In the past two proton blogs, we covered the history and development of Carbon Ion Radiotherapy (CIRT), as well as the key differences between this technique and Proton Therapy. CIRT was discovered in California during the 1940s when charged particle therapies (including proton therapy) were first researched. Similar to Proton Therapy, CIRT utilizes charged particles to eradicate cancerous cells. The key difference between these two therapies is attributed to the heavier weight of carbon ions; thus, leading to a higher linear energy transfer (LET) than protons. Higher LET provides a promising treatment choice for providing higher doses to targets than protons. In this blog, we will cover current CIRT research for different types of malignancies.
Intracranial tumors are an extremely difficult cancer because radiation to surrounding tissues can damage vital areas of the brain. CIRT has been proven to provide a high dose to tumors while sparing healthy tissues, making it a prime candidate for these types of malignancies. Multiple studies have confirmed the safety and favorable toxicity profile of carbon radiotherapy for intracranial malignancies. For example, high-grade gliomas (fast-growing tumors of the glial cells located in the brain and spinal cord) are typically radioresistant; however, the high LET of carbon ions is demonstrating to be a vital tool in the fight against this cancer. Currently, the CLEOPATRA trial and CINDERELLA trial are underway to determine the effectiveness of CIRT for progressive and recurrent gliomas.
Head and Neck Tumors
Results of proton therapy for cancers of the head and neck are difficult to interpret because protons were frequently used as a boost or combined with surgery. Studies at the National Institute of Radiological Sciences (NIRS) and the GSI Helmholtz Centre for Heavy Ion Research in Germany (HIT) showed that CIRT provided advantageous outcomes for patients with radioresistant head and neck tumors such as Mucosal Malignant Melanoma and Adenoid Cystic Carcinoma. The COSMIC trial is studying CIRT for inoperable Adenoid Cystic Carcinoma, a rare type of cancer that commonly arises in the major and minor salivary glands of the head and neck. Additional trials are being run for Parotid Gland, Nasopharyngeal cancer, Sinonasal, Otic, and Oral cancers. Nasopharyngeal carcinomas are indicating that they may benefit the most from CIRT.
Dosimetric studies have shown lower surrounding tissue doses and a more homogenous target dose for Non-small Cell Lung Cancer (NSCLC) with CIRT compared to photon therapy. A phase I study from the Gunma University Heavy Ion Medical Center treated unresectable stage III NSCLC. Six patients were treated with a response rate was 100% with no dose-limiting toxicity. Overall, CIRT results are superior to those reported for photon stereotactic body radiotherapy in terms of local control and lung toxicity. Furthermore, A dose-escalation study for single-fraction treatment is underway at NIRS. So far, results are showing that a combination of carbon ion radiotherapy with systemic therapy essential to improve survival.
CIRT has been used successfully in the treatment of squamous cell carcinoma of the esophagus. Furthermore, favorable results have been found for Pancreatic Cancer. The PHOENIX-1 trial was a phase I study at HIT evaluating the CIRT in the treatment of locally advanced pancreatic cancer. Although comparison of carbon ion radiotherapy with standard treatment is difficult, the results are showing that it is better to use a combined CIRT and surgery approach than surgery alone. HIT also has the PANODRA-01 phase I-II study, which studies dose escalation in the setting of recurrent and inoperable rectal cancer. Additional studies are being conducted for Hepatocellular Carcinoma, Liver Metastases, and Cholangiocarcinoma.
In a recent paper analyzing patients from NIRS and the Osaka registry, Mohamad et al. determined the risk of secondary malignancy was lower for patients treated with CIRT compared to conventional photon therapy for localized prostate cancer. Additionally, CIRT has been used with good efficacy and safety for the treatment of primary renal cell carcinoma.
In a Chinese series, 45 patients with squamous cell carcinoma, basal cell carcinoma, melanoma, Bowen’s disease, or Paget’s disease were treated with various dosages. CIRT had favorable local control rates at 1 year, ranging from 80 to 90% for all types. Another Chinese series showed CIRT to be successful in the treatment of keloids. A 95% success rate was achieved with a mean follow-up of 29.7 months.
In a systematic review of eight clinical studies from NIRS, Wang et al. concluded that carbon ion radiotherapy is safe and effective in the treatment of gynecologic cancers. Overall, local control and survival achieved in 57 patients seemed better than those for conventional photon therapy.
CIRT has also been used in combination with a brachytherapy boost for the treatment of locally advanced cervical cancer, with no dose-limiting toxicities.
Pediatric cancer is perhaps the most important application for CIRT since children are the most suspectable for future health problems arising due to the adverse effects of radiation therapy. Studies have shown that CIRT appears to have a lower rate of second malignancies compared to photons. Out of a group of 394 pediatric patients treated with CIRT in Germany between 1997 and 2007 for skull base tumors, there were no severe side effects.
Conclusion of CIRT
CIRT represents a promising new treatment technique, with early data suggesting that it is both safe and effective for a variety of tumors. Furthermore, research has indicated that CIRT can create a stronger immunological response. Despite the promising reports so far, more research is needed to confirm the benefits of CIRT over proton and traditional photon therapies. One of the major concerns regarding CIRT is dose uncertainty. Nuclear fragmentation creates uncertainty to tissues distal to the target to a greater degree than proton therapy. Furthermore, phase 3 clinical trials are still missing, and the number of patients treated with CIRT is too small to determine conclusive results. Extensive further prospective trials are needed to define the role of carbon ion therapy in clinical practice.
This is the final blog in a series of three covering CIRT. It is highly recommended to view the past two blogs to get a comprehensive understanding of this novel therapy. For more information not contained within these blogs, check out the resources below.