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Hong etal. published results of the largest prospective Phase 1/2 clinical trial on
stereotactic proton therapy for liver metastases in 2017, where the investigators
described the importance of tumour genotype also. Out of 89 patients, 34 were
colorectal liver metastases, and a maximum dose of 50Gy in ve fractions was
delivered (BED
10
= 100 Gy). The median tumour size was 2.5 cm, and majority
(61%) had solitary tumours; however, 24 tumours (16.8%) were 6 cm or larger in
size [86]. With no grades 3–5 radiation-related toxicity, 3-year local control and
overall survival rates were 61.2% (95% CI: 50.8–71.5%) and 20.8% (95%
CI:12.4%–30.8%), respectively. Colorectal metastases had worse LC than other
tumours, and KRAS mutant and/or p53 mutant tumours did signicantly worse than
KRAS and p53 wild-type tumours, due to inherent radio resistance. Large tumours
(>6cm) fared similar to smaller ones, presumed to be due to the ability of proton-
based SBRT to ensure liver dose constraints are maintained even in large tumours,
which would be difcult in photon-based SBRT.Of note, the local control in this
series was relatively low compared to other SBRT series and was attributed to doses
≤100 Gy BED
10
. Hence, dose escalation using protons especially in colorectal
metastases is an area worth further investigation.
Kang etal. of the Loma Linda University Medical Centre conducted a Phase I
trial to determine dose-limiting toxicity for patients with 1–3 liver metastases
treated with proton therapy [87]. While dose-limiting toxicity was not reached for
maximum planned dose in the study (60Gy in three fractions), a signicant propor-
tion of the liver, ranging from 523cc to 1361cc received <0.1Gy.
9.9 Role of PBT in Anal Canal Carcinoma
Carcinoma of the anal canal is treated with a combination of radiotherapy, mitomy-
cin C and 5FU with excellent local control rates and overall survival. The regime is
however associated with toxicity due to irradiation of the bowel, bone marrow and
skin of the groin; the rate of grade ≥ 2 reactions was 73% in RTOG 0529, which
investigated the benet of IMRT in the treatment of anal canal carcinoma [88].
Dosimetric studies carried out with scanning proton therapy, an older proton
therapy technique, have demonstrated signicant reduction in the mean dose to the
bone marrow, bladder and bowel, both in the ideal scenario as well as on accounting
for uncertainty related to positioning and range of protons [89]. This advantage is
maintained when assessing the volume of these structures receiving low-dose radia-
tion, the latter being associated with the risk of bowel and bone marrow toxicity
especially with concurrent chemotherapy [90, 91]. The largest benet (>90% reduc-
tion) was however noted in the dose received by the genitalia, indicating that proton
therapy would lead to reduction in sexual dysfunction following radiation.
Dosimetrically, proton therapy plans were noted to be superior to VMAT and
IMRT plans by Kronborg etal. [92] and Meir etal. [93] especially with regard to
sparing of the pelvic bone marrow.
Clinical outcomes have been reported in a feasibility study of the more sophisti-
cated pencil-beam scanning proton therapy technique by Wo et al. who noted a
9 Proton Beam Therapy inGastrointestinal Cancers: AParadigm Shift inRadiotherapy
176
halving of grade 3 dermatologic toxicity compared to a previously reported IMRT-
based RTOG study. The authors noted a colostomy-free survival and overall sur-
vival rates of 72% and 80% at 2years [94].
In an interesting case series, Buchberger et al. reported using pencil-beam
scanned proton therapy for sparing the pelvic kidney in four patients who developed
anal canal cancer following renal transplant. The mean kidney dose of the trans-
planted pelvic kidney was <1Gy in three of four patients [95].
Future Directions: Proton beam therapy has been demonstrated to be feasible
and safe in anal canal cancers with expectation of decreased normal tissue side
effects. These ndings hope to be validated in larger studies/registries. A prospec-
tive Phase II study at MD Anderson Cancer Centre is currently investigating the
clinical value of advanced techniques of IMPT in newly diagnosed anal canal can-
cers to this end [96].
9.10 Conclusions
In conclusion, proton beam therapy has been studied in most gastrointestinal cancer
subsites and indications for radiation and shows dosimetric and/or clinical benet in
most of them. With the emergence of pencil-beam scanning techniques, the imple-
mentation of proton therapy would become easier, and the technology would be
expected to become more easily available throughout the world. So it may be
expected that costs related to this technology will become lower, as this is one of the
factors that restricts its wide use at present. With the use of proton therapy, radiation
in GI cancers will be expected to become less toxic and hence more widely accepted
and applied. The initial clinical studies in most sites do already reect this outcome.
Further studies will be needed with respect to dose escalation to tumours while
maintaining minimal toxicity to the normal tissues. These will hopefully combine to
improve the outcomes for these aggressive cancers while maintaining a good qual-
ity of life.
Acknowledgements Dr. Anindita Das for her contributions towards illustrations and Dr.
Nagarjuna Burela for technical editing and proofreading.
Editorial Comments
Multimodal therapy has long been shown to improve survival in common
gastrointestinal malignancies such as gastro-oesophageal, pancreatic and
hepatocellular carcinomas. Both chemotherapy and radiotherapy are used in
this. Radiotherapy has been used with or without concomitant chemotherapy
(usually for its radiosensitising effect). The problem of radiotherapy in the
management of gastrointestinal cancer is high toxicity related to undesirable
A. S. Mathew and S. Nangia
177
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9 Proton Beam Therapy inGastrointestinal Cancers: AParadigm Shift inRadiotherapy
185
Chapter 10
Immunosuppression inLiver
Transplantation
PhilipG.Thomas andRaviMohanka
10.1 Introduction
Successful application of transplant surgery for denitive management of end-stage
organ disease occured while our understanding of immunology was still rudimen-
tary. Immunosuppression was developed by surgeons, about the middle of the last
century, battling with biological forces that nobody understood and often in the face
of opposition from those who thought they did. The primary function of the immune
system—to defend the body from invasion by foreign organisms—was being ‘sup-
pressed’, and that could only have deleterious effects! The undeniable success of
transplantation however led to a considerable evolution of our knowledge of how
the immune system works, especially of our understanding of mechanisms that ter-
minate an immune attack and regulate balance within the immune system. Today,
the term ‘immunomodulation’ might be better than the older ‘immunosuppression’
to describe what makes a transplant work.
Making a transplant work has primarily been the responsibility of surgeons.
Nowhere is this more true than in liver transplantation. The surgical skill required is
a high-order combination of different surgical disciplines, including GI surgery,
vascular surgery, and microvascular surgical techniques. Intraoperative anaesthesia,
management of coagulopathy, and postoperative intensive care of these patients
require skill, a dedicated team, and the accumulation of experience.
Immunosuppression in this cohort of patients, who present difcult management
problems related to uid volume, ventilation, nutrition, and infection, adds a level
P. G. Thomas (*)
Renaissance Transplant Institute, Doctors Hospital at Renaissance, Mc Allen, TX, USA
R. Mohanka
Department of Liver Transplant and Hepato-Biliary Surgery, Global Hospital, Mumbai, India
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2022
P. Sahni, S. Pal (eds.), GI Surgery Annual, GI Surgery Annual 26,
https://doi.org/10.1007/978-981-19-0828-6_10