Combined Use Of Radiation Therapy Research Articles

Abstract P062: PI3Kγδ inhibitor plus radiation enhances the antitumor immune effect of PD-1 blockade in syngenic murine breast cancer and humanized patient-derived xenograft model

Abstract Purpose: Breast cancer is generally viewed as immunologically ‘cold', imposing an immune-suppressive tumor microenvironment (TME) and responding poorly to lone immune checkpoint blockade (ICB). As an adjunct to ICB, radiation therapy (RT) holds promise in terms of in situ tumor vaccination effect, although it is known to promote immune suppression, increasing regulatory T cells (Treg), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs). It was our contention that combined use of RT and a PI3Kγδ inhibitor to combat immune suppression might enhance the efficacy of ICB. Methods: Murine breast cancer cells (4T1) were grown in both immune-competent and -deficient BALB/c mice, and tumors were irradiated by 3 fractions of 24 Gy. A PD-1 blockade and a PI3Kγδ inhibitor were then administered every other day for 2 weeks. Tumors from humanized patient-derived breast cancer xenograft (PDX) model was sequenced to identify immune-related pathways and to profile infiltrated immune cells. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas (TCGA) pan-cancer cohort, and the deconvolution algorithm was used to profile immune cell repertoire. Results: In the immune-competent syngenic 4T1 murine tumor model, PD-1 blockade alone led to tumor hyperprogression, whereas a three-pronged strategy of PI3Kγδ inhibitor, RT, and PD-1 blockade significantly delayed primary tumor growth, boosted abscopal effect, and improved animal survival by comparison. The immune-deficient syngenic 4T1 murine tumor model failed to show this synergism in delaying tumor growth and the abscopal effect. According to FACS analysis, RT significantly increased not only CD8+cytotoxic T-cell fractions but also immune-suppressive Tregcells, MDSCs, and M2 TAMs. However, PI3Kγδ inhibitor significantly lowered proportions of Treg, MDSCs, and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumor CD8+ T-cell populations after triple combination therapy. There were significantly decreased tumor expressions of p-AKT, PD-L1, and HIF1α by PI3Kγδ inhibition. Triple combination therapy significantly delayed primary tumor growth in humanized PDX model as well and analyses of RNA sequencing data of humanized PDX samples showed decreased immune suppressive pathways with decreased and M2 macrophage and increased CD8+ T-cell by triple combination therapy. In the TCGA pan-cancer cohort, high Treg/CD8+T-cell and M2/M1 TAM ratios and poor overall patient survival was associated with high PIK3CG (PI3Kγ) or PIK3CD (PI3Kδ) gene expression. Conclusion: These findings collectively indicate that PI3Kγ and PI3Kδ are clinically relevant targets in an immunosuppressive TME. Combining PI3Kγδ inhibitor, RT, and PD-1 blockade may thus be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors such as breast cancer. Citation Format: In Ah Kim, Min Guk Han, Bum Sup Jang, Mi Hyun Kang. PI3Kγδ inhibitor plus radiation enhances the antitumor immune effect of PD-1 blockade in syngenic murine breast cancer and humanized patient-derived xenograft model [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P062.

PI3Kγδ inhibitor plus radiation enhances the antitumour immune effect of PD-1 blockade in syngenic murine breast cancer and humanised patient-derived xenograft model

IntroductionWe hypothesised that the combined use of radiation therapy and a phosphoinositide 3-kinaseγδ inhibitor to reduce immune suppression would enhance the efficacy of an immune checkpoint inhibitor. MethodsMurine breast cancer cells (4T1) were grown in both immune-competent and -deficient BALB/c mice, and tumours were irradiated by 3 fractions of 24 Gy. A PD-1 blockade and a phosphoinositide 3-kinase (PI3K)γδ inhibitor were then administered every other day for 2 weeks. The same experiments were performed in humanised patient-derived breast cancer xenograft model and its tumour was sequenced to identify immune-related pathways and profile infiltrated immune cells. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas pan-cancer cohort, and the deconvolution algorithm was used to profile immune cell repertoire. ResultsUsing a PI3Kγδ inhibitor, radiation therapy (RT) and PD-1 blockade significantly delayed primary tumour growth, boosted the abscopal effect and improved animal survival. RT significantly increased CD8+cytotoxic T-cell fractions, immune-suppressive regulatory T cells (Tregs), myeloid-derived suppressor cells and M2 tumour-associated macrophages (TAMs). However, the PI3Kγδ inhibitor significantly lowered the proportions of Tregs, myeloid-derived suppressor cells and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumour CD8+ T-cell populations after triple combination therapy. In a humanised patient-derived breast cancer xenograft model, triple combination therapy significantly delayed tumour growth and decreased immune-suppressive pathways. In The Cancer Genome Atlas cohort, high Treg/CD8+ T cell and M2/M1 TAM ratios were associated with poor overall patient survival. ConclusionThese findings indicate PI3Kγ and PI3Kδ are clinically relevant targets in an immunosuppressive TME, and combining PI3Kγδ inhibitor, RT and PD-1 blockade may overcome the therapeutic resistance of immunologically cold tumours. SynopsisCombining PI3Kγδ inhibitor, RT, and PD-1 blockade may be a viable clinical approach, helping to overcome the therapeutic resistance of immunologically cold tumours such as breast cancer.

Abstract 1554: PI3Kγδ inhibitor combined with radiation enhances the antitumor immune effect of PD-1 blockade in syngenic murine breast cancer model and humanized patient-derived xenograft model

Abstract Purpose: Breast cancer is generally viewed as immunologically ‘cold', imposing an immune-suppressive tumor microenvironment (TME) and responding poorly to lone immune checkpoint blockade (ICB). As an adjunct to ICB, radiation therapy (RT) holds promise in terms of in situ tumor vaccination effect, although it is known to promote immune suppression, increasing regulatory T cells (Treg), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs). It was our contention that combined use of RT and a PI3Kγδ inhibitor to combat immune suppression might enhance the efficacy of ICB. Methods: Murine breast cancer cells (4T1) were grown in both immune-competent and -deficient BALB/c mice, and tumors were irradiated by 3 fractions of 24 Gy. A PD-1 blockade (10 mg/kg) and a PI3Kγδ inhibitor (IPI145; 15 mg/kg) were then administered every other day for 2 weeks. We analyzed mRNA-sequencing data from humanized patient-derived xenograft (PDX) model to identify differentially activated immune-related pathways. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas (TCGA) pan-cancer cohort, and the ‘xCell' deconvolution algorithm was used to profile immune cellular distributions at certain levels of PIK3C and PIK3CD expression. Results: In the immune-competent syngenic 4T1 murine tumor model, PD-1 blockade alone led to tumor hyperprogression, whereas a three-pronged strategy of PI3Kγδ inhibitor, RT, and PD-1 blockade significantly delayed primary tumor growth, boosted abscopal effect, and improved animal survival by comparison. The immune-deficient syngeneic 4T1 murine tumor model failed to show this synergism in delaying tumor growth and the abscopal effect. RT significantly increased not only CD8+cytotoxic T-cell fractions but also immune-suppressive Tregcells, MDSCs, and M2 TAMs. However, PI3Kγδ inhibitor significantly lowered proportions of Treg, MDSCs, and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumor CD8+ T-cell populations after triple combination therapy. Triple combination therapy significantly delayed tumor growth in humanized PDX model as well. Analyses of RNA sequencing data of humanized PDX samples showed triple combination increased immune response pathways and increased CD8+ T-cell and decreased Treg and M2 TAM. In the TCGA pan-cancer cohort, higher tumor purity-adjusted Treg/CD8+T-cell and M2/M1 TAM ratios and worse overall patient survival were associated with high PIK3CG (PI3Kγ) or PIK3CD (PI3Kδ) gene expression. Conclusion: These findings collectively indicate that PI3Kγ and PI3Kδ are clinically relevant targets in an immunosuppressive TME. Combining PI3Kγδ inhibitor, RT, and PD-1 blockade may thus be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors such as breast cancer. Citation Format: Min Guk Han, Bum-Sup Jang, Mi Hyun Kang, In Ah Kim. PI3Kγδ inhibitor combined with radiation enhances the antitumor immune effect of PD-1 blockade in syngenic murine breast cancer model and humanized patient-derived xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1554.

PI3Kγδ inhibitor combined radiation enhances the antitumor immune effect of PD-1 blockade in syngenic triple negative breast cancer models.

e13041 Background: Breast cancer is generally viewed as immunologically cold, imposing an immune-suppressive tumor microenvironment (TME) and responding poorly to lone immune checkpoint blockade (ICB). As an adjunct to ICB, radiation therapy (RT) holds promise in terms of in situ tumor vaccination effect, although it is known to promote immune suppression, increasing regulatory T cells (Treg), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs). It was our contention that combined use of RT and a PI3Kγδ inhibitor to combat immune suppression might enhance the efficacy of ICB. Methods: Murine breast cancer cells (4T1) were grown in both immune-competent BALB/c mice, humanized patient-derived xenograft (PDX) were established, and both were irradiated by 3 fractions of 24 Gy. A PD-1 blockade (10 mg/kg) and a PI3Kγδ inhibitor (IPI145; 15 mg/kg) were then administered every other day for 2 weeks. Tumors from humanized PDX was sequenced to identify immune-related pathways and to profile infiltrated immune cells. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas (TCGA) pan-cancer cohort, and the deconvolution algorithm was used to profile immune cellular distributions at certain levels (high vs. low) of PIK3Cand PIK3CD expression. Results: In the immune-competent syngenic 4T1 murine tumor model, PD-1 blockade alone led to tumor hyperprogression, whereas a three-pronged strategy of PI3Kγδ inhibitor, RT, and PD-1 blockade significantly delayed primary tumor growth, boosted abscopal effect, and improved animal survival. According to FACS analysis, RT significantly increased not only CD8+cytotoxic T-cell fractions but also immune-suppressive Tregcells, MDSCs, and M2 TAMs. However, PI3Kγδ inhibitor significantly lowered proportions of Treg, MDSCs, and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumor CD8+ T-cell populations after triple combination therapy. There were significantly decreased tumor expressions of p-AKT, PD-L1, and HIF1α by PI3Kγδ inhibition. Triple combination therapy significantly delayed primary tumor growth in humanized PDX model as well and analyses of RNA sequencing data of humanized PDX samples showed decreased immune suppressive pathways with decreased and M2 macrophage and increased CD8+ T-cell by triple combination therapy. In the TCGA pan-cancer cohort, high Treg/CD8+T-cell and M2/M1 TAM ratios and poor overall patient survival was associated with high PIK3CG (PI3Kγ) or PIK3CD (PI3Kδ) gene expression. Conclusions: These findings collectively indicate that PI3Kγ and PI3Kδ are clinically relevant targets in an immunosuppressive TME. Combining PI3Kγδ inhibitor, RT, and PD-1 blockade may thus be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors such as breast cancer.

Abstract PO-043: Radiation combined with PI3Kγδ inhibitor enhances the antitumor immune effect of PD-1 blockade in syngeneic murine breast cancer model and humanized patient-derived xenograft model

Abstract Purpose: Breast cancer is generally viewed as immunologically ‘cold’, imposing an immune-suppressive tumor microenvironment (TME) and responding poorly to lone immune checkpoint blockade (ICB). As an adjunct to ICB, radiation therapy (RT) holds promise in terms of in situ tumor vaccination effect, although it is known to promote immune suppression, increasing regulatory T cells (Treg), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs). It was our contention that combined use of RT and a PI3Kγδ inhibitor to combat immune suppression might enhance the efficacy of ICB. Methods: Murine breast cancer cells (4T1) were grown in both immune-competent and -deficient BALB/c mice, and tumors were irradiated by 3 fractions of 24 Gy. A PD-1 blockade (10 mg/kg) and a PI3Kγδ inhibitor (IPI145; 15 mg/kg) were then administered every other day for 2 weeks. We analyzed mRNA-sequencing data from humanized patient-derived xenograft (PDX) model to identify differentially activated immune-related pathways. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas (TCGA) pan-cancer cohort, and the ‘xCell’ deconvolution algorithm was used to profile immune cellular distributions at certain levels (high vs. low) of PIK3Cand PIK3CD expression. Results: In the immune-competent syngeneic 4T1 murine tumor model, PD-1 blockade alone led to tumor hyperprogression, whereas a three-pronged strategy of PI3Kγδ inhibitor, RT, and PD-1 blockade significantly delayed primary tumor growth, boosted abscopal effect, and improved animal survival by comparison. The immune-deficient syngeneic 4T1 murine tumor model failed to show this synergism in delaying tumor growth and the abscopal effect. According to FACS analysis, RT significantly increased not only CD8+cytotoxic T-cell fractions but also immune-suppressive Treg cells, MDSCs, and M2 TAMs. However, PI3Kγδ inhibitor significantly lowered proportions of Treg, MDSCs, and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumor CD8+ T-cell populations after triple combination therapy. Triple combination therapy significantly delayed primary tumor growth in humanized PDX model as well and analyses of RNA sequencing data of humanized PDX samples showed triple combination decreased immune suppressive pathways with decreased M2 macrophage and increased CD8+ T-cell. In the TCGA pan-cancer cohort, higher tumor purity-adjusted Treg/CD8+T-cell and M2/M1 TAM ratios and worse overall patient survival were associated with high PIK3CG (PI3Kγ) or PIK3CD (PI3Kδ) gene expression. Conclusion: These findings collectively indicate that PI3Kγ and PI3Kδ are clinically relevant targets in an immunosuppressive TME. Combining PI3Kγδ inhibitor, RT, and PD-1 blockade may thus be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors such as breast cancer. Citation Format: Min Guk Han, Bum-Sup Jang, Mi Hyun Kang, In Ah Kim. Radiation combined with PI3Kγδ inhibitor enhances the antitumor immune effect of PD-1 blockade in syngeneic murine breast cancer model and humanized patient-derived xenograft model [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-043.

Abstract PO-052: Radiation regimen and timing of PD1 blockade critically influence response to combination therapy in head and neck squamous cell carcinoma

Abstract Head and neck squamous cell carcinoma (HNSCC) constitute the sixth most common cancer worldwide, with a 5-year survival of less than 50% for advanced HNSCC patients. Radiation therapy (RT) is widely used in the treatment of HNSCC patients. Preclinical studies have shown that RT can trigger immune mediated response that potentiates tumor regression. However, the use of RT in combination with immune checkpoint inhibitor, specifically programmed death protein-1 blockade (αPD-1), has not been extensively examined in HNSCC. In vitro studies in our laboratory revealed that radiation increased PD-L1 expression in HNSCC tumor cells in a dose-dependent manner. Based on this observation, we hypothesized that the efficacy of RT and αPD-1 therapy would be critically influenced by the timing of αPD-1 of administration. To test this hypothesis, we conducted a preclinical study using a novel orthotopic immunocompetent mouse model of HNSCC (RPMOC1). Tumor bearing mice were randomized into the following arms: RT (single dose 10 Gy), fractionated RT (fRT- 2Gy x 5), RT prior to αPD-1(200 μg), RT post αPD-1, fRT prior to αPD-1 and fRT post αPD-1. Non-invasive magnetic resonance imaging (MRI) was used to monitor tumor response to therapy. All treatment regimens were well tolerated and did not result in weight loss during the experiment. The most potent tumor growth inhibition was observed in the RT (10 Gy) and αPD-1 combination therapy group. RT given either before or after αPD-1 therapy resulted in a significant decrease in tumor volumes (p<0.05) compared to other groups. Combination therapy with fractionated radiation did not show improved response compared to monotherapy. Overall, our observations indicate that tumor response to combined radiation and immunotherapy is critically influenced by the radiation regimen and timing of PD1 blockade in HNSCC. Citation Format: Aparajita Verma, Michael Habitzruther, Kristopher Attwood, Mukund Seshadri. Radiation regimen and timing of PD1 blockade critically influence response to combination therapy in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-052.

Combined Radiation and PI3Kγδ Inhibitor Enhances Anti-Tumor Effect of PD-1 Blockade in Immune-competent Syngeneic Breast Cancer Model

Breast cancer is generally viewed as immunologically ‘cold’, imposing an immune-suppressive tumor microenvironment (TME) and responding poorly to lone immune checkpoint blockade (ICB). As an adjunct to ICB, radiation therapy (RT) holds promise in terms of in situ tumor vaccination effect, although it is known to promote immune suppression, increasing regulatory T cells (Treg), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs). It was our contention that combined use of RT and a PI3Kγδ inhibitor to combat immune suppression might enhance the efficacy of ICB. Murine breast cancer cells (4T1) were grown in both immune-competent and -deficient BALB/c mice, and tumors were irradiated by 3 fractions of 24 Gy. A PD-1 blockade (10 mg/kg) and a PI3Kγδ inhibitor (IPI145; 15 mg/kg) were then administered every other day for 2 weeks. Fluorescence-activated cell sorting (FACS) and immunohistochemistry served to monitor subsequent changes in immune cell repertoire. We used mRNA-sequencing data of patient-derived breast cancer xenografts in a humanized NSG mouse model to analyze differentially expressed genes. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas (TCGA) pan-cancer cohort, and a deconvolution algorithm (xCell) was used to profile immune cellular distributions at certain levels (high vs. low) of PI3Kγδ expression. In the immune-competent syngeneic 4T1 murine tumor model, PD-1 blockade alone led to tumor hyperprogression, whereas a three-pronged strategy of PI3Kγδ inhibitor, RT, and PD-1 blockade significantly delayed primary tumor growth, boosted abscopal effect, and improved animal survival by comparison. The immune-deficient syngeneic 4T1 murine tumor model failed to show this synergism in delaying tumor growth. According to FACS analysis, RT significantly increased not only CD8+cytotoxic T-cell fractions but also immune-suppressive Treg cells, MDSCs, and M2 TAMs. However, PI3Kγδ inhibitor significantly lowered proportions of Treg, MDSCs, and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumor CD8+ T-cell populations after triple combination therapy. There was significantly decreased tumor expression of p-AKT, PD-L1, and HIF1α by PI3Kγδ inhibition. The analyses of RNAseq data of humanized PDX showed triple combination increased immune response pathways and increased CD8 T cell and decreased Treg and M2 macrophage shown by the Xcell deconvolution. In the TCGA pan-cancer cohort, higher tumor purity-adjusted Treg/CD8+T-cell and M2/M1 TAM ratios and worse overall patient survival were associated with high PIK3CG (PI3Kγ) or PIK3CD (PI3Kδ) expression. These findings collectively indicate that PI3Kγ and PI3Kδ are clinically relevant targets in an immunosuppressive TME. Combining PI3Kγδ inhibitor, RT, and PD-1 blockade may thus be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors such as breast cancer.

СРАВНИТЕЛЬНАЯ ОЦЕНКА МОДИФИКАЦИЙ РАЗЛИЧНЫХ МЕТОДОВ ЛУЧЕВОЙ ТЕРАПИИ У БОЛЬНЫХ РАКОМ ШЕЙКИ МАТКИ

The aim of the research is to make a comparative evaluation of the results of treatment of cervical cancer in patients who had the radiation therapy with the application of the modes of sequential and parallel methods of bringing the dose to the pathological focus. The results of combined radiation therapy in 120 patients with cervical cancer were analyzed. Depending on the treatment tactics, the patients were divided into 2 groups of 60 patients who underwent a sequential or parallel method of bringing the dose to the lesion and regional metastasis routes, when the total focal dose in both cases matched the optimally required parameters – 80-85 Gr in the primary tumor and points "A" and 60 Gr in points "B". Distance radiation therapy was carried out 5 times a week, followed by a break of 3-5 weeks and a further application of the intracavitary method. In the second case, a daily distance therapy was carried out to a total focal dose of 18 Gr, after which the number of sessions per week decreased to 3 times and in some days (2 times a week) there was done an intracavitary treatment. The following results were obtained: an objective therapeutic effect was observed in 108 (90%) patients. Full tumor regression was recorded in 95 (87.9%), partial – in 12.1%, and failures were detected in 10% of women. During the three-year follow-up period, 20.0% of patients of the first group and 10.9% of the second group showed progression of the disease manifested by recurrence in the irradiation zones, recurrence+metastases and metastases of the primary tumor, usually in the inguinal and paraaortic lymph nodes, pelvic bones, liver, lungs. The median of remission duration in the first group was 20 months with a three-year survival rate of 68.0%, and in the second it was 26 and 82.0%, respectively. Complications in the form of mucous response to radiation exposure, radiation cystitis, proctitis, enterocolitis in the second group of patients were significantly less common than in the first. Thus, for the treatment of patients with cervical cancer, the most effective is the use of combined radiation therapy in parallel irradiation.

Gold nanoparticle mediated combined cancer therapy

BackgroundThe combined use of radiation therapy and chemotherapy is commonly being used in cancer treatment. The side effects of the treatment can be further minimized through targeted delivery of anticancer drugs and local enhancement of the radiation dose. Gold nanoparticles (GNPs) can play a significant role in this regard since GNPs can be used as radiation dose enhancers and anticancer drug carriers. Anticancer drug, bleomycin, was chosen as the model drug, since it could be easily conjugated onto GNPs through the gold–thiol bond.MethodsGold nanoparticles of size 10 nm were synthesized using the citrate reduction method. The surface of The GNPs was modified with a peptide sequence (CKKKKKKGGRGDMFG) containing the RGD domain and anticancer drug, bleomycin. Human breast cancer cells (MDA-MB-231) were incubated with 0.3 nM concentration of GNP–drug complex for 16 h prior to irradiation with a 2 Gy single fraction of 6 MV X-rays. After the treatment, cells were trypsinized and seeded in 60 mm dishes for clonogenic assay. Damage to DNA was probed using immunofluorescence assay.ResultsCancer cells internalized with the GNP–drug complex had a 32 ± 9% decrease in cell survival and statistically significant enhancement in DNA (deoxyribonucleic acid) damage as compared to control cells (irradiated with no GNPs) after receiving a radiation dose of 2 Gy with 6 MV photons.ConclusionsThe experimental results demonstrate that GNP-mediated chemoradiation has the potential to improve cancer care in the near future through enhancement of the local radiation dose and controlled delivery of anticancer drugs.

The Modern View on the Effectiveness of Cradiotherapy of Prostate Cancer

For many years the main method of treatment of patients with prostate cancer remains surgical treatment, which consists in performing a difficult and traumatic operations, leading to reduced quality of life. Currently, as an equal alternative to radical prostatectomy is radiotherapy, presented with a standard 3D conformal beam radiation, stereotactic radiotherapy and brachytherapy using sources with a low or high dose. Brachytherapy using sources of high power is a safe and effective treatment for localized prostate cancer, providing a summing fatal dose to the tumor with the short period of hospitalization, minimal complications, which may be used in combination with external beam radiotherapy and standalone version. A brief review of the literature on the use of combined radiation therapy in the treatment of prostate cancer. Describes the comparative characteristics of results of treatment of this pathology, complications, early and late toxic reactions when used brachytherapy isotopes of different dose in combination with external beam radiation therapy. The vector of further research in this direction is justified.

Locally advanced prostate cancer: a population‐based study of treatment patterns

Study Type--Therapy (practice patterns). Level of Evidence 2b. What's known on the subject? And what does the study add? The treatment of locally advanced prostate cancer varies widely even though there is level one evidence supporting the use of multimodality therapy as compared with monotherapy. This study defines treatment patterns of locally advanced prostate cancer within the United States and identifies predicators of who receives multimodality therapy rather than monotherapy. • To identify treatment patterns and predictors of receiving multimodality therapy in patients with locally advanced prostate cancer (LAPC). • The cohort comprised patients ≥66 years with clinical stage T3 or T4 non-metastatic prostate cancer diagnosed between 1998 and 2005 identified from the Surveillance, Epidemiology and End Results (SEER) cancer registry records linked with Medicare claims. • Treatments were classified as radical prostatectomy (RP), radiation therapy (RT) and androgen deprivation therapy (ADT) received within 6 and 24 months of diagnosis. • We assessed trends over time and used multivariable logistic regression to identify predictors of multimodality treatment. • Within the first 6 months of diagnosis, 1060 of 3095 patients (34%) were treated with a combination of RT and ADT, 1486 (48%) received monotherapy (RT alone, ADT alone or RP alone), and 461 (15%) received no active treatment. • The proportion of patients who received RP increased, exceeding 10% in 2005. • Use of combined RT and ADT and use of ADT alone fluctuated throughout the study period. • In all 6% of patients received RT alone in 2005. • Multimodality therapy was less common in patients who were older, African American, unmarried, who lived in the south, and who had co-morbidities or stage T4 disease. • Treatment of LAPC varies widely, and treatment patterns shifted during the study period. • The slightly increased use of multimodality therapy since 2003 is encouraging, but further work is needed to increase combination therapy in appropriate patients and to define the role of RP.

Radiation therapy and androgen deprivation in the management of high risk prostate cancer

The combined use of radiation therapy (RT) and androgen deprivation for patients with localized high-risk prostate cancer is commonly accepted as the standard treatment among uro-oncologists. Preclinical studies have provided rationale for the use of this combination. Additionally, results of phase 3 studies using conventional doses of RT have supported the combined approach. Other phase 3 studies have also shown a benefit for using higher doses of RT; however, the role of androgen deprivation in this context is not clear. The optimal duration of the androgen deprivation, in both the neoadjuvant and adjuvant setting, is still under investigation. This article critically reviews the data on the use of RT combined with androgen deprivation for the treatment of high-risk prostate cancer with emphasis on the results of phase 3 trials.

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

We previously reported that intetumumab (CNTO 95), a fully human anti-αv integrin monoclonal antibody, is a radiosensitizer in mice with xenograft tumors. Because intetumumab does not cross-react with mouse integrins, but has cross-reactivity with rat integrins, we next studied the potential combined use of radiation therapy and intetumumab in human cancer xenograft models in nude rats to assess effects on both tumor cells and the tumor microenvironment. Nude rats bearing human head and neck cancer and non-small cell lung cancer (NSCLC) xenografts were treated with intetumumab and fractionated local tumor radiotherapy. Effects on tumor growth and metastasis, blood perfusion, oxygenation, and gastrointestinal toxicity were studied. Intetumumab alone had a moderate effect on tumor growth. When combined with fractionated radiation therapy, intetumumab significantly inhibited tumor growth and produced a tumor response rate that was significantly better than with radiation therapy alone. Treatment with intetumumab also significantly reduced lung metastasis in the A549 NSCLC xenograft model. The oxygenation and blood perfusion in xenograft tumors measured by microbubble-enhanced ultrasound imaging were substantially increased after treatment with intetumumab. The combined use of intetumumab and radiation therapy reduced the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. Toxicity studies showed that treatment with intetumumab did not cause the histopathologic changes in the lungs and did not sensitize the sensitive gastrointestinal epithelium to the effect of radiation therapy. Intetumumab can potentiate the efficacy of fractionated radiation therapy in human cancer xenograft tumors in nude rats without increased toxicity.

Radiation Therapy Potentiates Effective Oncolytic Viral Therapy in the Treatment of Lung Cancer

Replication-competent oncolytic herpes simplex viruses with deletion of the gamma(1)34.5 gene preferentially replicate in and kill malignant cells. The gamma(1)34.5 gene codes for ICP 34.5, a protein that enhances viral replication, and is homologous to growth arrest and DNA damage protein 34 (GADD34), a radiation-inducible DNA repair gene. We hypothesized that radiation therapy may potentiate efficacy of oncolytic viral therapy by upregulating GADD34 and promoting viral replication. The A549 and H1299 lung cancer cell lines were infected with NV1066, an oncolytic herpes simplex virus, at multiplicities of infection (number of viral particles per tumor cell) of 0.1 to 0.5 in vitro with radiation (2 to 10 Gy) or without radiation. Viral replication was determined by plaque assay, cell-to-cell spread was determined by flow cytometry, cell kill was determined by lactate dehydrogenase assay, and GADD34 induction was determined by real-time reverse transcription-polymerase chain reaction and Western blot method. Evidence of synergistic cytotoxicity dependence with GADD34 induction is further confirmed by small inhibitory RNA inhibition of GADD34 expression. Using both the isobologram method and combination index method of Chou and Talalay, significant synergism was demonstrated between radiation therapy and NV1066 both in vitro and in vivo. As a result of such synergism, a dose reduction for each agent (2- to 6,000-fold) can be accomplished for a wide range of therapeutic effect levels without sacrificing tumor cell kill. This effect is correlated with increased GADD34 expression and inhibited by transfection of small inhibitory RNA directed against GADD34. These data provide the cellular basis for the clinical investigation of combined use of radiation therapy with oncolytic herpes simplex virus therapy in the treatment of lung cancer to achieve synergistic efficacy while minimizing dosage and toxicity.

Long-term use of combined radiation therapy and hormonal therapy in the management of Stage D1 prostate cancer

Purpose : To determine tumor response, patterns of relapse, and prognostic indicators in patients followed long-term after combined hormonal radiation therapy of adenocarcinoma of the prostate in men with tumor metastatic to pelvic lymph nodes. Methods and Materials : Seventy-nine patients with adenocarcinoma of the prostate with pathologically confirmed pelvic lymph node metastases were treated with combined radiation therapy and hormonal therapy. Of these, 55 patients (70%) had T3 disease, with the remainder having earlier-stage disease; 45 (57%) patients had N2 disease (Whitmore-Jewett staging). No distant metastases were detected at initial staging, and no patient had radiographic or pathologic involvement of the para-aortic nodes. Pelvic lymph nodes were irradiated to a dose 45–54 Gy, and the prostate was irradiated to a dose 65–71.8 Gy. Hormonal therapy began up to 2 months before radiation and continued indefinitely. Patients were allowed to select their hormonal therapy and could choose diethylstilbestrol (DES) (2 patients), orchiectomy (21 patients), luteinizing hormone-releasing hormone agonist (12 patients), or combined androgen blockade (44 patients). Prognostic factors examined included microscopic vs. measurable lymph node involvement, one-sided vs. two-sided disease, T stage, pretreatment PSA, method of androgen blockade, and Gleason score. Log-rank analysis was used to determine statistical significance with respect to overall survival, disease-free survival, clinical freedom from progression, and biochemical freedom from progression; Cox multivariate analysis was employed to determine potential confounders. Results : Median follow-up was 6.7 years. There were 25 recurrences among the 79 patients, including 7 biochemical recurrences without clinical evidence of disease, three local recurrences in the prostate, and distant metastases in 14 patients; 2 patients were deceased, with cause of death listed as prostate cancer, though the location of recurrence was unknown. Patients with biochemical failure before 5 years were more likely to fail distantly, 16% vs. 4% ( p < 0.001). Overall actuarial survival at 5, 8, and 12 years was 86%, 72%, and 53%, respectively, whereas actuarial disease-free survival was 90%, 87%, and 81%. Ten patients died of intercurrent disease; these included 4 patients who died of a separate (nonpelvic) malignancy of nonadenocarcinomatous histology with no elevation in PSA. When the potential prognostic variables were examined, a trend toward increased biochemical recurrence in patients with Gleason score ≥8 was observed; this became statistically significant when the 4 patients with known residual lymph node disease after biopsy were excluded ( p < 0.03). Gleason score remained the only significant indicator on multivariate analysis. A single long-term toxic event, recto-ureteral fistula, was observed. Conclusion : Combined hormonal and radiation therapy continues to represent an effective treatment option for patients with adenocarcinoma of the prostate with metastasis confined to pelvic lymph nodes. All patient groups seem to have a better disease-free survival than that reported previously in single-modality hormone or radiation treatment series. There is a suggestion that patients with lower Gleason score have a lower risk for recurrence. Combined modality therapy may also extend disease-free survival and allow patients to maintain independent function.

Long term use of combined radiation therapy and hormonal therapy in the management of stage D1 prostate cancer

Purpose: To determine tumor response, patterns of relapse, and prognostic indicators in patients followed long term after combined hormonal-radiation therapy of adenocarcinoma of the prostate in men with tumor metastatic to pelvic lymph nodes. Materials and Methods: 79 patients with adenocarcinoma of the prostate with pathologically confirmed pelvic lymph node metastases were treated with combined radiation therapy and hormonal therapy. Of these, 55 patients (70%) had T3 disease, with the remainder having earlier stage disease, and 45 (57%) patients had N2 disease (Whitmore-Jewett staging). No distant metastases were detected at initial staging and no patient had radiographic or pathologic involvement of the para-aortic nodes. Pelvic lymph nodes were irradiated to a dose of 45 to 54 Gray (Gy) and the prostate was irradiated to a dose of 65 to 71.8 Gy. Hormonal therapy began up to 2 months before radiation and continued indefinitely. Patients were allowed to select their hormonal therapy and could choose Diethylstilbestrol (DES) (2 patients), orchiectomy (21 patients), Luteinizing Hormone-Releasing Hormone (LHRH) agonist (18 patients), or combined androgen blockade (38 patients). Prognostic factors examined included microscopic versus measurable lymph node involvement, one-sided versus two-sided disease, T-stage, pre-treatment PSA, method of androgen blockade, and Gleason score. Log-rank analysis was used to determine statistical significance with respect to overall survival, disease free survival, clinical freedom from progression, and biochemical freedom from progression. Results: Median follow-up is 6.7 years, and 20 patients (25%) have been followed for longer than 8 years. There have been 25 recurrences in the entire group including 3 local recurrences in the prostate, 7 patients with biochemical recurrences without clinical evidence of disease, 13 patients with distant metastases, and 2 patients where the location of recurrence was unknown. Patients with biochemical failure before 5 years were more likely to fail distantly: 16% versus 4% (p < 0.001). Overall actuarial survival at 5, 8, and 12 years is 86, 72, and 53%, respectively, while actuarial disease-free survival was 90, 87, and 81%. Ten patients died of intercurrent disease, and 4 of these died of a separate (non-pelvic) malignancy of non-adenocarcinomatous histology with no elevation in PSA. Of the potential prognostic variables examined, there was a trend toward increased biochemical recurrence in Gleason score ≥ 8 patients (p<0.08) and this became statistically significant when the 4 patients with known residual lymph node disease after biopsy were excluded (p<0.03). A single long-term toxic event of recto-ureteral fistula was observed. Conclusion: Combined hormonal and radiation therapy continues to represent an effective treatment option for patients with adenocarcinoma of the prostate with confined metastasis to pelvic lymph nodes. All patients appear to benefit from such treatment, although there is a suggestion that patients with lower Gleason score are at decreased risk for recurrence. Combined modality therapy may also extend disease-free survival and allow patients to maintain independent function.

Radiation Complications Following Breast Conserving Therapy.

BACKGROUND: Breast conserving therapy is being established as a standard therapeutic procedure for early breast cancer in Japan. However, the indications of radiotherapy and a standardized therapeutic procedure have not been established yet. In this study, complications following radiotherapy were evaluated in patients who had previously undergone breast conserving therapy at Tokushima University Hospital. METHODS From October 1989 to March 1996, 60 women with stage I or II breast cancer underwent radiation therapy after breast conserving surgery, and all patients were followed-up for a median of 27 months. Radiation morbidity scoring of the breast and adjacent organs was performed using the toxity criteria of the Radiation Therapy Oncology Group (RTOG) and European Organization for Research andTreatment of Cancer (EORTC). RESULTS: Only 1 patient developed local recurrence, and no distant metastasisor death was observed. The cause of recurrence in 1 case was considered to be due to extended intraductal component. Although transient dermal reaction was induced by irradiation of the breast, no side effects that may cause cosmetic problems were found. No serious radiation complications were found in the lungs, ribs, heart or other adjacent organs. CONCLUSION: The adverse reactions caused by irradiation does not reduce the merit of combined use of radiation therapy in breast conserving therapy, and therefore, are not the hesitation factor in application of radiotherapy.

Radiation therapy after prostatectomy: Now or later?

Patients with pathological stage T3 or T4 prostate cancers who have undetectable prostate-specific antigen (PSA) levels after radical retropubic prostatectomy (RRP) have a substantial risk of recurrence. The first sign of recurrence is a rising PSA level, which precedes clinical evidence of failure by months to years. Adjuvant radiation therapy can significantly reduce the risk of failure in these patients. Patients with rising PSA levels after RRP can be salvaged with radiation therapy. Larger series report that between 30% and 54% of carefully staged patients can be salvaged with radiation therapy alone. It is possible that more patients may be salvaged in the future with the use of combined radiation therapy and hormonal therapy. Although one cannot be certain which approach-adjuvant or salvage radiation therapy- is better, studies are being performed that will help clarify this clinical dilemma.

The use of combined radiation therapy and hormonal therapy in the management of lymph node-positive prostate cancer

To determine the rate of tumor response and patterns of relapse following combined hormonal-radiation therapy of adenocarcinoma of the prostate and to measure the survival in a group of men with tumor metastatic to pelvic lymph nodes. 66 patients with adenocarcinoma of the prostate with pathologically confirmed pelvic lymph node involvement were treated with combined radiation therapy and hormonal therapy. An additional five patients declined hormonal therapy. The patients treated with combined therapy represented a group with locally advanced disease including 44 patients (67%) with T3 or T4 tumors and 51 patients (80%) had N2 or N3 lymph node metastases. The pelvic lymph nodes were treated to a dose of 45 Gy and the prostate was boosted to a dose of 65 to 71 Gy. Hormonal therapy began up to 2 months before radiation and continued indefinitely. Patients were allowed to select their hormonal therapy and could choose DES (2 patients), orchiectomy (21 patients), LHRH agonist (7 patients) or combined androgen blockade (34 patients). Median follow-up is 49 months (range 12 to 131 months) and 21 patients have been followed for longer than 5 years. There have been 15 recurrences the entire group including three local recurrences in the prostate, seven patients with distant metastases, four patients with biochemical recurrences without clinical evidence of disease, and one patient where the location was unknown. Two of the PSA recurrences occurred in patients who elected to discontinue hormones after less than 3 years of therapy. The overall survival at 5 and 8 years is 94 and 84%, the clinical disease free survival is 85 and 67%, and the biochemical disease-free survival is 78 and 47%. There was no increased toxicity of the combined modality regimen compared to the expected effects of radiation and hormonal therapy. Combined hormonal and radiation therapy represents an effective treatment option for patients with adenocarcinoma of the prostate metastatic to pelvic lymph nodes. Combined modality therapy appears to extend the disease-free survival and allow patients to maintain their independent function.

Second Malignancies After Treatment for Laparotomy Staged IA-IIIB Hodgkin's Disease: Long-Term Analysis of Risk Factors and Outcome

The survival of patients with Hodgkin's disease has dramatically improved over the past 30 years because of advances in treatment. However, concern for the risk of long-term complications has resulted in a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. One major consequence of successful treatment of Hodgkin's disease is the development of second malignant neoplasms. We sought to determine the factors most important for development of second tumors in pathologically staged and treated Hodgkin's disease patients followed for long intervals to provide background information for future clinical trials and guidelines for routine patient follow-up. Between April 1969 and December 1988, 794 patients with laparotomy staged (PS) IA-IIIB Hodgkin's disease were treated with radiation therapy (RT) alone or combined radiation therapy and chemotherapy (CT). There were 8,500 person-years of follow-up (average of 10.7 person-years per patient). Age and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed to expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. Seventy-two patients have developed a second malignant neoplasm. Eight patients developed acute leukemia, 10 had non-Hodgkin's lymphoma (NHL), and 53 patients developed solid tumors at a median time of 5 years, 7.25 years, and 12.2 years, respectively, after Hodgkin's disease. One patient developed multiple myeloma 16.5 years after Hodgkin's disease. The relative risk (RR) of developing a second malignancy was 5.6. The absolute excess risk per 10,000 person-years (AR) of developing a second malignancy was 69.6 (7.0% excess risk per person per decade of follow-up). The highest RR occurred for the development of leukemia (RR = 66.2), however because of the low expected risk, the AR was only 9.3. The RR of solid tumors after Hodgkin's disease was lower (4.7); however, the AR was greater (49) than for acute leukemia. Among the solid tumors, breast, gastrointestinal, lung, and soft tissue cancers had the highest absolute excess risks. The risk for developing breast cancer after Hodgkin's disease was greatest in women who were under the age of 25 at treatment. The most significant risk factor for the development of both leukemia and solid tumors was the combined use of radiation therapy and chemotherapy. The RR following RT alone was 4.1 (AR = 51.1); for RT + CT (initially or at relapse) the RR was 9.75 (P < 0.05, nonoverlapping confidence limits, AR = 123.9). Survival following development of a second malignancy was poor in patients with leukemia, gastrointestinal tumors, lung cancer, and sarcoma. Survival from other malignancies including NHL and breast cancer was more encouraging. Second malignant neoplasms are a major cause of late morbidity and mortality following treatment for Hodgkin's disease. The most significant risk factor for the development of second tumors is the extent of treatment for Hodgkin's disease. Recommendations are presented for both prevention and early detection of these tumors.