QUALE EVIDENZA PER I TRATTAMENTI
LOCO-REGIONALI
Marta Scorsetti, M.D.,
Radiotherapy and Radiosurgery Dep.
Humanitas Clinical and Research Hospital Department of Biomedical Sciences,
Humanitas University, Milan, Italy marta.scorsetti@hunimed.eu
November 28, 2017
2017
Most patients die of metastatic disease, autopsy series showed that up to one-third of patients die of predominantly local disease.
RT has emerged as an important modality in preventing local progression.
Standard chemo-radiation delivered over 5-6 weeks has been shown to improve local control, but this approach delays full-dose systemic therapy and increases toxicity.
Background
Palliative RT Standard RT Hypo SBRT Surgery
Local approaches: Surgery and Radiotherapy
– Precise delivery of radiation to the tumor while minimizing dose to surrounding normal structures
– Increase efficacy – Decrease toxicity
– Lung SBRT comparable with surgery
Potters L, et al. IJROBP 2010 Onishi H, et al. IJROBP 2011
SBRT
60Gy/3frs
BED10=120Gy
60Gy/8frs
BED10=105 Gy
SBRT in NSCLC: role of fractionation
Ablative doses near an organ with serial
functional subunits, such as the GI tract, are difficult to be achieved without affecting
organ function.
If a radiosensitive structure is in close
proximity to a radioresistant target, ablative doses can be given reducing the number of fraction up to 3–6, if dose constraints of
healthy tissue are met.
SBRT Pancreatic Cancer
1) SBRT can be delivered as a hypofractionated regimen over 3-5 days in comparison to 25-30 days with conventional chemo-radiation (CRT)
2) SBRT allows for good local control while limiting the delay of additional therapies such as full-dose systemic chemotherapy or surgical resection
Rosati et al. Seminars in Radiation Oncology 2017
Chemotherapy Surgery SBRT
Moderate Hypofractionation Convetional Fractionation
Chemotherapy Surgery
Chemotherapy Surgery
Clinical rationale for SBRT treatment
3) SBRT results in minimal acute side effects and improves pain while preserving quality of life
4) The radiobiology of SBRT along with the ability to escalate the dose to more than 50 Gy at the tumor vessel interface may increase the likelihood of a margin-negative
resection and decrease the risk of a subsequent local recurrence
Rosati et al. Seminars in Radiation Oncology 2017
Clinical rationale for SBRT treatment
9 2016
Recommendation 2.1: […] CRT or SBRT may be offered up front, on the basis of patient and physician preference […]
Recommendation 3.1: If there is local disease progression after induction
chemotherapy, but without evidence of systemic spread, then CRT or SBRT may be offered to the patients
Recommendation 3.2: CRT or SBRT may be offered to patients who have
responded to initial 6 months of CT or have stable diasese but have developed unacceptable CT-related toxicities […]
Recommendation 3.3: if there is response or stable disease after 6 months of induction CT, CRT or SBRT may be offered as an alternative to continuing CT alone for any patient with LAPC.
10
NCCN Guidelines
Comito et al, Milano 2017
Results of SBRT
12 2008
16 patients received gemcitabine and SBRT in a single 25- Gy fraction by Cyberknife
19% developed local progression at 14, 16, and 21 months.
Acute gastrointestinal toxicity was mild, with 13% of Grade 2 and 6% of Grade 3.
Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4).
A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13).
Locally Advanced Pancreatic cancer
13 20 patients in prospective single-
institution study.
Gem Linac-based SBRT Gem 25 Gy in a single fraction
Median OS 11.8 months.
2011
94% at 1 year
50% at 1 year
Locally Advanced Pancreatic cancer
14 Phase 2 multi-institutional study. Aim of the study: reduction of late grade 2 - 4 GI toxicity compared with a previous trial of single fraction SBRT.
49 patients received up to 3 doses of GEM (1000 mg/m2) followed by a 1-week break and SBRT (33.0 Gy in 5 fractions) and GEM until disease progression or toxicity.
Toxicity and Quality of life were assessed using CTCAE 4.0 and pancreatic cancer-specific QLQ-PAN26 and QLQ-C30 before SBRT and at 4 weeks and 4 months after SBRT.
2015
Locally Advanced Pancreatic cancer
The median OS was 13.9 months. Rates of ≥G2 late toxicity was 11%.
Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections.
Patients reported a significant improvement in pancreatic pain (p =.001) at 4 weeks after SBRT on the QLQ-PAN26.
Locally Advanced Pancreatic cancer
16 2017
23 patients with histologically confirmed LAPC underwent SBRT (30 Gy in 3 fraction).
No grade 2 or higher acute or late toxicity was observed.
The overall local response ratio was 82.6% (14 partial response, 2 complete response, 3 stable disease). SBRT showed a good short-term efficacy in controlling both pain and QOL.
Median survival was 10.6 months, with a median follow-up of 9 months. The LAPC became resectable in 8% of the patients.
Locally Advanced Pancreatic cancer
Prescription dose of 45 Gy in 6 fractions.
45 patients were enrolled in a phase 2 trial.
Median follow-up was 13.5 months.
Freedom from local progression was 90% at 2 years.
2017
Humanitas trial
On univariate (P < .03) and multivariate analyses (P < .001), lesion size was statistically significant for FFLP.
On multivariate analysis, tumor size (P <
.001) and FFLP (P < .002) were significantly correlated with OS.
Multivariate analysis showed that FFLP(P
< .035), tumor diameter (P < .002), and CHT before SBRT (P < .001) were significantly correlated with OS.
p<0.03
p<0.015
No patients experienced G ≥ 3 toxicity
Results: Toxicity
According to the Numerical Rating Scale scoring system, 17 (39%) patients experienced pain before SBRT.
In 10 (62%) patients, pain control after treatment allowed suspension of analgesics administration;
In 5 (28%) patients, analgesics dosage was reduced by 50%
In 2 (10%) patients, administration was reduced by 20%.
Results: pain control
SBRT 45 Gy / 6 fx
Example of SBRT
22 LC at 1-year was 72.3%
Median OS is 17 months
Severe adverse events < 10%
Pancreatic SBRT literature: the issue of heterogeneity
2016
23 2017
14,331 patients; 4 treatment groups were identified:
chemotherapy alone,
chemotherapy combined with EBRT, chemotherapy combined with IMRT, chemotherapy combined with SBRT.
Propensity score models predicting the odds of receiving SBRT were created to control for potential selection bias.
The unadjusted median survival before matching was 9.9, 10.9, 12.0, and 13.9 months for patients treated with chemotherapy, EBRT, IMRT, and SBRT, respectively.
SBRT for unresectable pancreatic cancer
24 2017
After matching, patients who received SBRT had significantly improved median OS in comparison with chemotherapy alone (13.9 vs 10.2 months), and EBRT (13.9 vs 11.6 months). However, SBRT did not significantly advance survival over IMRT after matching (13.9 vs 12.2 months)
Pancreatic SBRT: comparison with other treatment
2017
National Cancer Data Base (NCDB): 8450 patients
cT2-4/N0-1/M0 adenocarcinoma of the pancreas diagnosed from 2004 to 2013 were analyzed
Radiation therapy delivered at ≤ 2 Gy was deemed CFRT, and radiation therapy delivered at ≥ 4 Gy per fraction was considered SBRT.
Pancreatic SBRT: comparison with other treatment
CONCLUSIONS: SBRT was associated with superior OS in comparison with CFRT for LAPC, and these findings remained significant in a propensity-matched analysis.
Pancreatic SBRT: comparison with other treatment
27
Gastro-intestinal tract (stomach, duodenum, bowel):
-
Bleeding-
Obstruction-
Stenosis-
Ulceration-
Fistula-
PerforationToxicity
2017
Toxicity and tumor control often depend on details of patient anatomy such as tumor location (head, body, and tail) as well as distance of the tumor from the duodenum or stomach.
A reasonable goal is to escalate SBRT dose to as close to a BED of 100 while keeping the risk of acute and late toxicity to < 5%-10%.
Alternative methods of further safe dose escalation may be realized with proton or carbon ion treatment.
Spacer implanted between the duodenum or stomach and the pancreatic tumor.
Toxicity
29
Toxicity
Comito et al, Milano 2017
Toxicity is a main issue in a number of the reports and is almost
exclusively gastrointestinal.
There is a dose toxicity-relationship which will be important for future prospective trials of SBRT.
Tumour Control Side effects
Toxicity
31
BRPC LAPC
Maximize CHT (4 – 6 moths)
Maximize CHT (> 6 moths)
SBRT / RT SBRT / RT
Surgery
Current approach
Chemotherapy
• SBRT seems to be more effective compared to standard chemoradiation with low toxicity rates
• Most patient affected by pancreatic cancer will die of pancreatic cancer. We need better systemic therapy and local therapy.
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Summary
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