EURURO Vol. 72 No. 2

E34 320

Letter to the Editor
Reply to Salvador Vale’s Letter to the Editor re: Cesare
Cozzarini. Whole-pelvis Radiotherapy in the Radiation
Treatment of Intermediate- and High-risk Prostate
Cancer: How to Improve the Therapeutic Ratio of a
Potentially Effective but still Unsatisfactory Treatment?
Eur Urol 2017;71:44–5. Preclinical Combinatory
Approach to Enhance Radiotherapy Effects and Reduce
its Morbidity may be Tested in the Clinic
Wider Whole-pelvis Radiotherapy Fields and Enhanced
Antitumoral Effect Mediated by T Lymphocytes: A Legit-
imate Hypothesis?
We read with interest Dr. Vale’s letter in response to a
Platinum Priority editorial in which he deals with the
unquestionably intriguing issue of investigating possible
additive/synergistic approaches to enhance the effects of
radiotherapy and reduce its potential morbidity. Given that
hypoxia reduces the antitumoral activity of irradiation, it is
plausible that one of the mechanisms adopted by tumors to
protect themselves from the cytocidal effects of radiother-
apy would be to adjust the microenvironment to minimize
vascular damage and reduce tumor oxygenation. Thus,
a strategy, such as that proposed by Vale, aimed at
reoxygenating the tumor microenvironment (TME) with
the combined use of radiosensitizers or angiostatic agents
in addition to irradiation, appears to be supported by a
strong rationale, and should theoretically lead to an
improved therapeutic ratio of radiotherapy, even at doses
lower than those currently adopted. Nevertheless if, on one
hand, the preclinical evidence is sufficient to support
clinical trials targeting the TME at the time of irradiation, on
the other, currently available data regarding putative
combinatorial approaches are still incomplete in terms of
long-term toxicity.
With respect to the highly debated issue of prophylactic
irradiation of pelvic lymph nodes in the treatment of prostate
cancer via whole-pelvis radiotherapy (WPRT), other mecha-
nisms that could ultimately enhance the therapeutic ratio
could be postulated. The key role of T lymphocytes in
antitumoral effects secondary to radiotherapy is well known.
In their valuable review, De Maria and Formenti
comprehensively described how radiotherapy, a treatment
traditionally considered immunosuppressive, can induce and
promote both antitumor T-cell activity, mainly via the
so-called abscopal effect, and enhanced tumor infiltration by
T cells, via radiation-induced remodeling of the abnormal
tumor vessels, which are typically less permeable to
infiltration. The findings of Spratt et al highlighting a
much greater clinical benefit of wider WPRT fields could
therefore also be explained in light of this likely additional
effect of irradiation. Vianello et al reported on aberrant
and enhanced T-cell extravasation in response to irradiation
at the level of the irradiated vessels. Consistently, we too
found an unexpectedly high (26%) incidence of grade 3
acute lymphopenia, albeit not leading to an additional risk of
infective episodes, in patients treated with quite wide WPRT
fields . Thus, the hypothesis that wider WPRT fields might
increase vessel permeability and thus facilitate extravasation
of T cells and tumor infiltration should be taken into account.
To thoroughly investigate this theory, we set up an
animal model to allow tracking of peripheral lymphocyte
relocation after irradiation. An increase in the fluorescent
signal, secondary to labeled lymphocyte accumulation in
the urinary bladder, was detected in animals treated with a
single dose of radiation (25 Gy) when compared to non-
irradiated controls (unpublished data). Further investiga-
tion aimed at correlating the amount of T-lymphocyte
extravasation with the degree of tumor control induced by
irradiation thus seems to be warranted.
Conflicts of interest: The authors have nothing to disclose.
References
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available at
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DOIs of original articles: , .
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.