Comparative evaluation of CT-based and respiratory-gated PET/CT-based planning target volume (PTV) in the definition of radiation treatment planning in lung cancer: preliminary results.

PURPOSE: The aim of this study was to compare planning target volume (PTV) defined on respiratory-gated positron emission tomography (PET)/CT (RG-PET/CT) to PTV based on ungated free-breathing CT and to evaluate if RG-PET/CT can be useful to personalize PTV by tailoring the target volume to the lesion motion in lung cancer patients. METHODS: Thirteen lung cancer patients (six men, mean age 70.0 years, 1 small cell lung cancer, 12 non-small cell lung cancer) who were candidates for radiation therapy were prospectively enrolled and submitted to RG-PET/CT. Ungated free-breathing CT images obtained during a PET/CT study were visually contoured by the radiation oncologist to define standard clinical target volumes (CTV1). Standard PTV (PTV1) resulted from CTV1 with the addition of 1-cm expansion of margins in all directions. RG-PET/CT images were contoured by the nuclear medicine physician and radiation oncologist according to a standardized institutional protocol for contouring gated images. Each CT and PET image of the patient's respiratory cycle phases was contoured to obtain the RG-CT-based CTV (CTV2) and the RG-PET/CT-based CTV (CTV3), respectively. RG-CT-based and RG-PET/CT-based PTV (PTV2 and PTV3, respectively) were then derived from gated CTVs with a margin expansion of 7-8 mm in head to feet direction and 5 mm in anterior to posterior and left to right direction. The portions of gated PTV2 and PTV3 geometrically not encompassed in PTV1 (PTV2 out PTV1 and PTV3 out PTV1) were also calculated. RESULTS: Mean ± SD CTV1, CTV2 and CTV3 were 30.5 ± 33.2, 43.1 ± 43.2 and 44.8 ± 45.2 ml, respectively. CTV1 was significantly smaller than CTV2 and CTV3 (p = 0.017 and 0.009 with Student's t test, respectively). No significant difference was found between CTV2 and CTV3. Mean ± SD of PTV1, PTV2 and PTV3 were 118.7 ± 94.1, 93.8 ± 80.2 and 97.0 ± 83.9 ml, respectively. PTV1 was significantly larger than PTV2 and PTV3 (p = 0.038 and 0.043 with Student's t test, respectively). No significant difference was found between PTV2 and PTV3. Mean ± SD values of PTV2 out PTV1 and PTV3 out PTV1 were 12.8 ± 25.4 and 14.3 ± 25.9 ml, respectively. The percentage values of PTV2 out PTV1 and PTV3 out PTV1 were not lower than 10 % of PTV1 in 6/13 cases (46.2 %) and than 20 % in 3/13 cases (23.1 %). CONCLUSION: Our preliminary data showed that RG-PET/CT in lung cancer can affect not only the volume of PTV but also its shape, as demonstrated by the assessment of gated PTVs outside standard PTV. The use of a gating technique is thus crucial for better delineating PTV by tailoring the target volume to the lesion motion in lung cancer patients.

Response to neoadjuvant therapy in locally advanced rectal cancer: assessment with diffusion-weighted MR imaging and 18FDG PET/CT.

The aim of this study was to evaluate the correlation between the changes of SUV(max) and of apparent diffusion coefficient (ADC) before and after neoadjuvant therapy, to enable us predict the therapy response, in patients with locally advanced rectal cancer (LARC). A total of 30 patients with LARC who underwent CRT were recruited for our study. All the patients underwent a whole body 18F-FDG-PET/CT scan and a pelvic MR examination including DW imaging for staging (PET/CT1 and RM1), and after the chemoradiation therapy (PET/CT2, and RM2). Histopathologic analysis of rectal specimen, according to tumor regression grade (Mandard's criteria) was used as the standard reference. MR and PET-CT images were analyzed, and measurements of ADC values and SUV(max) were taken. Diagnostic performance for selection of complete responders (TRG1-2) and overall diagnostic accuracy for each item were calculated. After neoadjuvant therapy, all patients were submitted to surgery. According to Mandard's criteria, 21 tumors showed complete (TRG1) or subtotal regression (TRG2) and were classified as responders; nine tumors were classified as non responders (TRG3, 4, and 5). In all the patients, mean value of SUV(max) in PET/CT1 was higher than those in PET/CT2 (P < 0.001), whereas mean ADC value was lower in RM1 than RM2 (P < 0.001), with a significant percentage decrease of values after the treatment (P < 0.005).The best predictors cut-off values for TRG response were SUV(max) of 4.4 and ADC of 1.28 × 10(3) mm(2)/s with sensitivity, specificity accuracy, negative predictive value, and positive predictive values of 77.3%, 88.9%, 80.7%, 61.5%, and 94.4%, respectively. We conclude from the overall data of this study that the absolute values of SUV(max) and ADC of rectal lesion after CRT were the best parameters to define the response to treatment, by differentiating fibrosis from viable tumor tissue.

Change in glucose metabolism measured by 18F-FDG PET/CT as a predictor of histopathologic response to neoadjuvant treatment in rectal cancer.

PURPOSE: In order to analyze the changes of glucose metabolism by maximum standardized uptake value (SUVmax) of 18F-FDG PET/CT in patients with rectal cancer submitted to neoadjuvant radiochemotherapy (nRCT) and to correlate SUV changes with tumor regression grade (TRG). METHODS AND MATERIAL: Three sequential 18F-FDG PET/CT studies were performed in 31 patients with rectal cancer at the following time point: before starting the treatment (PET/CT1), during the treatment (PET/CT2), and after completion of neoadjuvant treatment (PET/CT3). The SUVmax values of the rectal lesion in the PET/CT1 (SUV1), PET/CT2 (SUV2), and PET/CT3 (SUV3) were obtained; deltaSUV1 [(SUV1 - SUV2)/SUV1] and deltaSUV2 [(SUV1 - SUV3)/SUV1] were also calculated. Metabolic parameters were compared to TRG. RESULTS: Significant differences in pathologic responder and non-responder patients were found only for SUV2 (6.4 ± 2.9 in responder and 10.7 ± 4.8 in non-responder patients, respectively; P = 0.006) and SUV3 (3.6 ± 1.4 in responder and 6.6 ± 2.1 in non-responder patients, respectively; P = 0.0009). The best predictor for TRG response was SUV3 (threshold of 4.4) with sensitivity, specificity, accuracy, negative predictive value, and positive predictive value of 77.3%, 88.9%, 80.7%, 61.5%, and 94.4%, respectively. CONCLUSION: 18F-FDG PET/CT is a reliable and accurate technique to assess the response to nRCT in rectal cancer. In our population, the absolute value of SUVmax after treatment was the best predictor of pathological response.

Equipment, staffing, and provision of radiotherapy in Lombardy, Italy: Results of three surveys performed between 2012 and 2016.

INTRODUCTION:: Several efforts are being implemented at the European level to measure provision of up-to-date radiation treatments across the continent. METHODS:: A snapshot survey involving all radiation oncology centers within Lombardy, Italy, was performed in 2012 and repeated in 2014 and 2016, in cooperation with regional governmental officers. Centers were asked to provide detailed information concerning all individual patients being treated on the index day, and to report data on available local resources. RESULTS:: We observed an increase in the number of centers and of megavoltage units (MVU) (from 76 to 87, i.e., 8.7 MVU per million inhabitants in 2016). Mean number of MVU per center was 2.5. Average age of MVU increased from 5.3 to 7.5 years and patients on the waiting list also increased. Conformal 3D radiotherapy (RT) treatments decreased from 56% to 42% and were progressively replaced by intensity-modulated RT treatments (from 39% to 49%). Waiting times were overall satisfactory. Radiation oncologists treated on average 152 and radiation therapists 100 RT courses per year. Average reimbursement per course was €4,879 (range €2,476-€8,014). CONCLUSIONS:: The methodology of snapshot survey proved feasible and provided valuable information about radiation oncology provision and accessibility in Lombardy.

Quality indicators in radiotherapy.

BACKGROUND AND PURPOSE: There is a widespread and increasing tendency to develop hospital performance indicators in the field of accreditation/certification systems and quality benchmarking. A study has been undertaken to develop a set of performance indicators for a typical radiotherapy Centre and to evaluate their ability to provide a continuous quality improvement. MATERIALS AND METHODS: A working group consisting of radiation oncologists, medical physicists and radiation technologists under the coordination of experts in health technology assessment has elaborated a set of general indicators able to monitor performances and the quality level of a typical radiotherapy Centre. The work has been carried out through four steps: a preliminary set of indicators was selected; data on these indicators were collected in a number of Italian radiotherapy Centres and medical physics Services; problems in collection and analysis of data were discussed; a final set of indicators was developed. RESULTS: A final set of 13 indicators is here presented. They concern general structural and/or operational features, health physics activities and accuracy and technical complexity of the treatment. CONCLUSIONS: The indicators tested in a few Italian Centres of radiotherapy and medical physics Services are now ready to be utilized by a larger community.

Epirubicin-vinorelbine intravenous combination followed by oral vinorelbine as first-line treatment in metastatic breast cancer.

Epirubicin and vinorelbine are considered active drugs in metastatic breast cancer. The optimal duration of a chemotherapy regimen for metastatic breast cancer patients is still unknown. Nevertheless, epirubicin has a dose-limiting cardiotoxicity. Vinorelbine is also available as oral formulation. In a multicenter phase II study, we analyzed the feasibility and the efficacy of a maximum of six cycles of i.v. epirubicin plus vinorelbine, followed by oral vinorelbine. We enrolled 30 patients with metastatic breast cancer. Each patient received epirubicin (75 mg/m2 on day 1) and vinorelbine (25 mg/m2 on days 1-8), every 3 weeks, for three cycles or six cycles in case of objective response or stable disease. When a clinical benefit was obtained, patients received oral vinorelbine (60 mg/m2 on days 1-8 every 3 weeks for three cycles). The regimen demonstrated to be active and well tolerated in metastatic breast cancer, and 6-8 months represented the optimal treatment duration. Maintenance therapy with oral vinorelbine was feasible, effective, safe and well accepted by the patients.

Effects of IL-2 preoperative immunotherapy on surgery-induced changes in angiogenic regulation and its prevention of VEGF increase and IL-12 decline.

BACKGROUND/AIMS: IL-2 preoperative immunotherapy has been proven to abrogate surgery-induced immunosuppression in cancer patients. In contrast, at present there are no data about the possible influence of IL-2 on angiogenesis-related molecular changes determined by the surgical operation. At present, it is known that VEGF (vascular endothelial growth factor) is the main endogenous angiogenic factor, whereas the antitumor cytokine IL-12 has appeared to play an anti-angiogenetic role. On this basis, a study was planned to evaluate the influence of IL-2 presurgical immunotherapy on the perioperative changes in VEGF and IL-12 secretions. METHODOLOGY: The study was performed on 30 colorectal cancer patients undergoing radical surgery, who were randomly chosen to be treated with or without preoperative immunotherapy of IL-2 (12 million IU/day subcutaneously for 3 consecutive days prior to surgery). Serum levels of VEGF and IL-12 were measured by ELISA for blood samples collected before surgery, and at days 3, 7 and 10 of the postoperative period. RESULTS: VEGF mean concentrations progressively and significantly increased during the postoperative period in patients treated with surgery alone. Mean values of VEGF were enhanced also in patients pretreated with IL-2, but VEGF increase observed in the IL-2 group was delayed, more transient and significantly lower with respect to that found in controls. IL-12 mean concentrations significantly decreased during the postoperative period only in the control patients, whereas in the IL-2-treated patients IL-12 postoperative mean values were not significantly lower than those found before surgery. CONCLUSIONS: This preliminary study would suggest that IL-2 preoperative immunotherapy may abrogate surgery decline in IL-12 levels and reduce, although not completely prevent, VEGF increase during the postoperative period in surgically treated cancer patients. These results would suggest that IL-2 presurgical immunotherapy may counteract surgery-induced stimulation of the angiogenesis, by either opposing the decline in blood levels of the anti-angiogenetic cytokine IL-12, or reducing the increase in those of the angiogenic factor VEGF.

Efficacy of bromocriptine in the treatment of metastatic breast cancer- and prostate cancer-related hyperprolactinemia.

OBJECTIVE: Hyperprolactinemia is a frequent evidence occurring in both metastatic breast cancer and prostate cancer, and it has been proven to be associated with poor prognosis and reduced efficacy of the anticancer therapies. Therefore, the pharmacological control of cancer-related hyperprolactinemia could improve the prognosis of advanced breast and prostate carcinomas. Unfortunately, at present it is still controversial which may be the treatment of cancer-related hyperprolactinemia, which could depend at least in part on a direct autocrine production by cancer cells themselves. The present study was performed to evaluate the acute effects of the long-acting dopaminergic agonist bromocriptine on cancer-related hyperprolactinemia. METHODS: The study included 10 women affected by metastatic breast cancer and 10 men with metastatic prostate cancer, showing persistent hyperprolactinemia. Venous blood samples were collected before bromocriptine, and 2, 4, 10 and 24 hours after bromocriptine administration (2.5 mg orally) serum levels of PRL were measured with the double antibody RIA method. RESULTS: Bromocriptine induced a normalization of PRL levels in both groups of patients with breast and prostate cancers. Moreover, mean levels of PRL persisted significantly lower than those found before therapy during the whole 24-hour circadian period. DISCUSSION: This preliminary study shows that low-dose bromocriptine is sufficient to acutely normalize PRL secretion in both metastatic breast cancer and prostate carcinoma patients, irrespectively of the mechanisms involved in inducing cancer-related hyperprolactinemia. Therefore, low-dose bromocriptine could be recommended in association with the classical antitumor therapies in the treatment of metastatic breast cancer and prostate carcinoma patients showing cancer-related hyperprolactinemia, in an attempt to improve the efficacy of anticancer therapies themselves.

Psychooncology and cancer progression-related alterations of pleasure-associated neurochemical system: Abnormal neuroendocrine response to apomorphine in advanced cancer patients.

OBJECTIVES: The clinical approach of the Psychooncology is generally limited to the investigation of the only psychological status of cancer patients, without taking into consideration the well demonstrated cancer progression-related psychoneuroendocrine alterations, namely consisting of a progressive decline in the pineal endocrine function and an anomalous activity of brain opioid system. The endocrine response to apomorphine, a dopaminergic agent, has been proven to reflect the dopaminergic sensitivity, which would be involved at least in part in pleasure-related neurochemical mechanisms. The present study was performed to analyze the endocrine response to apomorphine in metastatic cancer patients, as a preliminary approach to the investigation of pleasure-related neuroendocrine mechanisms in human neoplasms. MATERIALS & METHODS: The study included 10 metastatic cancer male patients and 6 male volunteers as a control group. Apomorphine was given orally at 0.01 mg/kg body weight in the morning, and venous blood samples were collected before, and at 20, 60 and 120 minutes after apomorphine administration. The endocrine analysis consisted of the measurement of serum levels of GH, PRL and cortisol. RESULTS: All cancer patients presented alterations involving one or more endocrine responses to apomorphine. GH and cortisol mean levels after apomorphine were significantly higher in controls than in cancer patients, whereas no substantial difference occurred in those of PRL. CONCLUSIONS: This preliminary study, by showing an altered endocrine response to apomorphine in metastatic cancer patients, would suggest that cancer progression may be associated with an altered dopaminergic sensitivity. Because of the involvement of the dopaminergic system in pleasure-related neurochemical mechanisms, this finding would demonstrated that the decline in the perception of pleasure with cancer progression may depend not only on psychological factors, but also, at least in part, on psychochemical alterations occurring during the clinical course of the neoplastic disease.

Effect of bicalutamide therapy on prolactin response to L-dopa in metastatic prostate cancer patients.

OBJECTIVES: The secretion of prolactin (PRL), which is a growth factor for prostate cancer cell proliferation, has been proven to present profound alterations in advanced prostate cancer patients, consisting of abnormally elevated baseline levels and paradoxical response to L-dopa. Moreover, the efficacy of standard therapies for prostate cancer may be mediated at least in part by changes in PRL secretion. The present study was carried out to analyze the effects of the new antiandrogen agent bicalutamide on basal levels of PRL and on its response to L-dopa in metastatic prostate cancer patients. MATERIAL & METHODS: The study included 10 metastatic prostate cancer patients. They were treated with bicalutamide at a dose of 50 mg/day orally. They were investigated with L-dopa test before therapy and after one month of treatment. L-dopa was given orally at 500 mg, by collecting blood samples before and at 60, 120 and 180 minutes after L-dopa administration. Serum levels of PRL were measured by the RIA method. RESULTS: Abnormally basal levels of PRL were seen in 4/10 (40%) patients. Mean PRL basal levels decreased after bicalutamide therapy, without, however, significant differences. Before therapy, a paradoxical increase in PRL levels after L-dopa occurred in 4 patients, 3 of them showed basal concentrations of PRL within the normal range. Moreover, bicalutamide therapy significantly reduced PRL increase in response to L-dopa. CONCLUSIONS: This study would suggest that the measurement of the only basal levels is not sufficient to define as normal the secretion of PRL in advanced prostate cancer, because of the possible existence of altered response to the dynamic tests for PRL secretion. Moreover, the study shows that the antitumor therapy with the new anti-androgen bicalutamide may reduce PRL secretion and improve its paradoxical secretion in response to L.-Dopa. Further studies will be required to better define the possible prognostic impact of changes in PRL secretion on the efficacy of treatments for metastatic prostate cancer.

Quality assurance of 3D-CRT: indications and difficulties in their applications.

Although more advanced techniques such as intensity-modulated radiotherapy are rapidly spreading, 3D conformal radiotherapy (3D-CRT) remains the standard of treatment for many diseases. The authors outline essential indications to guarantee the quality of 3D-CRT treatments. Criteria for clinical indications and potential clinical advantages and disadvantages of 3D-CRT technology are presented. After briefly listing human and technological resources requirements, procedures for 3D-CRT and physical aspects peculiar to 3D-CRT are described. Medical physics support activities are also considered, including suggestions concerning quality control protocols. Difficulties in the application of correct quality procedures, particularly related to human and technological resources, procedures for patient positioning, imaging, contouring, treatment planning, in vivo dosimetry, set-up verification, follow-up, dose delivery are then discussed.

Endocrine effects of erythropoietin in cancer patients.

The recent advances in the knowledge of the psychoneuroimmunological pathogenesis of human neoplasms have demonstrated the existence of feed-back mechanisms operating between interleukins and endocrine secretions, which play an important role in the regulation of the immune responses, including the anticancer immunity. In contrast, few studies only have been performed to investigate the possible relation between endocrine activities and hematopoietic growth factors. The present study was performed to analyze the acute endocrine effects of erythropoietin-alpha (EPO) on the main endocrine secretions. The study was carried out in 10 advanced solid tumor patients. EPO was injected subcutaneously at a dose of 10,000 U, and venous blood samples were collected before and 2, 4 and 6 h after EPO administration. No significant changes in mean serum levels of FSH, LH and TSH were seen in response to EPO. Cortisol and DHEAS concentrations increased after EPO injection, whereas those of PRL decreased, but none of these differences was statistically significant. Finally, mean serum levels of both growth hormone (GH) and somatomedin-C (IGF-1) significantly decreased after EPO administration. This preliminary study shows that EPO may inhibit GH secretion from the pituitary gland and IGF-1 production. Since GH would stimulate EPO release, the results of this study may suggest the existence of feedback mechanism operating between GH secretion and EPO production, with inhibitory effect of EPO on GH secretion, and stimulatory action of GH on EPO production. Therefore, this study would describe the first example of hemato-endocrine feedback mechanisms. Moreover, this study, by showing an inhibitory effect of EPO on IGF-1 secretion, would suggest a possible use of EPO in the medical oncology not only for the treatment of cancer related anemia, but also to counteract tumor growth by blocking IGF-1 production, which has been proven to be a growth factor for several tumor histotypes. Obviously, IGF-1 is not the only tumor growth factor, but it could play a fundamental role in the regulation of production and activity of several other tumor growth factors. In any case, this study describes the only acute endocrine effects of EPO. Therefore, further studies, by evaluating the endocrine effects of a chronic treatment with EPO, will be required to establish which may be its effect on IGF-1 endogenous production, and its consequence on survival time.