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8th April 2022
A meta-analysis by researchers from Beijing Tongren Hospital, Capital Medical University, Beijing, China, has concluded that adding radiotherapy to immune checkpoint inhibitors (ICIs)for the treatment of patients with melanoma offers no overall survival benefit despite a significant improvement in 12-month progression-free survival.
According to the World Cancer Research Fund, melanoma is the 19th most commonly occurring cancer in men and women, with nearly 300,000 new cases reported in 2018. Among patients whose melanoma has undergone metastases, ICIs, monoclonal antibodies which target the programmed death cell protein 1 (PD-1), the programmed death-ligand 1 (PD-L1), or the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), represent the standard of care. Nevertheless, while effective, when used as mono-therapy, ICIs produce an overall response rate ranging from 0% to 17%, though these figures increase to more than 33.3% when the agents are combined.
Radiotherapy is routinely used in treatment of solid cancers, such as hepatocellular carcinoma (HCC) and several preclinical and clinical studies have explored the efficacy of combining radiotherapy and ICIs in HCC and with promising outcomes. Moreover, a meta-analysis of 11 studies found that combining ICIs with radiotherapy showed better local efficacy than ICI mono-therapy for treating melanoma brain metastasis.
Despite this, few studies have systematically examined the combined effect of ICIs and radiotherapy in the treatment of patients with melanoma. For the present study, the Chinese team set out to summarise the efficacy of radiotherapy in combination with ICIs in the treatment of non-brain metastatic melanoma. They included all available trials such as single-arm and control studies in which the endpoints of overall response rate (ORR), overall survival (OS) or progression-free survival (PFS) were reported. The team used regression analysis and presented their results using odds ratios.
Immune checkpoint inhibitors and radiotherapy outcomes
After an extensive literature search, 9 articles (7 retrospective studies and 2 prospective cohort trials) involving 624 patients were identified and included in the analysis.
Combing radiotherapy with ICIs led to a higher ORR compared with ICIs alone (35% vs 20.4%, p = 0.004) However, in terms of OS, the 12-month odds ratio (OR) comparing the combination to ICI treatment alone was 1.83 (95% CI 0.32 – 5.52, p = 0.69) and hence not significantly different.
While there was no significant difference between the two treatment options in PFS at 6-months (OR = 0.53, 95% CI 0.26 – 1.08, p = 0.08), this difference became significant at 12-months (OR = 0.48, 95% CI 0.29 – 0.80, p = 0.005).
Commenting on these findings, the authors highlighted that with most studies being retrospective in nature and no randomised trials, there was a need for prospective trials to further explore the efficacy of combining radiotherapy with ICIs in melanoma.
They concluded that while, at present, there was no evidence of a survival benefit by combining the two therapies, an improvement in PFS was evident but further high quality trials were required to confirm these findings.
Yin G et al. Efficacy of radiotherapy combined with immune checkpoint inhibitors in patients with melanoma: a systemic review and meta-analysis Melanoma Res 2022
12th November 2021
The use of oral arginine increased the effectiveness of radiation therapy in patient with unresectable brain metastases from solid tumours. This was the conclusion of a study by researchers from the Hematology and Oncology Division, Cornell University, New York, USA. Brain metastases (BMs) occur in 10% to 20% of adult patients with solid organ cancers and are 10 times more common than primary brain tumours. Use of compounds that improve blood flow to tumours might enhance the efficacy of both chemo- and radiotherapy and one suggested agent is nitric oxide (NO) which has been shown to act as an intrinsic radio-sensitiser in vivo.
For the present study, the US researchers considered the use of arginine, which is an endogenous substrate of the nitric oxide synthase enzyme, that naturally produces NO. Although its use in cancer patients has not previously been examined, data from patients with acute metabolic strokes has shown that administration of arginine therapy yields significant therapeutic benefit. Based on the fact that the amino acid appears to have a metabolic effect, the researchers measured levels of the tumour lactate concentration, in patients with BMs, which serves as a biomarker and driver of radio-resistance. The results showed that arginine consistently and significantly reduced tumour lactate concentrations in a small number of patients with BMs. Based on these findings the team undertook a proof-of-concept randomised trial to explore whether arginine increased the effect of radiation therapy in patients with unresectable BM from solid tumours.
A total of 63 patients with solid tumour cancers (including breast, melanoma and non-small cell lung cancer) and BMs were randomised to placebo (32) or oral arginine (10g) which was given 60 minutes before radiation therapy. Patients were followed for a median of 5 months and the overall response rate was 22% in the placebo group but 77.4% in the arginine arm, with a symptomatic response rate of 50% and 93.5% (placebo vs arginine, p = 0.002). In addition, the number of patients free from neurological progression at 6 months was 82% for arginine but only 20% for placebo. Finally, disease progression was observed in only 9.6% of those taking arginine compared to 43.7% of the placebo group.
The authors also reported that in those receiving arginine, functional imaging revealed a marked reduction in tumour lactate concentration, suggesting that the amino acid induced a metabolic effect on cancerous cells. They concluded that the amino acid could be used therapeutically in combination with radiation therapy in patients with brain metastases.
Marullo R et al. The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases. Sci Adv 2021
20th September 2021
A squamous cell carcinoma on the head or neck is the sixth most common cancer globally, with around 890,000 new cases and 450,000 deaths in 2018. The main form of treatment is curative radiotherapy and in patients with locoregionally advanced cancers, prior scanning with fluorodeoxyglucose positron emission tomography and computed tomography (PET-CT) has been shown to have good diagnostic performance for the detection of regional nodal metastasis. However, where there is a delay between radiotherapy and the initial PET-CT scan, does this impact on radiotherapy planning and might it be necessary to perform a second scan prior to radiotherapy? This was the question posed by researchers from the Department of Radiation Oncology, Inselspital, Bern University Hospital, Bern, Switzerland. The team performed a retrospective analysis of patients with advanced head or neck squamous cell carcinoma and who had received two PET-CT scans prior to radiotherapy, to determine whether the second scan led to any modifications to radiotherapy treatment. The team looked for changes in the primary tumour, lymphatic spread and the presence of distant metastases between the two scans. They categorised any changes as minor if there were modifications to the RT plans such as dose changes and major where treatment moved from curative to palliative or the addition of induction chemotherapy, a switch to surgery or any additional diagnostic work-up that led to postponement or cancellation of treatment.
There were 32 newly diagnosed patients with locoregionally advanced squamous cell cancer with a median age of 64 years (34% female). The median interval between the initial scan for staging assessment and the second scan was 42.5 days. Just over half (53%) of patients had a grade 2 and 41% a grade 3 tumour. Fortunately, a major treatment change occurred in only 1 patient although nodal upstaging occurred in 10% (3/29) of patients. Minor treatment changes were required in 52% (16/31) of patients with new lymph node metastases detected in all 16 patients and in 6 cases, there was evidence of progression of the primary tumour size.
In discussing their findings, the authors noted that despite an initial PET-CT scan to assess tumour staging, a second scan identified the need for minor changes in just over half of all patients. Based on these findings, they called for the potential benefits of a second scan to be further investigated and validated. They also noted that the practice of undertaking a second scan of patients where the delay was more than four weeks has become the established practice at their hospital.
Elicin O et al. Impact of pre-treatment second look 18FDG-PET/CT on stage and treatment changes in head and neck cancer. Clin Trans Radiat Oncol 2021