OPTIMIZED RADIOTHERAPY STRATEGIES · Ultimate goal of radiation therapy: ... Intensity Modulated...
Transcript of OPTIMIZED RADIOTHERAPY STRATEGIES · Ultimate goal of radiation therapy: ... Intensity Modulated...
OPTIMIZED RADIOTHERAPY STRATEGIES
Gastric cancer
Karin Haustermans
University Hospitals Leuven
DISCLOSURE OF INTEREST
No conflicts of interest
◆ Ultimate goal of radiation therapy:
◆ To maximize tumor control → better survival
◆ While sparing the surrounding normal tissue → less
side-effects and better QoL
◆ Inevitably some radiation dose is always deposited in the
healthy tissues…
Therapeutic ratio
TCP NTCP
THERAPEUTIC RATIO
◆ High chance of tumor control
◆ Low risk of side effects
THERAPEUTIC RATIO
◆ High chance of tumor control
◆ High risk of side effects
Barker et al. Nat Rev Cancer 2015
RADIATION SIDE EFFECTS
EVOLUTION IN TECHNOLOGY
2D conventional
radiotherapy
(2D RT)
3D conformal
radiotherapy
(3D CRT)
Image Guided
Radiotherapy
(IGRT)
Intensity Modulated
Radiotherapy
(IMRT)
Better 3D control of the dose distribution
Target volume adapted to tumor volume
Less dose to the surrounding normal tissues
Therapeutic ratio
EVOLUTION IN TECHNOLOGY
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ratio
EVOLUTION IN TECHNOLOGY
GOAL OF RADIOTHERAPY IN GEJ AND GASTRIC CANCER
◆ Downstage the tumour
◆ Increase R0 resection rate
◆ Decrease locoregional recurrence
◆ Improve survival
Recurrences Mean Range
Locoregional - only 54% (29-72%)
Locoregional - total 88% (38-94%)
Distant - only 25% (18-35%)
Gunderson et al. Int J Radiat Oncol Phys 1982; Smalley et al. Int J Radiat Oncol Phys 2002; Lim et al. Br J Cancer 2004
UICC TNM 8TH EDITION (2017)
◆ GEJ tumors involving the GEJ whose epicenter is
within the proximal 2 cm of the cardia (Siewert types
I/II)
◆ Cancers whose epicenter is more than 2 cm distal
from the GEJ will be staged using the Stomach
Cancer TNM even if the GEJ is involved
◆ All cardia cancers not involving the GEJ will be staged
using the Stomach Cancer TNM
Ajani et al. Nat Rev Dis Primers 2017
Lordick et al. Ann Oncol 2016
ESOPHAGEAL AND GEJ CANCER
CROSS TRIAL
◆ Randomized phase III trial with 366 patients
◆ Stage II or III: cT2-3/N0-1/M0
◆ AC (75%) or SCC (23%) esophagus (+/- 73%) or GEJ (+/- 24%)
◆ Primary objective: OS
Van Hagen et al. N Engl J Med 2012
Surgery
SurgeryCRT:
paclitaxel 50mg/m² + carboplatin AUC2 weekly
+ radiotherapy 41.4 Gy
CROSS TRIAL
Shapiro et al. Lancet Oncol 2015
POET TRIAL
◆ Randomized phase III trial with 126 patients
◆ uT3-4NxM0
◆ AC GEJ (100%)
Primary objective: OS
Stahl et al. J Clin Oncol 2009
GEJ cancer
Chemotherapy
2x cisplatin + 5FU + LV
CRT30.0 Gy + cisplatin
+ etoposide
Surgery
Chemotherapy2,5x cisplatin + 5FU
Surgery
POET TRIAL
Stahl et al. J Clin Oncol 2009
Arm A Arm B P-value
Treatment No. % No. % P
Patients with
resection
49 100.0 45 100.0
pT0 N0 M0 1 2.0 7 15.6 .03*
pT1-4 N0 M0 17 34.7 22 48.9
pT0-4 N0 M0† 18 36.7 29 64.4 .01*
pTall N M0 27 55.1 14 31.1
pTall N M1 4 8.2 2 4.5
Fisher´s exact test.
† Bold text indicates data summarized from patients with pT0 N0 M0 and pT1-4 N0 M0.
POET TRIAL
Stahl et al. Eur J Cancer 2017
cT1 N+ or cT2-4a N0/+, M0 adenocarcinoma of esophagus or GEJ
Primary endpoint: OS
594 patients
Reynolds et al. BMC Cancer 2017
Hoeppner et al. BMC Cancer 2016
ESOPEC TRIAL NEO-AEGIS TRIAL
Smyth et al. Ann Oncol 2016
GASTRIC CANCER
SWOG 9008/INT 0116
556 patients
Gastric: +/- 80%
GEJ: +/- 20%
45.0 Gy (1.8 Gy/fx) 2D-RT
5-FU/LV = fluorouracil/leucovorin
Macdonald et al. N Engl J Med 2001
SWOG 9008/INT 0116
Macdonald et al. N Engl J Med 2001
Smalley et al. J Clin Oncol 2002
Surgery CRT + surgery p-value
Median DFS 19 months 30 months 0,001
3 year survival
Median survival
40 %
27 months
50%
36 months0,03
SWOG 9008/INT 0116
◆ Significant improvement in OS and DFS
◆ Effect mainly on local failure rate (19 vs 29%)
◆ Acceptable toxicity
But:
◆ Randomization after surgery
◆ No optimal surgery: 54% < D1 resection
◆ Chemotherapy regimen: not optimal
◆ Few patients in stage IB (n=39)
◆ Results not completely in agreement with what was expected on failure pattern
ARTIST TRIAL
◆ Randomized phase III trial with 458 patients
◆ Excluding cT2aN0
◆ AC gastric (100%)
Primary objective: DFS
Lee et al. J Clin Oncol 2012
Gastric cancer
Surgery
Chemotherapy2x cisplatin + capecitabine
CRT45.0 Gy +
capecitabine
Chemotherapy
2x cisplatin + capecitabine
Surgery
Chemotherapy6x cisplatin + capecitabine
ARTIST TRIAL
Lee et al. J Clin Oncol 2012
DFS LN+ patients
ARTIST II trial
DFS all patients
ARTIST II TRIAL
NCT01761461
Operable GEJ or gastric cancer
D2 surgery
ChemotherapySOX x 2
CRT45.0 Gy + S1
Chemotherapy
SOX x 4
ChemotherapyS1 x 8
ChemotherapySOX x 8
◆ Phase III
◆ 900 patients
◆ Stage II-III N+
◆ AC GEJ or gastric
Primary endpoint: 3y DFS
SOX = S1 + oxaliplatin
ARTIST II TRIAL
Park et al. ASCO 2019; #4001
ARTIST II TRIAL
Park et al. ASCO 2019; #4001
ARTIST II TRIAL
Park et al. ASCO 2019; #4001
ARTIST II TRIAL
Park et al. ASCO 2019; #4001
CRITICS
Dikken et al. BMC Cancer 2011
≥ 87% undergoing D1+
788 patientsGastric: 83%GEJ: 17%
3D-CRT/IMRTECC: epirubine/cisplatin/capectabine
CRITICS
Cats et al. Lancet Oncol 2018
CT CRT
5-year OS
[% (95% CI)]
42 (37-48) 40 (35-46)
Median OS [months
(95% CI)]
43 (31-57) 37 (30-48)
PREOPERATIVE CHEMORADIOTHERAPY?
Rationale/potential advantages◆ Enhance resectability
◆ Assess response in primary tumour
◆ Improve local control
◆ Treat micrometastases early
◆ Better tolerance than postoperative treatment
Potential disadvantages◆ Staging less adequate
◆ Increased postoperative morbidity
◆ Disease progression
PRE- VS. POSTOPERATIVE CRT
Tolerance adjuvant treatment Proportion in study
SWOG/INT 0116 CRT: 65%
ARTIST CT: 75% - CRT 81,7%
CRITICS CT: 47% - CRT 52%
?
TOPGEAR
Leong et al. BMC Cancer 2015
Leong et al. Ann Surg Oncol 2017
Currently recruiting patients
◆ 120 patients phase II
→ results published
◆ 450 patients phase III
◆ cT3-4 or N+
◆ AC GEJ or gastric
Primary endpoint: 5y OS
Estimated Primary Completion Date: December 2020
Operable GEJ or gastric cancer
Chemotherapy
ECF/ECX/EOX x 2 or FLOT x 3
CRT45 Gy + 5FU/X
Surgery
ChemotherapyECF/ECX/EOX x 3
or FLOT x 4
Surgery
Chemotherapy
ECF/ECX/EOX x 3 or FLOT x 4
TOPGEAR: COMPARISON FLOT VS. ECX/F
Michael et al. IGCC 2019
◆ Overall toxicity profile of FLOT regimen was acceptable in the TOPGEAR trial
and did not impact on treatment completion relative to ECF/X regardless of the
treatment groups
◆ Higher febrile neutropenia rates relative to ECF/X (16.2% vs 6.6%. P = 0.036)
◆ No significant FLOT-related toxicity differences between the treatment groups: Group 1
(Chemo + Surgery) vs Group 2 (CRT + surgery)
◆ Surgical completion rates were not influenced by the FLOT regimen relative to ECX/F
overall and regardless of the treatment groups.
CRITICS II
Slachter et al. BMJ Cancer 2018
Marcel Verheij - NCT02931890
Currently recruiting patients
◆ Phase II
◆ 207 patients
◆ Stage Ib-IIIC
◆ AC GEJ or gastric
Primary endpoint:
1y event-free survivalDOC= docetaxel/oxaliplatin/capecitabine
POSTOPERATIVE TARGET VOLUME
According to CRITICS
CTV: ◆ anastomosis
◆ gastric bed/remnant
◆ lymph nodes
PREOPERATIVE
TARGET VOLUME
According to TOPGEAR
RADIATION DELIVERY TECHNIQUE
Hartgrink et al. Lancet 2009
3D VS. IMRT COMPARISON
Chandra et al. Int J Radiat Oncol Phys 2005
“We gave PTV coverage and lung sparing higher priority than the other structures”
IMRT plans reduced the amount of lung treated compared to 3D-CRT“No clinically meaningful differences were observed with respect to irradiated volumes of spinal cord, heart, liver, or total body integral doses”
“In general, V40 and V50 were kept to <50 and <30%, respectively, for the heart.”
IMRT
lower incidence of cardiac and unknown related deaths
Lee et al. Int J Radiat Oncol Phys 2012
HOW ABOUT PROTONS?
Courtesy of Matt Palmer, MD Anderson
Schematic depth dose diagram of a
proton beam Bragg peak, the spread
out Bragg peak and a megavoltage X-
ray beam
The grey shaded areas indicate the
extent of dose reduction
Wang et al. Int J Radiat Oncol Phys 2013
Impact of radiation dose to OAR on postoperative complications and
outcome
Davuluri et al. Int J Radiat Oncol Phys 2017
Lymphopenia - correlation with survival
Predictors G4 lymphopenia:
◆ Distal tumor location
◆ Definitive CRT
◆ Taxane/5-FU chemotherapy
◆ Photon-based radiation (vs.
proton-based)
Shiraishi et al. Radiother Oncol 2017
Lymphopenia - correlation with survival
CONCLUSIONS
◆ The role of radiotherapy in GEJ cancer and gastric cancer needs further study
◆ Perioperative chemotherapy versus preoperative chemoradiotherapy followed by postoperative
chemotherapy
◆ Total dose and fractionation should be standardised
◆ Guidelines for target delineation and OAR with dose constraints should be
implemented
◆ Pretreatment review of radiotherapy treatment plans (contouring and isodose
distribution)
◆ Advanced radiotherapy delivery techniques including image guidance and motion
management
CONCLUSIONS
A multidisciplinary approach is essential in the treatment of this
disease!
◆ Which type of treatment?
◆ Which drugs?
◆ What volume to irradiate, radiation technique?
◆ What type of operation?