Mauro Signorelli

Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer - results from two randomised studies

INTRODUCTION Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled. METHODS Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. RESULTS In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01). CONCLUSION Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.

Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production

Yondelis (Trabectedin) is a novel antitumor agent of marine origin extracted from the tunicate Ecteinascidia turbinata. This original compound is active against several human tumors including sarcoma and ovarian and breast adenocarcinoma, as evidenced in phase II clinical trials in advanced multitreated patients. Yondelis is a DNA minor groove binder that blocks cell cycle and interferes with inducible gene transcription in a selective manner. In this study, we investigated the immunomodulatory properties of Yondelis on leukocytes. Human blood monocytes were highly susceptible in vitro to its cytotoxic effect and underwent apoptosis at pharmacologically relevant concentrations (5 nmol/L), whereas lymphocytes were up to 5-fold less sensitive. Macrophages differentiated in vitro with macrophage colony-stimulating factor and tumor-associated macrophages (TAM), isolated from patients with ovarian cancer, were also susceptible. At subcytotoxic concentrations, Yondelis inhibited the in vitro differentiation of monocytes to macrophages. In tumor-treated patients, drug infusion caused a selective decrease of monocyte counts and of ex vivo macrophage differentiation. The in vitro production of two proinflammatory mediators, CCL2 and IL-6, was markedly reduced by Yondelis in monocytes, macrophages, TAM, and freshly isolated ovarian tumor cells. The chemokine CCL2 is the major determinant of monocyte recruitment at tumor sites, whereas IL-6 is a growth factor for ovarian tumors. In view of the protumor activity of TAM and of the strong association between chronic inflammation and cancer progression, the inhibitory effect of Yondelis on macrophage viability, differentiation, and cytokine production is likely to contribute to the antitumor activity of this agent in inflammation-associated human tumors.

Role of the integrated FDG PET/CT in the surgical management of patients with high risk clinical early stage endometrial cancer: Detection of pelvic nodal metastases

BACKGROUND High risk clinical stage I endometrial cancer (grade 2 and deep myometrial invasion, grade 3 and serous and clear-cell carcinoma) had 10-35% of nodal involvement. Surgical staging is considered reasonable in this setting of women, although unnecessary in 70-90%. The purpose of this study was to determine prospectively the diagnostic accuracy of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography 18F-FDG PET/CT in the detection of nodal metastases in patients with high risk endometrial cancer. METHODS Eleven women with grade 2 and deep myometrial invasion and 26 with grade 3 endometrial cancer underwent 18F-FDG PET/CT, followed by total hysterectomy, bilateral salpingo-oophorectomy and systematic pelvic lymphadenectomy. Histopathological findings served as the reference standard. Diagnostic performance of 18F-FDG PET/CT in nodal disease detection was reported in terms of accuracy value both in a patient-based and a lesion site-based analysis. RESULTS Pelvic nodes metastases were found at histopathological analysis in 9 of the 37 patients (24.3%). Patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG PET/CT for detection of nodal disease were 77.8%, 100.0%, 100.0%, 93.1% and 94.4%, respectively. Nodal lesion site-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG PET/CT were 66.7%, 99.4%, 90.9%, 97.2% and 96.8%, respectively. CONCLUSION This study shows that 18F-FDG PET/CT is an accurate method for the presurgical evaluation of pelvic nodes metastases. The high negative predictive value may be useful in selecting patients who only may benefit from lymphadenectomy, minimizing operative and surgical complications.

Endometrial Cancer: Correlation of Apparent Diffusion Coefficient With Tumor Grade, Depth of Myometrial Invasion, and Presence of Lymph Node Metastases

OBJECTIVE The objective of our study was to investigate whether apparent diffusion coefficient (ADC) values of endometrial cancer differ from those of normal endometrium and myometrium and whether they vary according to histologic tumor grade, the depth of myometrial invasion, or lymph node status. SUBJECTS AND METHODS Seventy patients with histologically proved endometrial cancer and 36 control subjects with normal endometrium were enrolled in this prospective study. T2-weighted, dynamic T1-weighted, and diffusion-weighted images with b values of 0 and 1000 s/mm(2) were obtained of all patients. The ADC values of endometrial cancer, normal endometrium, and normal myometrium were recorded. Tumor grade, the depth of myometrial invasion, and lymph node status were assessed at postoperative histopathologic analysis. RESULTS The mean (± SD) ADC value (10(-3) mm(2)/s) of endometrial cancer (0.77 ± 0.12) was significantly lower than that of normal endometrium (1.31 ± 0.11, p < 0.0001) and normal myometrium (1.52 ± 0.21, p < 0.0001), with no overlap between the two former distributions. There was no significant difference between ADC values of endometrial cancer tissue in patients with tumor grade 1 (0.79 ± 0.08, n = 14), grade 2 (0.76 ± 0.14, n = 40), or grade 3 (0.75 ± 0.12, n = 16) (p = 0.67); in patients with deep (0.77 ± 0.13, n = 18) and those with superficial (0.76 ± 0.12, n = 52) myometrial invasion (p = 0.87); and in patients with (0.78 ± 0.10, n = 6) and those without (0.75 ± 0.14, n = 39) lymph node metastases (p = 0.64). CONCLUSION ADC values allow normal endometrium to be differentiated from endometrial carcinoma; however, they do not correlate with histologic tumor grade, the depth of myometrial invasion, or whether lymph node metastases are present.

18F-FDG PET/CT can predict nodal metastases but not recurrence in early stage uterine cervical cancer

OBJECTIVES To evaluate the role of the metabolic characteristics of cervical tumor uptake as predictors of a) lymph node (LN) metastases, b) recurrence, in the preoperative staging of early-stage cervical cancer. METHODS 89 patients with FIGO stage IB1 and IIA<4 cm cervical cancer were imaged with FDG-PET/CT before radical hysterectomy and pelvic lymphadenectomy. PET/CT images were analyzed and correlated to histological findings. Maximum and mean standardized uptake value (SUVmax, SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG) of cervical lesions were calculated by an iterative adaptive algorithm. These parameters were correlated to the presence of: a) LN metastases, b) relapse after primary treatment. RESULTS Out of the 89 patients who underwent preoperative PET/CT scan for staging purpose, 16 were negative at cervical level: they were all pN0 and without recurrence during follow-up (mean 34.1±14.5 months). In 69 patients MTV and TLG were significantly higher (p=0.0006 and p=0.03) in pN1 patients in comparison to pN0 patients, while SUV values did not show significant differences between the two groups. No significant correlations were found between SUVmax, SUVmean, MTV, TLG and the evidence of relapse (mean follow-up 29.2±15.5 months). CONCLUSIONS In early-stage cervical cancer MTV and TLG correlate with the presence of nodal metastases, but their clinical impact on patients management has to be clarified. The absence of pathological cervical uptake could be a good prognostic factor, while SUVmax, SUVmean, MTV, TLG of the cervical uptake have not been found predictors of recurrence.

Preoperative staging of cervical cancer: Is 18-FDG-PET/CT really effective in patients with early stage disease?

OBJECTIVE Nodal status is one of the most important findings in patients with early-stage cervical cancer that requires post-surgical adjuvant therapies and influences prognosis of patients. The purpose of this study was to determine the diagnostic accuracy of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG-PET/CT) in the detection of nodal metastases. METHODS From 2004 to 2010 women with Ib1-IIa <4cm cervical cancer underwent 18F-FDG-PET/CT followed by radical hysterectomy and pelvic lymphadenectomy in our institution. 18F-FDG-PET/CT images were analyzed and histopathological findings served as the reference standard. Diagnostic performance of 18F-FDG-PET/CT in nodal disease detection was reported in terms of accuracy value. A sub analysis of women with tumor diameter <2cm (group 1) or 2-4cm (group 2) was performed in order to verify the efficacy of 18F-FDG-PET/CT in each group. RESULTS One hundred fifty-nine women were enrolled. 65% had squamous histotype and 51% had grade 3 disease. Median number of nodes dissected was 29 (range 11-61). 28/159 women (18%) showed nodal metastases. Overall patient-based sensitivity, specificity, positive and negative predictive value of 18F-FDG-PET/CT for detection of nodal disease were 32.1%, 96.9%, 69.2%and 87.0% respectively. Among the 97 (61%) women included in group 1, 8 had nodal metastases (8.2%) and 2 was discovered through 18F-FDG-PET/CT (25%), while 20/62 women of the group 2 (32.3%) had nodal involvement, of which 7 (35%) was detected by 18F-FDG-PET/CT. CONCLUSIONS This study showed that 18F-FDG-PET/CT had low sensitivity and had a minimal clinical impact in the pretreatment planning of stage Ib1-IIa <4cm cervical cancer.

Tailoring systematic lymphadenectomy in high-risk clinical early stage endometrial cancer: The role of 18F-FDG PET/CT

OBJECTIVES To evaluate the role of FDG PET/CT in the preoperative N-staging of high-risk clinical stage I endometrial cancer. The correlation between the metabolic characteristics of endometrial tumor uptake as predictors of a) lymph-node (LN) metastases and b) recurrence, was also evaluated. METHODS Seventy-six high-risk (G2 with deep myometrial invasion, G3, serous/clear-cell carcinoma) clinical stage I endometrial cancer patients underwent preoperative PET/CT scan followed by total hysterectomy, bilateral salpingo-oophorectomy and lymphadenectomy. PET/CT images were analyzed and correlated to histological findings. Maximal and mean standardized uptake value (SUVmax, SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG, defined as the product between SUVmean and MTV) of endometrial lesions were calculated and correlated to: a) presence of LN metastases, b) recurrences. RESULTS PET/CT resulted positive at LNs in 12/76 patients: 11/12 truly positive, 1/12 falsely positive. Conversely PET/CT was negative in 64/76 patients: 61/64 truly negative and 3/64 falsely negative. On pt-based analysis, sensitivity, specificity, accuracy, positive and negative predictive value of PET/CT in detecting LN metastases were 78.6%, 98.4%, 94.7%, 91.7%, 95.3%, respectively. A significant association was found between the presence of LN metastases and SUVmax (p=0.038), MTV (p=0.007), TLG (p=0.003) of the primary tumor. No correlations were found between the metabolic parameters and relapse (median follow-up 25.4months). CONCLUSIONS In high-risk clinical stage I endometrial cancer FDG PET/CT demonstrated moderate sensitivity, high specificity and accuracy for the nodal status assessment. SUVmax, MTV and TLG of the primary tumor are significantly correlated to LN metastases, while none of these parameters is predictor of recurrence.

Integration of hybrid single-photon emission computed tomography/computed tomography in the preoperative assessment of sentinel node in patients with cervical and endometrial cancer: our experience and literature review.

Objective The purpose of this study was to assess whether there is an additional value of single-photon emission computed tomography/computed tomography (SPECT/CT) over lymphoscintigraphy (LSG) alone for sentinel node (SN) mapping in endometrial and cervical cancer. Methods Ten women with clinically cervical stage IA2 to stage IB1 and 25 women with stage I endometrial cancer underwent preoperative LSG for SN mapping. Technetium Tc 99m albumin nanocolloid was injected submucosally at 4 points of the cervix. Patients underwent SPECT/CT emission-transmission study at least 3 hours after standard planar images. Methylene blue was injected into the cervix just before surgery under general anesthesia. All patients underwent hysterectomy, bilateral salpingo-oophorectomy, and radical regional nodal dissection. Hot and/or blue nodes were labeled as SNs. Results Conventional planar imaging detection rate was 50%, whereas the detection rate of at least one SN with SPECT/CT was 91% (32/35); bilateral detection was achieved in 7 (39%) of 18 women in planar and in 17 (53%) of 32 women in SPECT/CT imaging, respectively. Bilateral detection was achieved in 57% of women (20/35). Sentinel nodes were located in external and internal iliac nodes (66%), obturator nodes (5%), internal iliac nodes (11%), common iliac nodes (9%), and presacral nodes (9%). Lymph node involvement was identified in 5 patients (14%). Sentinel node correctly predicted lymph node involvement in all node-positive patients. Sentinel node sensitivity and negative predictive value of SPECT/CT were 100%. Conclusions Single photon emission computed tomography/computed tomography seems to improve intraoperative identification of SNs and provides additional useful information about the anatomic location of SNs compared to planar LSG in cervical and endometrial cancer.

Preoperative 18F-FDG PET/CT in the management of advanced epithelial ovarian cancer

OBJECTIVE The introduction of 18-FDG-PET/CT during preoperative evaluation of patients with epithelial ovarian cancer (EOC) has led to an increase of the detection of extra-abdominal metastases. However, the clinical impact of this upstage remains unclear. METHODS Patients with suspected advanced EOC underwent 18-FDG-PET/CT within two weeks prior to debulking surgery. RESULTS Between 2006 and 2011 95 patients met the inclusion criteria. Based on the concordance or the discrepancy of clinical and PET/CT stage, patients were divided into 3 groups (A: clinical and PET III; B: clinical III and PET IV; C: clinical and PET IV). Twenty-five patients were upstaged from FIGO stage III to stage IV by PET/CT. The proportion of patients who achieved a residual tumor <1cm in group B and C was similar, whereas it was significantly lower compared to group A. Similarly, complete response to adjuvant chemotherapy was achieved more frequently in patients in group A. PFS was similar in the three groups (17, 17 and 12 months in group A, B and C), as well as OS (51, 41 and 35 months). CONCLUSIONS PET/CT is able to detect distant metastases in EOC patients. The presence of extra-abdominal disease probably indicates a more aggressive disease which also shows a lower response to standard chemotherapy. However, upstaged patients have a similar prognosis compared to stage III patients, probably because intra-abdominal disease is more likely to lead patients to death. This might also explain why residual tumor is the most important prognostic factor for advanced EOC patients.

Staging of High-Risk Endometrial Cancer With PET/CT and Sentinel Lymph Node Mapping

Purpose The aim of this study was to evaluate the role of PET/CT and sentinel lymph node (SLN) biopsy in staging high-risk endometrial cancer patients (G2 and deep myometrial invasion, G3, serous clear cell carcinoma or carcinosarcoma) in early clinical stage. Patients and Methods From January 2006 to December 2012, high-risk early-stage endometrial cancer patients performing PET/CT scan followed by surgery (systematic pelvic ± aortic lymphadenectomy) were included. From December 2010, SLN mapping with 99mTc-albumin nanocolloid and blue dye cervical injection was included in our clinical practice and additionally performed. Histological findings were used as the reference standard. Results Ninety-three patients were included, of which 22 of 93 had both PET/CT and SLN biopsy. The median number of dissected lymph nodes (LNs) was 28. Nineteen women (20.4%) had pelvic LN metastases; 14 were correctly identified by PET/CT. Among 5 false-negative cases, 3 occurred after the introduction of SLN mapping due to detection of micrometastases by ultrastaging. On overall patient-based analysis, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of PET/CT for pelvic LN metastases were 73.7%, 98.7%, 93.6%, 93.3%, 93.6%, respectively. Conclusions PET/CT demonstrated moderate sensitivity and high specificity in detecting pelvic LN metastases; its high positive predictive value (93.3%) is useful to refer patients to appropriate debulking surgery. Sentinel LN mapping and histological ultrastaging increased the identification of metastases (incidence, 18.3%-27.3%) not detectable by PET/CT because of its spatial resolution. The combination of both modalities is promising for nodal staging purpose.