Preoperative short-course radiation therapy with PROtons compared to photons in high-risk RECTal cancer (PRORECT): Initial dosimetric experience.

Background and purpose: Neoadjuvant short-course radiotherapy (SCRT) followed by full-dose systemic chemotherapy is an established treatment modality in locally advanced rectal cancer (LARC). Until recently, SCRT has been exclusively delivered with photons. Proton beam therapy (PBT) may minimize acute toxicity, which in turn likely impacts favorably on the tolerability to subsequent chemotherapy. The aim of this study is a dosimetric comparison between SCRT with photons and protons in the randomized phase II trial PRORECT (NCT04525989). Materials and methods: From June 2021 to June 2022, twenty consecutive patients with LARC have been treated according to study protocol. For each patient, both a VMAT and a PBT treatment plans have been generated and compared pairwise. Results: Dose-volume histogram (DVH) analysis revealed that SCRT with protons significantly reduced radiation dose to pelvic organs at risk including bladder, bones, and bowel in comparison to SCRT with photons. Photon and proton treatment plans had equivalent conformity and homogeneity indexes. Conclusion: Preoperative SCRT with protons offers a significant reduction of radiation dose to normal tissues compared with current photon-based radiotherapy technique. Demonstrated dosimetric advantages may translate into measurable clinical benefits in patients with LARC. Clinical implications of the dosimetric superiority of SCRT with protons will be presented in the coming reports from the PRORECT trial.

Predicting the benefit of stereotactic body radiotherapy of colorectal cancer metastases.

Aim: To evaluate Stereotactic body radiotherapy (SBRT) in metastatic colorectal cancer (mCRC) and identify the benefit of the treatment by using a predictive algorithm. Methods: 85 patients treated with SBRT for mCRC were retrospectively analyzed. The CLInical Categorical Algorithm (CLICAL©) was used to predict probability of relapse after SBRT. Variables pre-SBRT were tested for significance for time to relapse (TTR). The patients' CLICAL© score was the mean of sub-scores of each significant variable's effect on the endpoint. Patients with similar scores were grouped into four signatures dependent on level of benefit after SBRT. Results: Median age was 69 years (42-88), 63 % had a performance status 0 and 47 % were treated for a single metastasis. At the time of the analysis, 90 % had relapsed (95 % out-of-field). Median TTR was 7.3 months (4.6-8.5), and the 2-year relapse-free rate was 15 % (95 %CI = 7-22). The CLICAL© signature III-IV predicted a low risk of relapse if receiving high dose SBRT to all metastases or to lung metastases only. Signature I-II had a short TTR, why SBRT for these patients was judged non-beneficial. Conclusion: The benefit from SBRT varies among mCRC patients. CLICAL© may serve as a screening tool for SBRT referrals but needs to be validated.

Quality of life in patients treated for anal carcinoma-a systematic literature review.

PURPOSE: Anal cancer is a mainly treated with chemoradiotherapy. A small number of patients undergo salvage surgery. There are few published studies investigating quality of life and functional outcome after treatment for anal cancer. The aim of this review was to explore the literature and identify areas for further research. METHODS: A search was conducted in Medline using MESH terms related to anal cancer and quality of life. Two investigators selected and reviewed articles based on titles and abstracts. Three investigators read and reviewed the included articles and collected relevant data. The included articles were evaluated using the minimum standard checklist, and key findings were summarised in a chart. RESULTS: Some 15 articles, and a total of 802 patients, were deemed eligible. The results differed slightly among the studies. The incidence of symptoms such as fatigue, nausea, insomnia and appetite loss was higher than among healthy volunteers. Bowel function, urinary function and sexual function were negatively affected. Some studies found that, compared with the normal population, anal cancer survivors scored clinically significant worse in the functional scales in QLQ-C30. CONCLUSION: In conclusion, it is apparent that several functional problems affect the quality of life of patients with anal cancer. There are few studies which have investigated quality of life after treatment for anal cancer. Interventions to address issues related to anal cancer treatment may improve long-term quality of life in this patient group. TRIAL REGISTRATION: CRD42017059787.

Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients.

Telomerase is expressed in 85-90 % of pancreatic adenocarcinomas and might be a target for active cancer immunotherapy. A study was conducted to investigate safety and immunogenicity in non-resectable pancreatic carcinoma patients using a 16-amino acid telomerase peptide (GV1001) for vaccination in combination with GM-CSF and gemcitabine as first line treatment. Three different vaccine treatment schedules were used; [A (n=6), B (n=6) and C (n=5)]. Groups A/B received GV1001, GM-CSF and gemcitabine concurrently. Group C received initially GV1001 and GM-CSF while gemcitabine was added at disease progression. Group D (n=4) was treated with gemcitabine alone. Adverse events (AE) related to vaccination were mild (grades I-II). Grade III AEs were few and transient. An induced GV 1001­specific immune response was defined as an increase ≥2 above the baseline value in one of the assays (DTH, proliferation, ELISPOT and cytokine secretion assays, respectively). A telomerase­specific immune response was noted in 4/6 patients in group A, 4/6 patients in group B and 2/5 patients in group C. An induced ras­specific immune response (antigenic spreading) was seen in 5 of the 17 patients. The cytokine pattern was that of a Th1-like profile. A treatment induced telomerase or ras response was also noted in group D. All responses were weak and transient. A significant decrease in regulatory T-cells over time was noted in patients in groups A and B (p<0.05). Telomerase vaccination (GV1001) in combination with chemotherapy appeared to be safe but the immune responses were weak and transient. Measures have to be taken to optimize immune responses of GV1001 for it to be considered of clinical interest.

Induction of IgM, IgA and IgE antibodies in colorectal cancer patients vaccinated with a recombinant CEA protein.

PURPOSE: Previous clinical studies have indicated that natural IgM antibodies have the ability to induce apoptosis of tumor cells but IgE and IgA may also mediate tumor cell killing (in addition to IgG). The aim of the study was to analyse induction of IgM, IgA and IgE antibodies in patients vaccinated with the tumor associated antigen CEA. METHODS: Twenty-four resected CRC patients without macroscopic disease were immunized seven times with CEA ± GM-CSF. Four different dose schedules were used over a 12-month period. IgM, IgA and IgE antibody responses against recombinant CEA were determined by ELISA. Patients were monitored immunologically for 36 months and clinically for 147 months. RESULTS: GM-CSF significantly augmented the anti-CEA response for all three antibody classes. Low dose of CEA tended to induce a higher IgM, IgA or IgE anti-CEA antibody response than higher. Anti-CEA IgA antibodies could lyse CEA positive tumor cells in antibody dependent cellular cytotoxicity (ADCC) as well as in complement dependent cytotoxicity (CDC). A significant correlation between survival and high IgA anti-CEA titers was noted (p = 0.02) irrespective of GM-CSF treatment. CONCLUSIONS: The observation that IgA anti-CEA antibodies were cytotoxic and associated with improved survival might indicate that also these antibodies may exert a clinical anti-tumor effect.

A Phase I safety study of plasmid DNA immunization targeting carcinoembryonic antigen in colorectal cancer patients.

A plasmid DNA vaccine, encoding a truncated form of human CEA fused to a T-helper epitope (CEA66 DNA) was delivered three times intradermally at 2 mg or intramuscularly at 8 mg by Biojector® to patients with colorectal cancer. Prior to the first vaccination, all patients received cyclophosphamide (300 mg/m²) intravenously. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered subcutaneously with each vaccination. All patients completed the vaccine schedule. There were no grade 3 or 4 adverse events (AE). The most frequently reported AE grades 1 and 2 were injection site reactions, fatigue, headache, arthralgia, chest tightness and myalgia. Vaccination with CEA66 DNA in combination with GM-CSF was well tolerated and no signs of autoimmunity have been detected.