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Advances in Minimising Radiation-Related Toxicities

M3 India Newsdesk Feb 13, 2024

Explore the transformative impact of advanced radiotherapy techniques and personalised approaches in cancer treatment. Discover how innovations in technology and targeted strategies are revolutionising outcomes, improving patient well-being, and minimising radiation-induced toxicities.

The efficacy of cancer radiotherapy hinges on effectively eliminating tumour cells while sparing normal ones as much as possible. Advancements in technology have equipped us with cutting-edge instruments, allowing for highly precise delivery of radiotherapy (RT) to tumour sites while minimising harm to healthy tissues.

Furthermore, enhanced comprehension of radiobiology, especially regarding the mechanisms behind tumour sensitivity and resistance to radiation, as well as the toxicity in normal tissues, has boosted the effectiveness of radiotherapy treatments.

Approaches to reduce radiation-induced toxicities involve:

  •  Modern radiation techniques
  • Personalised treatment approaches
  • Strategies to enhance the sensitivity of cancer cells to radiation 

Modern radiation techniques

Radiation therapy has seen advancements over the years that have enhanced its efficacy, reduced complications and broadened its scope of applications. These advances are summarised in the following table. 

Modern radiotherapy modalities

External beam radiation therapy

Three-dimensional (3D) conformal radiation therapy (CRT)
  • Uses CT or MRI to create a 3D picture of the tumour.
  • Computerised planning is done to direct the beam precisely to avoid normal tissues.
Intensity-modulated radiation therapy (IMRT)

A specialised form of 3DCRT where radiation is broken into many beamlets and the intensity of each can be adjusted individually to further spare normal tissues.

Four-dimensional radiation therapy (4th dimension being time)

It is a form of Gated radiotherapy to treat tumours that move with breathing, such as lung, breast, and liver tumours. It involves synchronising the delivery of radiation with the patient’s respiratory cycle so that the radiation is delivered only when the tumour is in the treatment field. This technique can help reduce the amount of radiation that healthy organs receive, leading to fewer complications.

Stereotactic radiosurgery Multiple radiation beams converge on the intracranial tumour in a single fraction, delivering high-dose radiation to the target, but trivial to surrounding critical structures. 
Stereotactic body radiation therapy Highly focussed radiation is delivered to extracranial tumours in 3-5 fractions resulting in the least amount of damage to the surrounding healthy tissues.
Adaptive Radiotherapy The dose delivery for subsequent treatment fractions can be modified to compensate for inaccuracies arising from tumour shrinkage, patient’s weight loss etc which forms the basis for Adaptive Radiotherapy. It facilitates the reduction of unnecessary radiation exposure to normal tissues.
Internal radiation therapy
Temporary brachytherapy implant  The radiation source is placed inside tissue or cavity via the catheter and subsequently removed. Accessible cancers like that of the cervix, vagina, oral cavity or breast are treated with this form of brachytherapy. 
Permanent brachytherapy implant  Prostate cancer is treated by this form of brachytherapy where low-dose rate radioactive seeds are placed inside the prostate via an applicator which dissipates radiation over months but seeds aren’t removed later. 
Systemic radiation therapy Systemically administered radioisotopes target tumours like Iodine-131 for thyroid cancer; strontium-89 and samarium-153 for painful bony metastases; yttrium-90 ibritumomab and iodine-131 tositumomab for non-Hodgkin lymphoma, SIRT for liver tumours (single delivery of 90yttrium microspheres into the hepatic artery). This enables selective targeting of tumours while maintaining optimal sparing of normal tissues.
CT = computed tomography; MRI = magnetic resonance imaging, SIRT- Selective internal radiation therapy

Personalised treatment approaches (or Biomarker guided personalised radiotherapy)

Significant progress has occurred in understanding the biological aspects of radiation response and their molecular foundations, including DNA damage response and repair mechanisms, intracellular signalling pathways, and the tumour microenvironment. These strides forward have unveiled a multitude of potential biomarkers stemming from our deeper comprehension of radiation's effects on biological systems.

Though existing evidences are limited for clinical use this approach of biomarker-guided radiotherapy is certainly the future of radiation oncology. A few examples of predictive biomarkers and their therapeutic implications are described below.

  1. The prognosis for oropharyngeal carcinoma OPC associated with Human Papillomavirus (HPV) is typically more promising than for cases not linked to HPV. This distinction has driven the exploration of de-intensification treatment approaches as novel strategies to uphold superior oncologic outcomes while lessening treatment-related adverse effects. Expression of p16 (assessed by Immunohistochemistry) may serve as a surrogate for HPV detection [1].
  2. In efforts to enhance the outcomes of RT on prostate cancer, trials focused on escalating the radiation dosage were conducted. Patients from unfavourable subgroups (PSA > 10 ng/mL), had a notable benefit with a dose increase to 73–78 Gy, whereas those with lower PSA levels (<10 ng/mL) did not experience similar advantages. The effect was even pronounced in patients with initial PSA levels exceeding 20 ng/mL who had a remarkable 40% increase in the 5-year biochemical no evidence of disease (bNED) [2].
  3. EGFR is detected in a considerable number of rectal tumours. The presence of EGFRpositive staining prior to radiotherapy signifies a poor response and lower rates of disease-free survival [3].

Strategies to enhance the sensitivity of cancer cells to radiation

  1. Targeting reactive oxygen species (ROS) [4]
    • Ionising radiation induces radiolysis of water and triggers ROS production which in turn results in DNA damage contributing to RT-induced injury. Numerous preclinical studies have demonstrated that blocking intracellular antioxidants (glutathione, thioredoxin, peroxiredoxin and superoxide dismutase, etc.) can heighten radiation sensitivity and conversely, elevation of these redox-regulating enzymes can shield against radiation-induced damage.
    • Various ROS modulators, such as 2-deoxy D-glucose, nicotinamide, curcumin, and parthenolide, have been shown to improve the relative intracellular redox status. Notably, curcumin has been investigated in several clinical trials as a radiation modulator for treating prostate cancer (NCT01749323) and breast cancer (NCT02724618).
    • In the same vein, there has been the development of radioprotective agents functioning as free radical scavengers or antioxidants. Notably, Amifostine (WR2721) is the singular radioprotector endorsed by the US Food and Drug Administration (FDA) for clinical use. It is designated to reduce the frequency and severity of acute and chronic xerostomia in individuals with head and neck squamous carcinoma, all while maintaining the effectiveness of radiation.
  2. Targeting radiation-induced DNA Damage Response (DDR) signalling [4]

Mechanisms involved in DNA damage and repair have been extensively studied over the years. Reduced expression of genetic signatures involved in DNA repair pathways has been seen to be associated with reduced patient survival rates and adverse clinical features.

  • Hsp90, a key player in rectifying protein misfolding within its client proteins, directly governs around 725 of these clients. Noteworthy among these are numerous proteins linked to DDR signalling, such as ATM, NBS1, and ATR. Ganetespib, an inhibitor of Hsp90, has been in clinical trials as a radiosensitiser in the treatment of rectal cancer (NCT01554969) and oesophageal cancer (NCT02389751).
  1. Targeting tumour hypoxia [4]
    • Clinical trials have evaluated hypoxic radiosensitisers such as hyperbaric oxygen, carbogen breathing, and nitroimidazoles to augment the effectiveness of radiation treatment. These approaches have demonstrated potential in enhancing locoregional control and disease-free survival in head and neck squamous cell carcinoma (HNSCC) when compared to radiation treatment alone. Similarly, Nimorazole has shown exceptional results as a radiosensitiser in Danish trials which led to its routine use in Denmark in cases with (HNSCC).

Radiation therapy remains a crucial cornerstone in cancer treatment, with continuous endeavours aimed at innovating new modalities and techniques to enhance the survival and quality of life for cancer patients. As clinical outcomes improve, there is a growing emphasis on mitigating radiation-related toxicities. The integration of mechanistic biological research alongside advancements in radiation technology has facilitated enhanced sparing of normal tissues while improving tumour control at the same time.


Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

Dr. Rituparna Biswas is an Assistant Professor in the Department of Radiotherapy at Malda Medical College & Hospital, West Bengal.

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