreas cancer: selecting patients for XRT on the basis of Tumor Biology

Restage Induction

chemotherapy

Localized

Metastatic

Chemo XRT

2nd Line Rx or

Best supportive

care

Observation

RT Technique

Baseline CT scans and CA19-9 concentrations should be obtained before initiation of adjuvant treatment.

Set up

– Supine, arms above head

– IV contrast

– Breath hold CT and 4D CT

RT dose: 45-54 Gy in 1.8-2 Gy/F to the gross tumor and gross lymph nodes

•The patients were scanned in supine position within personal body-fi x

pillow (BlueBAG BodyFix, Insight Technologies, Nevada, USA).

•During the scans, patients breathed freely, with the advice to maintain

a breathing cycle as regular as possible.

•The CTV consisted of the pancreatic or suspected tumor and regional

lymph nodes considered radiologically involved and/or PET positive; no

prophylactic nodal irradiation was planned.

•Daily correction of patient set-up by MVCT using HT

has been routinely performed

•4D-PTVs were smaller than STD-PTVs with a volume reduction equal to

37%.

The 4D-PTV was obtained using the following contouring procedure: a CTV was manually contoured on each respiratory phase, resulting in four different CTVs; a 4D-ITV ( “ Internal Target Volume ” ) was created by the convolution of these four contours, using the Eclipse TPS, and then expanded by a margin of 5/5/7 mm to obtain a 4D-PTV.

The standard PTV creation entailed the expansion of an intermediate phase CTV by 10/10/15 mm into the STD-PTV to account for mobility and set-up; the use of an intermediate phase reduces the contribution to the positioning error related to periodic motion of the tumor.

PTV-STD = blue

4D-PTV=red

PET for delineation target?

There is currently no evidence defending the use of PET for TV delineation in pancreatic cancer.

E. Ben-Josef et al. ASTRO 2011

UMCC 2006.018: A PHASE I/II RADIATION DOSE-ESCALATION STUDY OF INTENSITY-MODULATED RADIOTHERAPY (IMRT) WITH CONCURRENT GEMCITABINE IN PATIENTS WITH UNRESECTABLE PANCREATIC CANCER


ABC technique/ IMRT

Volume

GTV = primary tumor + any involved regional LNs identifiable on CT scan.

CTV = GTV + 0.5 cm.

PTV = CTV +0.5 cm.

Results: 50 pts were accrued in 2 institutions.

Dose limiting toxicities in 11 pts (G3/4 anorexia, nausea vomiting, and/or dehydration [7 pts]; duodenal bleed [3]; duodenal perforation [1]). 2 pts died of causes possibly related to therapy.

Other G3/4 toxicity: neutropenia: 18%, thrombocytopenia: 4%, nausea 2%, and vomiting 1%.

The median and 2-yr OS =14.8 mo (95% CI 12.6-22.2) and 30% (95% CI 17-45).

Only 8 pts (17%) progressed locally.

The 2-yr freedom from local progression =59% (CI 32-79).

29 (63%) progressed with DM at a median of 10.2 months.

12 pts have undergone resection (10 R0, 2 R1).

Pathologic responses were CR: 2, near-CR: 3 and PR: 7.

Pts who underwent resection had a median survival of 32 mo and local control of 92%. Conclusion: High dose RT (55-57.5 Gy) with concurrent FDR-G can be delivered safely. This regimen can convert pts to resectability and results in high rates of pCR/nCR, local control and survival. The results suggest that intensification of local therapy may improve survival in a subset of pts with unresectable tumors.


Outlines

Pancreatic cancer




Cholangiocarcinoma



Cholangiocarcinoma

Distribution

– 20% distal

– 60% hilar

– 20% intrahepatic

Extrahepatic

Outlines

Pancreatic cancer




Cholangiocarcinoma



Hilar cholangiocarcinoma Surgical resection 15-40% are resectable

Positive margins common

Gross residual in 1/3

50% positive nodes

5 yr survival 10-40%

LR after R0 resection: 25-40%

Extrahepatic cholangiocarcinoma Radiotherapy indications

Adjuvant therapy following resection

Preoperative therapy prior to transplant

Primary therapy

– EBRT (with chemo)

– Brachytherapy

– SBRT

series year treatment pts Median survival

5 yr survival

EORTC (R1 resection) Amsterdam Tsukuba (R1 resection) Johns Hopkins

1999 2003 2000 1995

S S+ EBRT/brachy S S+ EBRT S+ EBRT/brachy S S+IORT+ EBRT S S+EBRT/brachy

17 38 20 30 41 19 28 17 14

8 mo 19 mo 8 mo 30 mo 21 mo 10 mo 32 mo 20 mo 20 mo

3 yr 10% 3 yr 31% 11% 24% 17% 14% 34%

Hilar cholangiocarcinoma adjuvant radiotherapy

Tsukuba study

47 Klatskin tumors with R1 resection

28 irradiated pts: 17 IORT + PORT, 6 IORT, 5 PORT

PORT: mean 43.6 Gy, range 27-61.2 Gy

IORT: mean 21 Gy, range 15-35 Gy

LR control 31% vs 79% in S vs S+RT, 5 yr sur 14% vs 34%

Todoroki et al, Red 2000

Int. J. Radiation Oncology Biol. Phys., 2009

- A retrospective analysis of resected pts who had undergone chemoradiotherapy.

- 45 pts (13 with proximal and 32 with distal disease) underwent resection

plus RT (to tumor bed + regional LN; porta hepatic, pericholedochal, celiac,

pancreaticoduodenal, median dose = 50.4 Gy).

- The median follow-up was 30 mo for all pts and 40 mo for survivors.

-Results: Of the 45 pts, 33 underwent adjuvant RT, and 12 were treated

neoadjuvant.

-The 5-yr actuarial OS, DFS, metastasis-free survival, and LR control rates were

33%, 37%, 42%, and 78%, respectively.

-The median survival was 34 months.

-No patient died perioperatively.

Patient age #60 yrs and perineural involvement adversely affected survival on univariate analysis.

Pts undergoing R0 resection had a significantly improved rate of LC but no survival advantage.

Despite having more advanced disease at presentation, pts treated neoadjuvantly had a longer survival (5-yr sur 53% vs. 23%, p = 0.16) and similar rates of Grade 2-3 surgical morbidity (16% vs. 33%, p = 0.24) compared with those treated in the postoperative setting.

Int. J. Radiation Oncology Biol. Phys., 2009

Hilar cholangiocarcinoma Adjuvant RT conclusion

Adjuvant RT may decrease risk locoregional relapse

Indication

– R1 or R2 resection

– Positive nodes?

– R0 with close margins (T2-T4)?

RT+ chemo liver transplant

Primary therapy: RT + chemo

Unresectable hilar cholangiocarcinoma

Unresectable hilar cholangiocarcinoma Liver Transplant

Rationale: 20-30% resectable, > 60% local recurrence rate, distant mets relatively uncommon

Liver Transplantation with Neoadjuvant Chemoradiation is More Effective than Resection for Hilar Cholangiocarcinoma Mayo protocol

RT 45 Gy in 30 bid concurrent with 5-FU or capecitabine

Brachytherapy 20-30 Gy with Ir-192

Continuous infusion 5-FU or capecitabine until transplant

Exploratory laparotomy

5 yr relapse after orthotopic liver transplantation : 12%

Median time to relapse 22 mo (7-65)

Rea, et al. ann sur. 2005;242(3):451-461

1 yr sur 3 yr sur 5 yr sur

After transplantation 92% 82% 82%

After resection 82% 48% 21%, p= 0.022

Dose response

18 pts, unresectable, phase I-II

45 Gy EBRT + HDR brachy

Dose 52 Gy Med sur 9 mo, 59 Gy-12

mo, 65 Gy-20 mo

Unresectable hilar cholangiocarcinoma EBRT

Lu Cancer J 2002:8:74-8

A retrospective study

37 pts underwent EBRT (to gross dis) with concurrent CMT (5-FU) and/or brachytherapy (BT) for locally advanced extrahepatic cholangiocarcinoma.

23 pts received EBRT alone, 8 pts received EBRT + BT, and 6 pts received BT alone (median F/U = 14 mo).

Actuarial OS and LC rates – at 1 yr = 59% and 90%

– At 2 yr = 22% and 71%

Int J. Radiat Oncolo Biol Phys 2010

On univariate analysis, EBRT with or without BT improved LC compared to BT alone (97% vs. 56% at 1 yr; 75% vs. 56% at 2 yrs; p = 0.096).

Patients who received EBRT alone vs. BT alone also had improved LC (96% vs. 56% at 1 year; 80% vs. 56% at 2 yrs; p = 0.113).


Hilar cholangiocarcinoma conclusion

No treatment 1-3 mo

Biliary drainage (stent only) 4-6 mo

EBRT, brachy, 5-FU 10-17 mo, 5

yr 10-20%

Resection 5 yr 20-30%

Liver transplantation 5 yr 20-30%

EBRT, brachy, 5FU, OLT 5 yr 75-80%

Outlines

Pancreatic cancer




Cholangiocarcinoma



Intrahepatic cholangiocarcinoma

5%-10% of all biliary tract cancers

10%-20% of primary liver malignancies

The resectability rate = 30-50%

5 yr sur = 0 vs 51% (p <.0001)

Patterns of failure after Sx : liver (56%), regional lymph node (20%), and peritoneal seeding (24%)

The role of postoperative adjuvant radiotherapy with or without chemotherapy in the management of intrahepatic cholangiocarcinoma is controversial.

A classification of regional lymph nodes in liver cancer

by the Liver Cancer Study Group of Japan

3 major routes of lymphatic spread of ICC:

hepatoduodenal route

cardiac route (through the lesser omentum to the cardiac portion of the stomach

the gastric lesser curvature), and diaphragmatic route

Yang J et al. World Journal of

Gastroenterology 2008;14(4):6289-97

A retrospective analysis of 3,839 pts with IHC collected from the Surveillance, Epidemiology, and End Results (SEER) database.

Pts received

– Sx alone (25%)

– RT (10%)

– Sx+adjuvant RT (7%)

– no treatment (58%).


The OS was significantly different between Sx alone and Sx+RT (p = 0.014) and RT alone and no treatment (p < 0.0001).

Use of Sx+RT conferred the greatest benefit on OS (HR = 0.40; 95% CI, 0.34–0.47), followed by Sx alone (hazard ratio [HR], 0.49; 95% CI, 0.44–0.54) and RT alone (HR,0.68; 95% CI, 0.59–0.77) compared with no treatment, on multivariate analysis.


3D-CRT with hepatic arterial floxuridine in 128 pts.

The RT dose was based on a normal-tissue complication probability model and subjected the pt to an estimated maximum risk of RT-induced liver dis.of 10-15%.

The median RT dose =60.75 Gy (1.5-Gy, bid).

At a median follow-up time of 16 mo (26 mo in patients who were alive) the median survival was 15.8 mo (95% CI, 12.6 to 18.3 mo), significantly longer than in the historical control.

The actuarial 3-yr survival was 17%.

Overall toxicity was acceptable, with 27 pts (21%) and 11 pts (9%) developing grade 3 and 4 toxicity, respectively, and one treatment-related death.

J Clin Oncol 2005 23:8739-8747

GTV = gross tumor from CT or MRI

CTV = GTV plus a 1-cm margin within the liver

PTV = CTV + 0.5 cm uniform expansion for setup uncertainty, plus an additional 0.3 to 3 cm margin in the craniocaudal dimension to account for breathing motion.

J Clin Oncol 2005 23:8739-8747

The total dose was the only significant predictor of survival.

J Clin Oncol 2005 23:8739-8747

J Clin Oncol 2005 23:8739-8747

A retrospective study, 84 pts with unresectable ICC.

– 35 pts received RT (median dose =50 Gy range,30-60 Gy, 5F/wk in 1.8-2.0 Gy/F daily; EBRT group)

– 49 pts comprised the non-EBRT group.

Results: CR = 8.6%, PR = 28.5% , and CR and PR of LN metastases =20% and 40%

Multivariate analysis revealed that clinical symptoms, larger tumor size, no EBRT, multiple nodules and synchronous LN metastases were associated with poorer prognosis.

Yi-Xing Chen et al. BMC Cancer 2010

Median survival times

– Non-EBRT gr: 5.1 mo, EBRT gr: 9.5 mo (p = 0.003).

1- survival rates for EBRT vs non-EBRT group = 38.5% vs 16.4%,

2 yr sur EBRT vs non-EBRT = 9.6% vs 4.9%

Yi-Xing Chen et al. BMC Cancer 2010

RT technique

CTV = GTV + 1.5 cm margin, especially along the bile duct and potential lymphatic drainage areas, which include nodes along the porta hepatis, pancreaticoduodenal system, and celiac axis

PTV = CTV + 0.5 to 1 cm

Consider extending field 3–5 cm into liver to cover additional intrahepatic bile duct length for margin.

Dose: 45-50 Gy, 1.8-2 Gy/F, if boost-dose irradiation is feasible with brachytherapy techniques, the GTV is carried to 45 to 50 Gy with external techniques, and 20 to 30 Gy is delivered via an intraluminal the catheter/ conedown to tumor bed to 60 Gy

Stereotactic radiotherapy in the liver hilum

Median survival = 5-32 months

Outlines

Pancreatic cancer




Cholangiocarcinoma



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Concurrent chemoradiotherapy in pancreatic cancer and ... · mesenteric LNs and third portion of the duodenum Upper: occasionally more superior with body lesions to obtain adequate