Thursday, January 28, 2021

Dose Painting: simultaneous integrated boost (SIB) to the dominant intraprostatic lesion (DIL)

Two technologies have come together to allow for a new kind of radiation treatment known as simultaneous integrated boost (SIB), or, more informally, “dose painting.” The two technologies are: 
  1. improved imaging by multiparametric MRIs that can more precisely locate tumors within the prostate, and 
  2. improved external beam technology that can deliver doses with submillimeter accuracy. 
Dose painting can be achieved with brachytherapy as well. But just because it can be done, doesn’t mean it should be done. That is, the following two questions must be answered:
  1. Is there any benefit in terms of oncological outcomes?
  2. Is there any increase in treatment toxicity attributable to it?
The arguments for dose painting include:
  • There is often a dominant intraprostatic lesion (DIL) or index tumor. There is some evidence that cancer spreads via clones from it. Because such tumors are often large and high grade, some think that the index tumor may be relatively radioresistant, perhaps because of hypoxia or cancer stem cells. Therefore, a higher dose of radiation may be necessary to kill its cancer cells.
  • By concentrating the radiation’s killing power at the DIL, it may be possible to reduce the radiation dose where it is less needed, and thus spare organs at risk (e.g., bladder and rectum).
The arguments against dose painting include:
  • The index tumor hypothesis is far from proven. In fact, prostate cancer is multifocal in about 80% of men. Reducing the dose elsewhere is risky because cancer cells may survive and propagate.
  • If the dose needed to kill the cancer cells is inadequate, why not increase the dose throughout the prostate to a dose that is adequate? With today’s pinpoint technology, the clinical target volume (the prostate) can be defined with sub-millimeter accuracy and near-perfect shaping.
  • Using mpMRI to precisely delineate the DIL may miss much of it. In fact, a study at UCLA found that tumors delineated by mpMRI missed 80% of the tumor's actual volume.
  • While mpMRI is good at finding large high-grade tumors, sometimes the highest grade tumor is not large, and mpMRI cannot locate it.
  • Intense foci of radiation may increase the probability of normal tissue complications, including damage to the urethra, bladder neck, sphincter, rectum and bowel.
With all these pros and cons in mind, the FLAME randomized clinical trial was instituted to determine whether dose painting is effective and safe in real-world application. Kerkmeijer et al. reported the results of 571 patients treated at 4 institutions in Belgium and the Netherlands from 2009 to 2015. Patients were:
  • Predominantly (85%) high risk
  • Adjuvant ADT was given to 65% for a median of 18 months.
  • Received hypofractionated radiation to the prostate: 77 Gy in 35 treatments, which is biologically equivalent to 82 Gy in 41 treatments.
  • Half received a SIB to the DIL as well: 95 Gy in 35 treatments, which is biologically equivalent to 116 Gy in 58 treatments.
  • The boost dose was reduced sometimes to meet very tight dose constraints on organs at risk.
After 6 years of follow-up:
  • 5-year biochemical disease-free survival (bDFS) was 92% for those that received the SIB and 85% for those who didn't, a significant difference.
  • Both biochemical failures and clinical recurrences were cut in half by the SIB
  • In the limited follow-up period, there weren't enough distant metastases or deaths to detect a significant difference.
  • There were no significant differences in Grade 2 or Grade 3 urinary or rectal  toxicity,
  • As previously reported, late-term Grade 2 or greater toxicity was 10% for rectal, 27% for urinary with no significant differences.
  • There was no late-term Grade 3 rectal toxicity, and minimal late-term Grade 3 urinary toxicity in either arm.
  • There were no significant differences in patient-reported quality of life for urinary, rectal or sexual outcomes.
Because oncological results were as good as brachy boost therapy, the current gold standard for treating high-risk patients, and late-term urinary toxicity was minimal, hypofractionated IMRT with SIB is poised to become the new standard of care for high-risk patients. Longer follow-up will determine whether the results hold up.

There are some opportunities for improving results for patients even further.
  • SBRT with SIB: As we've seen extreme hypofractionation may provide more lasting results with equally good toxicity. Whole gland treatment with as high as 47.5 Gy in 5 fractions did not incur any excess toxicity in trials (see this link). 
  • Tumor detection and delineation with PSMA PET/CT scan: a small comparative study showed that PSMA PET/CT had superior sensitivity and positive predictive value compared to mpMRI. More importantly, it can eliminate patients who would not benefit from localized treatment because of occult metastases.
  • Genomics to detect radio-resistant tumors and radiation sensitivity
  • Imaging to detect hypoxic tumors (e.g., BOLD MRI, FAZA PET, or MISO PET)

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