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April 2020 : what did we learn ?

Last month, the impact of Covid-19 on cancer treatment has been discussed in many articles. Several more studies have also been published showing the benefits of Proton Therapy for Pediatric Ewing Sarcoma, Head & Neck, Oropharyngeal, Breast, Lung, Esophageal, and Prostate cancers, and for re-irradiation.

Read our selection.

COVID-19 : global consequences for oncology

This pandemic will undoubtedly change the way we work. But the oncology community is relentlessly devoted to the patients, and we will certainly weather this unprecedented storm !


Editorial| Volume 21, ISSUE 4, P467, April 01, 2020

COVID-19: global consequences for oncology
The Lancet Oncology

Challenges posed by COVID-19 to children with cancer

⚠️ Let’s get ready !
Let’s work all together and let’s optimize all our resources to make sure our young patients receive the right treatment at the right time !
👉 “The coming months will pose many further challenges, which might include accessibility to scarce resources, effects on drug manufacture and supply, and the effect on care of children with cancer from low-income and middle-income countries. Continued collaboration among the international pediatric oncology community is required to get through such uncertain times.”

Rishi S Kotecha
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30205-9/fulltext


Treating childhood cancer : a necessity not a choice

“Inadequate access to care, late diagnosis, financial toxicity, and poor-quality care are ubiquitous barriers for children with cancer worldwide and have a crucial impact on survival outcomes. Owing to population growth and inequitable access to cancer care, 80% of the global cancer burden–in terms of both incidence and mortality is estimated to fall on children in low-income and middle-income countries (LMICs)—a humanitarian situation that demands immediate attention.”

Allison Landman
David Collingridge
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30145-5/fulltext


Pediatric Ewing Sarcoma : Depending on the chest wall subregion, proton treatment has the potential to minimize pulmonary, cardiac, renal, and hepatic toxicity, as well as second malignancies.

👉 Target conformity and homogeneity indices are generally better for the IMPT plans with beam aperture.
👉 Doses to the lung, heart, and liver for all patients are substantially lower with the 3DPT and IMPT plans than those of IMRT plans.
👉 In the IMPT plans with large spot without beam aperture, some OAR doses are higher than those of 3DCPT plans. The integral dose of each photon IMRT plan ranged from 2 to 4.3 times of proton plans.
👉 Compared to IMRT, proton therapy delivers significant lower dose to almost all OARs and much lower healthy tissue integral dose. Compared to 3DCPT, IMPT with small beam spot size or using beam aperture has better dose conformity to the target.
👉 Treatment plan using the smaller beam spot with beam apertures provided the best combination of target coverage and OAR sparing.

Impact of different treatment techniques for pediatric Ewing sarcoma of the chest wall: IMRT, 3DCPT, and IMPT with/without beam aperture
Zhong Su et al.
https://aapm.onlinelibrary.wiley.com/doi/full/10.1002/acm2.12870#.XpmY6trKGJk.linkedin

For patients with HPV-positive oropharyngeal cancer, the predicted risk of secondary malignant neoplasms (SMN) is significantly reduced statistically for treatment with Intensity Modulated Proton Therapy (IMPT) compared with Intensity Modulated photon Radiation Therapy (IMRT).

👉 Although both modalities afforded good target coverage, IMPT plans were able to achieve improved healthy-tissue sparing : significant reductions in mean mandible, contralateral parotid, lung and skin organ equivalent doses with IMPT compared with IMRT plans (P < .001).
👉 This reduction in integral dose led to a predicted decrease of 436 additional cases of SMNs for every 10 000 patients/y (or 4 per 100 patients/y) for treatment with protons instead of photons

Predicted Secondary Malignancies following Proton versus Photon Radiation for Oropharyngeal Cancers – Jain et al
https://www.theijpt.org/doi/pdf/10.14338/IJPT-19-00076.1

Oropharyngeal cancer : proton therapy improves Patient-reported outcomes

👉 Intensity Modulated Proton Therapy is associated with improved Patient-reported outcomes, reduced percutaneous endoscopic gastrostomy -tube placement, hospitalization, and narcotic requirements.
👉 Mucositis, dysphagia, and pain were decreased with IMPT.
👉 Benefits were predominantly seen in patients treated definitively or with chemoradiotherapy.

Comparative analysis of acute toxicities and patient reported outcomes between intensity-modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) for the treatment of oropharyngeal cancer
Manzar et al.
https://www.sciencedirect.com/science/article/pii/S0167814020301195

Particle therapies, such as proton therapy or carbon ion therapy, proposed to reduce the burden of xerostomia in patients following chemoradiotherapy for HNSCC

👉 Particle therapies are especially able to reduce moderate to low dose exposure to the oral cavity (minor salivary glands), submandibular glands, and parotid glands with similar target coverage based on the physical properties of the Bragg peak energy deposition of these approaches.

Sticky stuff: xerostomia in patients undergoing head and neck radiotherapy-prevalence, prevention, and palliative care.
Snider JW 3rd, Paine CC 2nd Annals of Palliative Medicine, 25 Mar 2020 10.21037/apm.2020.02.36


Be aware of Radiation-Induced Cardiotoxicity (RIC), and support advanced delivery techniques

👉 Breast cancer
Based on available data, a clear relationship exists between whole-heart dose and risk of cardiac events following Radiotherapy for breast cancer with a significant increase in risk for left-sided breast cancer patients (…) Patients, with a particular focus on those with left-sided disease, should be evaluated for cardiac-sparing techniques, including but not limited to deep-inspiration breath hold (DIBH), gating, prone positioning, and/or proton therapy, to achieve the lowest dose possible.
👉 Thoracic Malignancies (Lung and Esophageal cancers)
Because of the anatomic proximity of these cancers to the heart, however, radiomodulatory techniques such as DIBH or gating may not be as helpful in reducing heart dose; thus, other techniques, such as proton therapy, may be needed.

Nichols et al.
Cardiotoxicity and Radiation Therapy: A Review of Clinical Impact in Breast and Thoracic Malignancies
https://appliedradiationoncology.com/articles/cardiotoxicity-and-radiation-therapy-a-review-of-clinical-impact-in-breast-and-thoracic-malignancies

For locally advanced esophageal cancer, ProtonTherapy (PBT) reduced the risk and severity of Adverse Eventss compared with IMRT while maintaining similar progression-free survival (PFS)

👉 The posterior mean total toxicity burden (TTB) was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than (PBT) (17.4; 10.5-25.0).
👉 The mean postoperative complications (POCs) score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2).
👉 The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial’s stopping boundary of 0.9942 at the 67% interim analysis.
👉 The 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar.

Randomized Phase IIB Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for Locally Advanced Esophageal Cancer
Lin SH, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.02503.


Re-irradiation with proton therapy is a safe and effective treatment in patients with recurrent glioblastoma

Proton therapy does not negatively effect on health-related quality of life (HRQOL), but rather it seems to preserve HRQOL until the time of disease progression :
👉 The treatment was associated with improvement or stability in most of the preselected HRQOL domains.
👉 Global health improved over time with a maximum difference of six points between baseline and 3-months follow-up.
👉 Social functioning and motor dysfunction improved over time with a maximum difference of eight and two points, respectively.
👉 Non-significant decrease in cognitive and emotional functioning.
👉 Fatigue remained stable during the analysis such as the other preselected domains.

Proton therapy re-irradiation preserves health-related quality of life in large recurrent glioblastoma
Scartoni et al.
https://link.springer.com/article/10.1007/s00432-020-03187-w


The high conformality and lack of exit dose with proton therapy offer significant advantages for reirradiation

👉 By decreasing dose to adjacent normal tissues, proton therapy can more safely deliver definitive instead of palliative doses of reirradiation, more safely dose escalate reirradiation treatment, and more safely allow for concurrent systemic therapy in the reirradiation setting.

Proton Reirradiation: Expert Recommendations for Reducing Toxicities and Offering New Chances of Cure in Patients With Challenging Recurrence Malignancies
Simone et al.

Rectal Hydrogel Spacer Improves Late Gastrointestinal Toxicity

👉 compared with rectal balloon immobilization, treatment with the hydrogel spacer significantly reduced the risk of clinically relevant (grade 2+), late rectal bleeding and was associated with a significantly lower decrease in patient-reported bowel quality of life
👉 “the rectal-sparing benefit of the hydrogel spacer, particularly for reducing late rectal bleeding, was even greater than expected. These findings can hold interest for urologists who counsel patients about their treatment options for localized prostate cancer,” added Dr. Ellis, professor and vice-chair of urology, University of Washington, Seattle.

Dinh TT et al.
Rectal Hydrogel Spacer Improves Late Gastrointestinal Toxicity Compared to Rectal Balloon Immobilization After Proton Beam Radiation Therapy for Localized Prostate Cancer: A Retrospective Observational Study.
https://www.ncbi.nlm.nih.gov/pubmed/32035187

Prostate cancer : Hydrogel spacer reduce the rectal dose

👉 Significant rectal dose reduction (P < 0.001) between the treatment plans on pre- and post-CT images were achieved for all modalities for D50%, D20% and D2%.
👉 In particular, the dose reduction of high-dose (D2%) ranges were : −40.61 ± 11.19 for proton therapy −32.44 ± 5.51 for CK −25.90 ± 9.89 for HT −13.63 ± 8.27 for VMAT −8.06 ± 4.19% for 3DCRT
👉 The results of this study demonstrated that all external radiotherapy modalities with hydrogel spacer could reduce the rectal dose.”

Comparison of rectal dose reduction by a hydrogel spacer among 3D conformal radiotherapy (3DCRT), volumetric-modulated arc therapy (VMAT), helical tomotherapy (HT), CyberKnife (CK) and proton therapy – Saito et al.
Journal of Radiation Research, rraa013, https://lnkd.in/dU9-Zcw

Figure : Typical dose distribution of SO(−) and SO(+) and the results of five modalities: (a) 3DCRT, (b) VMAT, (c) HT, (d) CK and (e) proton. The contour of the orange color illustrates the rectum.

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Takeaway from BJR Proton Therapy special feature

Targeting cancer stem cells: protons versus photons – Dini et al.

👉 preclinical data suggest that protons and photons differ in their biological effects on cancer stem cells, with protons offering potential advantages, although the heterogeneity of cancer stem cells and the different proton irradiation modalities make the comparison of the results not so easy. 

Is there a role for arcing techniques in proton therapy ? – Carabe-Fernandez et al.

👉 although Proton Arc Therapy (PAT) may not produce better physical dose distributions than intensity modulated proton therapy, the radiobiological considerations associated with particular PAT techniques could offer the possibility of an increased therapeutic index.

Proton minibeams—a springboard for physics, biology and clinical creativity – Avraham Dilmanian et al.

👉 Proton minibeam therapy (PMBT) is a form of spatially fractionated radiotherapy wherein broad beam radiation is replaced with segmented minibeams—either parallel, planar minibeam arrays generated by a multislit collimator or scanned pencil beams that converge laterally at depth to create a uniform dose layer at the tumor. By doing so, the spatial pattern of entrance dose is considerably modified while still maintaining tumor dose and efficacy. Recent studies using computational modeling, phantom experiments, in vitro and in vivo preclinical models, and early clinical feasibility assessments suggest that unique physical and biological attributes of PMBT can be exploited for future clinical benefit

FLASH and minibeams in radiation therapy: the effect of microstructures on time and space and their potential application to protontherapy – Mazal et al.

👉 the combination of FLASH and minibeams using proton beams, in spite of their complexity, may help to optimize the benefits of several or all the reviewed aspects, through the following concepts:
(1)  the intrinsic advantages of protons to reduce the integral mid and low doses, will be volumetrically combined in synergy with the FLASH and minibeam effects as a whole;
(2)  to reduce mid and high equivalent doses in critical organs around the tumour volume using the FLASH effect with high dose rates achievable with proton beams, both with passive or pencil beam approaches;
(3) to reduce healthy tissue complications by the minibeams space modulation in every beam path, where protons can be focalized with a steep penumbra and hence a high peak to valley ratio;
(4) to deliver an homogeneous dose to the target at any depth using the multiple scattering of proton minibeams in depth, and/or with multiple fields, or even setting a controlled inhomogeneous “vertex” doses escalation approach, optimizing intensity modulated proton therapy with robust solutions;
(5) to modify present approaches of immunological responses by the combination of concentration of lattice doses in very short time with a slight increase in LET, and the microstructure in time and space of both effects and
(6) to deliver single or hypofractionated treatments in very short time per fraction, facilitating the treatment of moving organs, specially when using pencil beam approaches and the associated risk of interplay effects, as well as the optimal use of minibeams with minimal risk of movement during the fraction.
Proton beams have in consequence one of the highest potentials to optimize the use of FLASH and Minibeams effects in radiation therapy, individually or in a synergistic combination.

Re-irradiation with protons or heavy ions with focus on head and neck, skull base and brain malignancies – Seidensaal et al.

👉 Re-irradiation can offer a potentially curative solution in case of progression after initial therapy; however, a second course of radiotherapy can be associated with an increased risk of severe side-effects. Particle therapy with protons and especially carbon ions spares surrounding tissue better than most photon techniques, thus it is of high potential for re-irradiation. Irradiation of tumors of the brain, head and neck and skull base involves several delicate risk organs, e.g. optic system, brainstem, salivary gland or swallowing muscles. Adequate local control rates with tolerable side-effects have been described for several tumors of these locations as meningioma, adenoid cystic carcinoma, chordoma or chondrosarcoma and head and neck tumors.

Reduced radiation-induced toxicity by using proton therapy for the treatment of oropharyngeal cancer – Meijer et al.

👉 proton therapy results in lower dose levels in multiple organs at risk, which translates into reduced acute toxicity (i.e. up to 3 months after radiotherapy), while preserving tumour control. Next to reducing mucositis, tube feeding, xerostomia and distortion of the sense of taste, protons can improve general well-being by decreasing fatigue and nausea. Proton therapy results in decreased rates of tube feeding dependency and severe weight loss up to 1 year after radiotherapy, and may decrease the risk of radionecrosis of the mandible.

Photons or protons for reirradiation in (non-)small cell lung cancer: Results of the multicentric ROCOCO in silico study – Troost et al.

👉 IMPT was able to statistically significantly decrease the radiation doses to the OARs. IMPT was superior in achieving the highest tumour dose while also decreasing the dose to the organs at risk.

Paediatric proton therapy – Thomas et al.

👉 Along with high cure rates, the rate of (late) toxicities is reduced using this radiotherapy modality

Articles cited above and many more are available in Proton therapy special feature, The British Journal of Radiology 2020 93:1107