We aimed to provide evidence for radiotherapy treatment regimens in patients with clinically recurrent ovarian cancer. We analyzed the survival and prognostic factors in 43 patients who were treated for recurrent ovarian cancer at 58 tumor sites using three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) during January 2006-December 2017. t years 1, 2, and 3, overall survival (OS) rate was 82.4%, 68.4%, and 57.9%; local control (LC) rate was 100%, 100% and 80%; recurrence free survival (RFS) rate was 86.8%, 66.6%, and 61.1%; and disease-free survival (DFS) rate was 79.7%, 56.7%, and 46.8%, respectively. The radiotherapy technique was determined to be an independent prognostic factor for survival; the survival rate of patients was significantly improved with IMRT compared to 3D-CRT (P = 0.035). Radiotherapy dose was an independent prognostic factor; survival rate improved when patients were treated with a radiation dose ≥ 60 Gy as compared to < 60 Gy (P = 0.046). Elective nodal prophylactic radiation therapy (ENRT) did not lead to a significant improvement in survival when compared to involved-field radiation therapy (IFRT). The toxicities of 3D-CRT and IMRT were tolerable. One patient (2.3%) had grade 3 acute gastrointestinal (GI) toxicity, 2 (4.6%) grade 3 late GI toxicity, 5 (11.6%) grade 3 hematological toxicity, and 2 (4.6%) had grade 4 hematological toxicity. IMRT improved LC and OS in patients with recurrent ovarian cancer after surgery and multiple chemotherapy; toxicities were tolerable. The IMRT technique and radiotherapy dose of ≥ 60 Gy had independent prognostic significance for the survival of such patients.

Epithelial ovarian cancer accounts for around 1.9% of all malignancies and often presents late at an advanced stage. Prognosis is therefore poor. Currently the mainstay of treatment is radical cytoreductive surgery and chemotherapy but, in the past, the standard of care also included adjuvant whole abdominal radiotherapy. This is no longer standard practice, largely due to high toxicity rates and the effectiveness of platinum-based chemotherapy. Presently, a role is emerging for modern radiotherapy techniques in both the salvage and palliative settings. This review aims to examine the historical use of radiotherapy in ovarian cancer before looking forward to its potential future role.© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Data supporting stereotactic body radiotherapy for oligometastatic patients are increasing; however, the outcomes for gynecological cancer patients have yet to be fully explored. Our aim is to analyze the clinical outcomes of stereotactic body radiotherapy in the treatment of patients with recurrent or oligometastatic ovarian cancer or cervical cancer.The clinical data of 29 patients (35 lesions) with oligometastatic cervical cancer (21 patients, 72%) and ovarian carcinoma (8 patients, 28%) who were treated with stereotactic body radiotherapy for metastatic sites were retrospectively evaluated. All patients had <5 metastases at diagnosis or during progression, and were treated with stereotactic body radiotherapy for oligometastatic disease. Patients with ≥5 metastases or with brain metastases and those who underwent re-irradiation for primary site were excluded. Age, progression time, mean biologically effective dose, and treatment response were compared for overall survival and progression-free survival.A total of 29 patients were included in the study. De novo oligometastatic disease was observed in 7 patients (24%), and 22 patients (76%) had oligoprogression. The median follow-up was 15.3 months (range 1.9-95.2). The 1 and 2 year overall survival rates were 85% and 62%, respectively, and the 1 and 2 year progression-free survival rates were 27% and 18%, respectively. The 1 and 2 year local control rates for all patients were 84% and 84%, respectively. All disease progressions were observed at a median time of 7.7 months (range 1.0-16.0) after the completion of stereotactic body radiotherapy. Patients with a complete response after stereotactic body radiotherapy for oligometastasis had a significantly higher 2 year overall survival and progression-free survival compared with their counterparts. In multivariate analysis, early progression (≤12 months) and complete response after stereotactic body radiotherapy for oligometastasis were the significant prognostic factors for improved overall survival. However, no significant factor was found for progression-free survival in the multivariable analysis. No patients experienced grade 3 or higher acute or late toxicities.Patients with early detection of oligometastasis (≤12 months) and with complete response observed at the stereotactic body radiotherapy site had a better survival compared with their counterparts. Stereotactic body radiotherapy at the oligometastatic site resulted in excellent local control rates with minimal toxicity, and can potentially contribute to long-term survival.© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Recent studies have reported improvement of outcomes (progression-free survival, overall survival, and prolongation of androgen deprivation treatment-free survival) with stereotactic body radiotherapy (SBRT) in non-small cell lung cancer and prostate cancer. The aim of this retrospective, multicenter study (MITO RT-01) was to define activity and safety of SBRT in a very large, real-world data set of patients with metastatic, persistent, and recurrent ovarian cancer (MPR-OC).

Stereotactic body radiotherapy (SBRT, also referred to as stereotactic ablative radiotherapy (SABR)) has been used in the treatment of primary and metastatic solid tumors, and increasingly so in gynecologic oncology. This review article aims to summarize the current literature describing the utility of SBRT in the primary, recurrent, and limited metastatic settings for gynecologic malignancies. The use of SBRT in both retrospective and prospective reports has been associated with adequate control of the treated site, particularly in the setting of oligometastatic disease. It is not, however, recommended as an alternative to brachytherapy for intact disease unless all efforts to use brachytherapy are exhausted. While phase I and II trials have established the relative safety and potential toxicities of SBRT, there remains a dearth of phase III randomized evidence, including the use of immunotherapy, in order to better establish the role of this technique as a method of improving more global outcomes for our patients with gynecologic cancers.© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.

The original rationale for proton therapy was the highly conformal depth-dose distributions that protons are able to produce, compared to photons, which allow greater sparing of normal tissues and escalation of tumor doses, thus potentially improving outcomes. Additionally, recent research, which is still ongoing, has revealed previously unrecognized advantages of proton therapy. For instance, the higher relative biological effectiveness (RBE) near the end of the proton range can be exploited to increase the difference in biologically effective dose in tumors vs. normal tissues. Moreover, the smaller "dose bath", i.e., the compact nature of proton dose distributions has been found to reduce exposure of circulating lymphocytes and the immune organs at risk. There is emerging evidence that the resulting sparing of the immune system has the potential to improve outcomes. Protons, accelerated to therapeutic energies ranging from 70 to 250 MeV, are transported to the treatment room where they enter the treatment head mounted on a rotating gantry. The initially narrow beams of protons are spread laterally and longitudinally and shaped appropriately to deliver treatments. Spreading and shaping can be achieved by electro-mechanically for "passively-scattered proton therapy' (PSPT); or using magnetic scanning of thin "beamlets" of protons of a sequence of initial energies. The latter technique is used to treat patients with optimized intensity modulated proton therapy (IMPT), the most powerful proton therapy modality, which is rapidly supplanting PSPT. Treatment planning and plan evaluation for proton therapy require different techniques compared to photon therapy due, in part, to the greater vulnerability of protons to uncertainties, especially those introduced by inter- and intra-fractional variations in anatomy. In addition to anatomic variations, other sources of uncertainty in the treatments delivered include the approximations and assumptions of models used for computing dose distributions and the current practice of proton therapy of assuming the RBE to have a constant value of 1.1. In reality, the RBE is variable and a complex function of proton energy, dose per fraction, tissue and cell type, end point, etc. Despite the high theoretical potential of proton therapy, the clinical evidence supporting its broad use has so far been mixed. The uncertainties and approximations mentioned above, and the technological limitations of proton therapy may have diminished its true clinical potential. It is generally acknowledged that proton therapy is safe, effective and recommended for many types of pediatric cancers, ocular melanomas, chordomas and chondrosarcomas. Promising results have been and continue to be reported for many other types of cancers as well; however, they are based on small studies. At the same time, there have been reports of unforeseen toxicities. Furthermore, because of the high cost of establishing and operating proton therapy centers, questions are often raised about the value of proton therapy. The general consensus is that there is a need for continued improvement in the state of the art of proton therapy. There is also a need to conduct randomized trials and/or collect outcomes data in multi-institutional registries to generate high level evidence of the advantages of protons. Fortuitously, such efforts are taking currently place. Ongoing research is aimed at better understanding the biological and immunomodulatory effects of proton therapy and the consequences of the physical uncertainties on proton therapy and reducing them through image-guidance and adaptive radiotherapy. Since residual uncertainties will remain despite our best efforts, in order to increase the resilience of dose distributions in the face of uncertainties and improve our confidence in dose distributions seen on treatment plans, robust optimization techniques are being developed and implemented and continue to be perfected. Such research and continuing technological advancements in planning and delivery methods are likely to help demonstrate the superiority of protons.

Proton beam therapy is an external beam radiotherapy modality that offers potentially similar efficacy and reduced toxicity compared with photon radiotherapy due to little to no exit dose of radiation beyond the intended target. Improvements in radiotherapy from two-dimensional, to three-dimensional, to intensity-modulated radiation therapy have offered comparable to improved efficacy of radiation therapy with progressive reductions in toxicity. Proton beam therapy may offer further improvements, with multiple dosimetric studies demonstrating potential reductions in exposure of normal tissue to radiation, particularly bowel and bone marrow. Proton beam therapy offers avenues for dose escalation or re-irradiation, which were previously not feasible with photon radiotherapy. Although early clinical data generally demonstrate safety, feasibility, and efficacy in a few series, prospective clinical trials are limited and needed to better define who might benefit from proton therapy. In this review, we discuss the history, dosimetry, available clinical data, and technical needs to deliver high-quality proton therapy.© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.

The efficacy and feasibility of proton beam therapy (PBT) for recurrent ovarian carcinoma had not been determined. Here we presented a case of recurrent ovarian carcinoma that was successfully treated with PBT. A 48‐year‐old woman who was diagnosed as left ovarian clear cell carcinoma underwent surgery without removal of two tumors. After achieving complete remission with postoperative chemotherapy, a recurrent tumor was found in the sigmoid colon, for which a colostomy was performed. Because second‐line chemotherapy was not effective, PBT was selected; there were no complications, except for a transient low‐grade fever. After 1 year of PBT, the tumor completely disappeared and the patient had been disease‐free for over 8 years. PBT may be an effective and less invasive treatment modality for recurrent ovarian carcinoma.

Ovarian clear cell carcinoma (OCCC) is one of the five histological types of epithelial ovarian cancer (EOC). OCCC comprises 23% of all EOC cases in Japan, whereas the rate of OCCC in North America and Europe is much lower. OCCC is generally categorized as a rare gynecologic malignancy, and there is limited evidence for specific treatment. The clinical basis for treatment of OCCC is mostly based on retrospective studies, many of which were performed in Japan. Until recently, most randomized clinical trials for EOC have included OCCC; therefore, current treatment for OCCC is basically the same as that for other histologic types of EOC. However, the clinical characteristics of OCCC differ from those of high‐grade serous carcinoma, particularly for chemosensitivity, and there is a need to develop new treatment for OCCC. The molecular background of OCCC has unique features: tumors are usually negative for p53 mutations and positive for ARID1A and/or PIK3CA mutations, whereas p53 mutations are common in high‐grade serous or endometrioid carcinomas. These features may help in development of new treatment for OCCC. In this review, we described the current evidence for treatment of OCCC, including surgery, radiotherapy, chemotherapy, molecular targeted therapy and immunotherapy, and we discuss ongoing clinical trials and preclinical studies of new treatment approaches for OCCC.

To evaluate the effectiveness of definitive involved-field radiation therapy (IFRT) for selected patients with locoregionally-recurrent ovarian cancer.We retrospectively reviewed records of 102 epithelial ovarian cancer patients treated with definitive IFRT (≥45Gy). IFRT was directed to localized nodal (49%) and extranodal (51%) recurrences.The median time from diagnosis to IFRT was 36 months (range, 1-311), and the median follow-up after IFRT was 37 months (range, 1-123). Patients received a median of three chemotherapy courses before IFRT (range, 0-9). Five-year overall (OS) and progression-free survival (PFS) rates after IFRT were 40% and 24% respectively; the 5-year in-field disease control rate was 71%. Thirty-five patients (35%) had no evidence of disease at a median of 38 months after IFRT (range, 7-122), including 25 continuously without disease for a median of 61 months (range, 17-122) and 10 with salvage treatment following disease recurrence, disease-free for a median of 39 months after salvage treatment (range, 7-92). Eight clear cell carcinoma patients had higher 5-year OS (88% versus 37%; p=0.05) and PFS (75% versus 20%; p=0.01) rates than other patients. Patients sensitive to initial platinum chemotherapy had a higher 5-year OS rate than platinum-resistant patients (43% versus 27%, p=0.03). Patients who required chemotherapy for recurrence after IFRT often benefitted from longer chemotherapy-free intervals after than before IFRT.Definitive IFRT can yield excellent local control, protracted disease-free intervals, and even cures in carefully selected patients. RT should be considered a tool in the curative management of locoregionally-recurrent ovarian cancer.Copyright © 2013 Elsevier Inc. All rights reserved.

To evaluate the initial experience and clinical utility of first-line adjuvant intensity-modulated whole abdominal radiation therapy (WART) in women with ovarian clear cell cancer (OCCC) referred to an academic center.Progression-free and overall survival was analyzed in a pragmatic observational cohort study of histologically pure OCCC patients over-expressing HNF-1ß treated between 2013 and end-December 2018. An in-house intensity-modulated WART program was developed from a published pre-clinical model. Radiation dose-volume data was curated to American Association of Physics in Medicine (AAPM) Task Group 263 recommendations. A dedicated database prospectively recorded presenting characteristics and outcomes in a standardized fashion.Five women with FIGO (2018) stage IA to IIIA2 OCCC were treated with first-line WART. Median age was 58 years (range 47-68 years). At diagnosis CA-125 was elevated in 4 cases (median 56 kU/L: range 18.4-370 kU/L) before primary de-bulking surgery. Severe premorbid endometriosis was documented in 3 patients. At a median follow-up of 77 months (range 16-83 mo.), all patients remain alive and progression-free on clinical, biochemical (CA-125), and Fluoro-deoxyglucose (FDG) PET/CT re-evaluation. Late radiation toxicity was significant (G3) in 1 case who required a limited bowel resection and chronic nutritional support at 9 months post-WART; 2 further patients had asymptomatic (G2) osteoporotic fragility fractures of axial skeleton at 12 months post-radiation treated with anti-resorptive agents (denosumab).The clinical utility of intensity-modulated WART in OCCC over-expressing HNF-1β was suggested in this small observational cohort study. The hypothesis that HNF-1β is a portent of platinum-resistance and an important predictive biomarker in OCCC needs further confirmation. Curating multi-institutional cohort studies utilizing WART by means of "Big Data" may improve OCCC care standards in the future.

Oligometastatic disease has been proposed as an intermediate state between localised and systemically metastasised disease. In the absence of randomised phase 3 trials, early clinical studies show improved survival when radical local therapy is added to standard systemic therapy for oligometastatic disease. However, since no biomarker for the identification of patients with true oligometastatic disease is clinically available, the diagnosis of oligometastatic disease is based solely on imaging findings. A small number of metastases on imaging could represent different clinical scenarios, which are associated with different prognoses and might require different treatment strategies. 20 international experts including 19 members of the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer OligoCare project developed a comprehensive system for characterisation and classification of oligometastatic disease. We first did a systematic review of the literature to identify inclusion and exclusion criteria of prospective interventional oligometastatic disease clinical trials. Next, we used a Delphi consensus process to select a total of 17 oligometastatic disease characterisation factors that should be assessed in all patients treated with radical local therapy for oligometastatic disease, both within and outside of clinical trials. Using a second round of the Delphi method, we established a decision tree for oligometastatic disease classification together with a nomenclature. We agreed oligometastatic disease as the overall umbrella term. A history of polymetastatic disease before diagnosis of oligometastatic disease was used as the criterion to differentiate between induced oligometastatic disease (previous history of polymetastatic disease) and genuine oligometastatic disease (no history of polymetastatic disease). We further subclassified genuine oligometastatic disease into repeat oligometastatic disease (previous history of oligometastatic disease) and de-novo oligometastatic disease (first time diagnosis of oligometastatic disease). In de-novo oligometastatic disease, we differentiated between synchronous and metachronous oligometastatic disease. We did a final subclassification into oligorecurrence, oligoprogression, and oligopersistence, considering whether oligometastatic disease is diagnosed during a treatment-free interval or during active systemic therapy and whether or not an oligometastatic lesion is progressing on current imaging. This oligometastatic disease classification and nomenclature needs to be prospectively evaluated by the OligoCare study.Copyright © 2020 Elsevier Ltd. All rights reserved.

We present a large real-world multicentric dataset of ovarian, uterine and cervical oligometastatic lesions treated with SBRT exploring efficacy and clinical outcomes. In addition, an exploratory machine learning analysis was performed.A pooled analysis of gynecological oligometastases in terms of efficacy and clinical outcomes as well an exploratory machine learning model to predict the CR to SBRT were carried out. The CR rate following radiotherapy (RT) was the study main endpoint. The secondary endpoints included the 2-year actuarial LC, DMFS, PFS, and OS.501 patients from 21 radiation oncology institutions with 846 gynecological metastases were analyzed, mainly ovarian (53.1%) and uterine metastases(32.1%).Multiple fraction radiotherapy was used in 762 metastases(90.1%).The most frequent schedule was 24 Gy in 3 fractions(13.4%). CR was observed in 538(63.7%) lesions. The Machine learning analysis showed a poor ability to find covariates strong enough to predict CR in the whole series. Analyzing them separately, in uterine cancer, if RT dose≥78.3Gy, the CR probability was 75.4%; if volume was <13.7 cc, the CR probability became 85.1%. In ovarian cancer, if the lesion was a lymph node, the CR probability was 71.4%; if volume was <17 cc, the CR probability rose to 78.4%. No covariate predicted the CR for cervical lesions. The overall 2-year actuarial LC was 79.2%, however it was 91.5% for CR and 52.5% for not CR lesions(p < 0.001). The overall 2-year DMFS, PFS and OS rate were 27.3%, 24.8% and 71.0%, with significant differences between CR and not CR.CR was substantially associated to patient outcomes in our series of gynecological cancer oligometastatic lesions. The ability to predict a CR through artificial intelligence could also drive treatment choices in the context of personalized oncology.Copyright © 2024 Elsevier Inc. All rights reserved.

Radiotherapy is an important treatment for cancer. The main mode of action is thought to be the irreversible damage to tumor cell DNA, but there is evidence that irradiation mobilizes tumor-specific immunity, and recent studies showed that the efficacy of high-dose radiotherapy depends on the presence of CD8(+) T cells. We show in this study that the efficacy of radiotherapy given as a single, high dose (10 Gy) crucially depends on dendritic cells and CD8(+) T cells, whereas CD4(+) T cells or macrophages are dispensable. We show that local high-dose irradiation results in activation of tumor-associated dendritic cells that in turn support tumor-specific effector CD8(+) T cells, thus identifying the mechanism that underlies radiotherapy-induced mobilization of tumor-specific immunity. We propose that in the absence of irradiation, the activation status of dendritic cells rather than the amount of tumor-derived Ag is the bottleneck, which precludes efficient anti-tumor immunity.

Definitive and adjuvant radiation and chemoradiation have been mainstays in the management of multiple gynecologic malignancies for decades. However, despite these treatments, the prognosis of patients with locally advanced, recurrent, refractory, and metastatic disease continues to be poor. Over the last decade, immune checkpoint inhibitors have emerged as a promising therapeutic modality, but response rates to monotherapy are low. Mounting basic science and translational research suggests that immunotherapy and radiation may act synergistically with the potential to improve clinical outcomes across multiple disease sites relative to monotherapy with either radiation or immunotherapy alone. Results from early clinical trials in other disease sites, and burgeoning trials within the gynecologic malignancies space hold promise for combined modality treatment. With increasing clinical data supporting combined modality therapy, there is interest in reevaluating treatment paradigms in gynecologic malignancies to improve the current standards of care. In this review, current proposed mechanisms, rationale, and evidence for treatment of gynecologic malignancies with combined radiation and immunotherapy, specifically immune checkpoint inhibitors, will be discussed. Additionally, although currently early and limited, existing clinical data will be summarized as it applies to cervical, endometrial, ovarian, and vulvar cancers. The status of current clinical trials investigating the sequencing, dosing, and fractionation of combined radiation and immunotherapy in these disease sites will also be reviewed.2021 Translational Cancer Research. All rights reserved.

The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV).Patients were treated with veliparib, 40-400mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor material and quality of life were serially assessed.32pts were treated. Median follow-up was 45months (10-50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250mg PO BID. Median PFS was 3.6months and median OS was 9.1months. In OV patients, OS was longer for platinum-sensitive patients (10.9mo) compared to platinum-resistant patients (5.8mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed.ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient.Copyright © 2017 Elsevier Inc. All rights reserved.

Poly (ADP-ribose) polymerase inhibitors (PARPi) have become a new standard of care for the maintenance treatment of advanced epithelial ovarian cancer. This study aims to evaluate the efficacy and safety of combining stereotactic body radiotherapy with PARPi continuation as a strategy to treat ovarian cancer oligoprogression on PARPi.This is a multicenter retrospective study including ovarian cancer patients treated with stereotactic body radiotherapy and PARPi continuation for oligoprogression under PARPi maintenance therapy between June 2012 and May 2023 in three Italian centers. PARPi treatment was continued until further disease progression or unacceptable toxicity. The primary endpoint was the next-line systemic therapy-free interval. The Kaplan-Meier method was used to assess local control, progression-free survival, and overall survival. Univariate and multivariate Cox regression analyses were performed to evaluate potential clinical outcomes predictors.46 patients were included, with a total of 89 lesions treated over 63 radiotherapy treatments. Lymph nodes were the most frequently treated lesions (80, 89.9%), followed by visceral lesions (8, 9%) and one case with a bone lesion (1.1%). Median follow-up was 25.9 months (range 2.8-122). The median next-line systemic therapy-free interval was 12.4 months (95% CI 8.3 to 19.5). A number of prior chemotherapy lines greater than five was significantly associated with a reduced next-line systemic therapy-free interval (HR 3.21, 95% CI 1.11 to 9.32, p=0.032). At the time of analysis, 32 (69.6%) patients started a new systemic therapy regimen, while 14 (30.4%) remained on the PARPi regimen. The 2-year progression-free survival, local failure-free survival, and overall survival rates were 10.7%, 78.1%, and 76.5%, respectively. Four patients (8.7%) experienced acute toxicity with G1 gastrointestinal events.Stereotactic body radiotherapy combined with PARPi continuation may be an effective and safe strategy for managing ovarian cancer patients with oligoprogression on PARPi maintenance therapy. Prospective research is warranted to shed more light on this approach.© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.

Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. αVβ3 integrin (αVβ3) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant αVβ3-positive OCPM mouse models, we studied the theranostic potential of an αVβ3-specific radiopeptide, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment.