(chemo)radiotherapy

Overview

(Chemo)radiotherapy — encompassing both radiotherapy (RT) alone and chemoradiotherapy (CRT), in which ionizing radiation is combined with systemic chemotherapeutic agents — represents one of the foundational pillars of modern oncological treatment. Radiotherapy leverages high-energy ionizing radiation to induce DNA double-strand breaks, disrupt cellular replication, and drive tumor cell death, while the concurrent or sequential addition of chemotherapy agents (chemoradiotherapy) exploits pharmacological radiosensitization to enhance tumor cell kill beyond what either modality achieves independently. The biological rationale for combining these modalities includes spatial cooperation (chemotherapy targeting distant micrometastases while radiation controls the locoregional disease), temporal cooperation (chemotherapy sensitizing cells to radiation-induced damage), and the exploitation of complementary mechanisms of DNA damage and repair inhibition. (Chemo)radiotherapy is applied across an exceptionally broad range of malignancies — including head and neck Cancers, esophageal squamous cell carcinoma, cervical cancer, diffuse intrinsic pontine glioma, rectal cancer, breast cancer, and prostate cancer — where it functions as a definitive, neoadjuvant, adjuvant, or palliative treatment depending on disease stage and patient factors.

The efficacy of (chemo)radiotherapy is governed by complex tumor biology, including the capacity of cancer cells to repair radiation-induced DNA damage via pathways such as homologous recombination (HR) and the Shieldin complex, the oxygenation status of the tumor microenvironment, and the molecular landscape of the tumor. Resistance to radiotherapy — radioresistance — remains a critical clinical challenge and is an active focus of translational research, with investigators identifying specific molecular targets such as EZH2, Pol θ (theta), and mitochondrial RNA polymerase as candidate vulnerabilities. Parallel efforts focus on radiosensitization strategies employing small molecules, natural compounds, nanoparticle delivery systems, and emerging physical modalities such as hyperthermia patches.

Recent Publications Summary

Recent publications on (chemo)radiotherapy focused on its use as part of multimodal cancer treatment and on factors that may modify response. In resectable esophageal squamous cell carcinoma, PET/CT-guided neoadjuvant tislelizumab plus chemotherapy/chemoradiotherapy was evaluated in the RATIONALE-213 final analysis 41770095Mar. In locally advanced pancreatic cancer, proton beam therapy combined with chemotherapy was assessed as an alternative to conventional photon therapy, with chemotherapy-alone outcomes included for reference 42373264Jun. A phase 2 study in newly diagnosed unmethylated MGMT glioblastoma examined postoperative anlotinib plus radiotherapy, motivated by the limited benefit of standard temozolomide chemoradiotherapy in this subgroup 42339996Jun.

Several studies addressed radiotherapy tailoring or intensification. In cT1-2N1 breast cancer after primary systemic therapy, the RAPCHEM prospective registry study reported 10-year follow-up of radiotherapy tailored to nodal response after primary chemotherapy, building on previously reported excellent locoregional control 42372742Jun. In breast cancer more broadly, another study examined changing practice patterns over time for endocrine therapy and radiation therapy in women aged 65 and older, in the context of uncertainty about optimal treatment delivery 42159636May. For nasopharyngeal carcinoma, a stretchable hyperthermia patch was developed to enhance radiotherapy sensitivity; in cell and mouse models, the combined approach reduced clonogenic survival, increased apoptosis, and suppressed migration compared with radiotherapy alone 42134820May.

Mechanistic studies also linked tumor biology to chemoradiotherapy resistance. In cholangiocarcinoma, H3K4 methylation-driven CALB2 upregulation promoted immune evasion and chemoradioresistance through a CALB2/KRT7/PD-L1 axis; CALB2 silencing sensitized tumors to gemcitabine plus radiotherapy, and this effect was attenuated by KRT7 overexpression 41936307Apr. In glioblastoma modeling, vascularized cerebral organoids with microglia recapitulated glioma stem cell interactions and showed recurrence after radiotherapy, providing a platform to study radiotherapy response in a more physiologic brain-tumor niche 42092360May.

Other publications placed (chemo)radiotherapy in broader therapeutic comparisons or clinical contexts. A study in castration-resistant prostate cancer compared mortality among patients receiving oral androgen receptor pathway inhibitors versus chemotherapy, including those with and without pre-existing cardiovascular disease 42322109Jun. In non-secretory multiple myeloma, a case report described treatment with chemotherapy after diagnosis by bone marrow study, underscoring the diagnostic challenges that can delay appropriate therapy 42375076Jun.

What Changes, What Holds

1. Multimodal regimens are extending (chemo)radiotherapy into response-adapted and substitution strategies
NEW DIRECTION PET/CT-guided neoadjuvant immunochemotherapy around resectable esophageal squamous cell carcinoma, proton beam therapy with chemotherapy in pancreatic cancer, and postoperative anlotinib plus radiotherapy in unmethylated MGMT glioblastoma do not overturn the established role of (chemo)radiotherapy, but they do broaden its clinical framing. The new work suggests that radiation-based treatment is increasingly being embedded in biomarker-guided multimodal pathways and, in some settings, that nonstandard systemic partners may be explored when standard chemoradiotherapy is expected to underperform 41770095Mar42373264Jun42339996Jun.

2. Response-adapted and age-sensitive tailoring looks more central than fixed radiotherapy delivery
REINFORCES Long-term registry follow-up in breast cancer strengthens the baseline view that (chemo)radiotherapy is not a one-size-fits-all intervention but is adjusted to disease biology and treatment response. The practice-pattern study in older women adds that real-world delivery remains unsettled in routine care, especially where endocrine therapy and radiation decisions intersect. Together these findings sharpen, rather than change, the established idea that radiotherapy is often individualized according to nodal response, age, and competing treatment priorities 42372742Jun42159636May.

3. tumor-intrinsic programs can drive chemoradioresistance and may be therapeutically targetable
REINFORCES The cholangiocarcinoma work and the glioblastoma organoid model both deepen the baseline account of resistance by tying poor response to specific tumor biology rather than to radiation failure alone. CALB2-linked immune evasion supports the existing view that molecular pathways can blunt chemoradiotherapy efficacy, while the organoid system offers a more physiologic way to observe recurrence after irradiation. These studies do not displace the established resistance framework; they make it more concrete and suggest additional targets and models for testing 41936307Apr42092360May.

4. Comparative treatment studies keep (chemo)radiotherapy in a broader therapeutic landscape without changing its core role
NEW DIRECTION The prostate cancer mortality comparison and the multiple myeloma case report place chemotherapy and related systemic treatment decisions in adjacent clinical contexts, but they do not revise what (chemo)radiotherapy is understood to do. Their main contribution is to remind readers that treatment choice is shaped by comorbidity, disease subtype, and diagnostic delay, not just by tumor control logic. Because the baseline does not discuss these specific comparative or diagnostic issues, the work adds context rather than altering the established account 42322109Jun42375076Jun.

Overview update candidates: biomarker-guided and response-adapted multimodal use of radiotherapy; proton beam therapy with chemotherapy as an alternative to conventional photon therapy in pancreatic cancer; nonstandard systemic partners for radiotherapy in MGMT-unmethylated glioblastoma; stretchable hyperthermia patch as a radiosensitizer; CALB2/KRT7/PD-L1-linked chemoradioresistance; vascularized cerebral organoids with microglia as a radiotherapy-response model.