Anna Nasierowska-Guttmejer

Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study

BACKGROUND To evaluate the clinical and radiological effectiveness of [DOTA(0), D-Phe(1), Tyr(3)]-octreotate (DOTATATE) Y-90 in patients with extensive progressive gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs). MATERIALS AND METHODS Sixty patients with histologically proven GEP-NETs were treated with DOTATATE Y-90. Clinical responses were assessed 6 weeks after completing therapy and then after each of the 3- to 6-month intervals. The radiological response was classified according to RECIST criteria. RESULTS At 6 months after final treatment, radiological partial response (PR; at least a 30% decrease in the sum of the longest diameter of target lesions) was observed in 13 patients (23%), and the remaining patients had stable disease (SD; less than 30% decrease in the sum of the longest diameter of target lesions or less than 20% increase in the sum of the longest diameter of target lesions) (77%). Clinical PR at 6 months was in 43 patients (72%), nine patients had SD and progressive disease (PD) was noted in eight patients. Median progression-free survival (PFS) was 17 months, while the median overall survival (OS) was 22 months. In eight patients with early PD, the PFS was 4.5 and OS 9.5 months, while in those with SD or PR, PFS and OS were 19.5 and 23.5 months, respectively. After 12 months of follow-up, five patients had World Health Organization (WHO) grade 2 or 3 renal toxicity. Haematological toxicity (WHO grade 3 and 4) was noted during therapy in 10% of patients and persisted in 5%. CONCLUSIONS DOTATATE Y-90 therapy is effective and relatively safe in patients with GEP-NET. Standard doses of DOTATATE Y-90 result in a relatively low risk of myelotoxicity. However, due to ongoing risk of renal toxicity, careful monitoring of the kidney is recommended.

Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour - the impact of tumour rupture on patient outcomes.

BACKGROUND Approval of imatinib for adjuvant treatment of gastrointestinal stromal tumours (GIST) raised discussion about accuracy of prognostic factors in GIST and the clinical significance of the available risk stratification criteria. METHODS We studied the influence of a new modification of the NIH Consensus Criteria (the Joensuu risk criteria), NCCN-AFIP criteria, and several clinicopathological factors, including tumour rupture, on relapse-free survival (RFS) in a prospectively collected tumour registry series consisting of 640 consecutive patients with primary, resectable, CD117-immunopositive GIST. The median follow-up time after tumour resection was 39 months. None of the patients received adjuvant imatinib. RESULTS The median RFS time after surgery was 50 months. In univariable analyses, high Joensuu risk group, tumour mitotic count >5/50 HPF, size >5 cm, non-gastric location, tumour rupture (7% of cases; P = 0.0014) and male gender had adverse influence on RFS. In a multivariable analysis mitotic count >5/50HPF, tumour size >5 cm and non-gastric location were independent adverse prognostic factors. Forty, 151, 86 and 348 patients were assigned according to the Joensuu criteria to very low, low, intermediate and high risk groups and had 5-year RFS of 94%, 94%, 86% and 29%, respectively. CONCLUSION The Joensuu criteria, which include 4 prognostic factors (tumour size, site, mitotic count and rupture) and 3 categories for the mitotic count, were found to be a reliable tool for assessing prognosis of operable GIST. The Joensuu criteria identified particularly well high risk patients, who are likely the proper candidates for adjuvant therapy.

Survival Analysis and Clinicopathological Factors Associated With False-Negative Sentinel Lymph Node Biopsy Findings in Patients with Cutaneous Melanoma

We analyzed the outcomes and factors associated with false-negative (FN) results of sentinel lymph node (SLN) biopsy findings in patients with cutaneous melanoma. SLN biopsy failure rate was defined as nodal recurrence in the biopsied regional basin without previous local or in-transit recurrence. Between April 1997 and December 2004, a total of 1207 patients with cutaneous melanoma with a median Breslow thickness of 2.4 mm underwent SLN biopsy by preoperative and intraoperative lymphoscintigraphy combined with dye injection. In 228 cases, we found positive SLNs; of these, 220 underwent completion lymph node dissection (CLND). Median follow-up was 3 years. The SLN biopsy failure rate was 5.8% (57 of 979 SLN negative). Median time to occurrence of FN relapse after SLN biopsy was 16 months (range, 3–74 months). The FN SLN biopsy results correlated with primary tumor thickness >4 mm (P = .0012), primary tumor ulceration (P = .0002), primary tumor level of invasion Clark stage IV/V (P = .0005), and nodular melanoma histological type (P = .0375). Five-year overall survival, calculated from the date of primary tumor excision, in the FN group was 53.7%, which was not statistically significantly worse than the CLND group (56.8%; P = .9). The FN group was characterized by a higher ratio of two or more metastatic nodes and extracapsular involvement of lymph nodes after LND compared with the CLND group (P < .0001 and P < .0001, respectively). Additional detailed pathological review of FN SLN revealed metastatic disease in 14 patients, which decreased the SLN biopsy failure rate to 4.4% (43 of 979). Survival of patients with FN results of SLN biopsy does not differ statistically significantly from that of patients undergoing CLND, although it is slightly lower. The SLN biopsy failure rate is approximately 5.0% in long-term follow-up and is associated mainly with the same factors that indicate a poor prognosis in primary melanoma.

The accuracy of the sentinel lymph node concept in early stage squamous cell vulvar carcinoma

OBJECTIVE The purpose of the study was to determine the feasibility and accuracy of the sentinel lymph node (SLN) identification in vulvar carcinoma patients. METHODS Sixty-two patients with clinical early stage vulvar cancer underwent SLN detection procedure, followed by a complete inguinofemoral lymphadenectomy. The SLN was identified intraoperatively using lymphoscintigraphy with technetium-99m as well as patent blue V staining. The resected lymph nodes (LN) were submitted for histological examination by hematoxylin-eosin staining (H-E) and cytokeratin immunohistochemistry (IHC) and examined by the reverse transcriptase-polymerase chain reaction (RT-PCR) assay. RESULTS A total of 109 inguinal LN were dissected in 56 patients. SLNs were identified in 76% groins with patent blue V and in 99% with the use of Tc-99m. The accuracy differed significantly (p<0.0001). An H-E examination combined with IHC revealed 7 false-negative SLNs. The sensitivity of this method was 73% (95% CI, 64% to 81%) and the negative predictive value for a negative SLN finding was 92% (95% CI, 87% to 97%). The RT-PCR assay showed 8 false-negative SLNs. The sensitivity of the RT-PCR-based assay was 83% (95% CI, 75% to 90%) and the negative predictive value for a negative SLN was 88% (95% CI, 82% to 94%). The two diagnostic methods were found not to differ significantly. CONCLUSIONS In SLN mapping, the Tc-99m colloid lymphoscintigraphy is superior to the blue dye staining. Our data do not support the concept of the SLN identification as a highly accurate procedure in predicting the inguinofemoral LN status in patients with early stage vulvar cancer.

Tumour regression grading in patients with residual rectal cancer after preoperative chemoradiation

BACKGROUND AND PURPOSE To explore the utility of tumour regression grading (TRG, the amount of residual tumour cells in relation to extension of fibrosis) after chemoradiation of rectal cancer. MATERIALS AND METHODS Of 131 patients who received preoperative chemoradiation in the frame of the randomized trial, pathological complete response (pCR, TRG0), good regression (TRG1), moderate regression (TRG2), and poor regression (TRG3) were recorded in 17%, 31%, 31%, and 22% of patients, respectively. RESULTS The rates of ypN-positive category for TRG0, TRG1, TRG2, and TRG3 groups were 5%, 23%, 45%, and 46%, respectively, p=0.001. When ypT-category and TRG were evaluated by the logistic regression analysis, only ypT-category remained significant for independent prediction of the risk for mesorectal nodal metastases, p=0.006. The 4-year (median follow-up) disease-free survival (DFS) for TRG0, TRG1, TRG2, and TRG3 groups were 91%, 67%, 54%, and 47%. When patients with persistent disease (TRG1 vs. TRG2 vs. TRG3) were analyzed separately, TRG had no prognostic value for DFS, p=0.402. CONCLUSIONS TRG in patients with residual cancer had no prognostic value for the incidence of nodal disease and for DFS. Our findings and literature data question the need for the inclusion of TRG assessment into a routine pathological report.

Lymph node status and survival in cutaneous malignant melanoma—sentinel lymph node biopsy impact

AIM The survival benefit of sentinel lymph node biopsy (SLB) with lymphadenectomy for microscopic melanoma metastases to regional lymph nodes (SLND) is uncertain. The aim of the study was to analyse the factors influencing clinical outcome (overall survival (OS) and disease free survival (DFS)) of patients undergone lymph node dissection (LND) as result of positive sentinel lymph node disease (SLND) or as consequence of clinically detected metastases (CLND). PATIENTS AND METHODS This was a single-institution retrospective analysis of survival data of 350 consecutive, prospectively collected, melanoma patients who underwent radical LND in 1995-2001. One hundred and forty-five patients underwent SLND and 205 underwent CLND. RESULTS The median OS and DFS times of the entire group of melanoma patients, computed from the date of primary lesion excision, were 46.3 months and 26.5 months (5-year OS ratio 41.8% and 5-year DFS ratio 31.5%). The factors which correlated with poor OS by multivariate analysis were: primary tumour Breslow thickness >4 mm (p=0.001), extracapsular extension of lymph node metastases (p=0.004), male sex (p=0.001) and metastases to more than one regional lymph node (p=0.04). The negative factors for DFS were: nodal extracapsular invasion (p=0.00002) and primary tumour Breslow thickness >4 mm (p=0.004). There were no significant differences in OS and DFS between SLND and CLND groups, when calculated from the date of primary tumour excision. However, if OS and DFS were estimated from the date of LND, the SLND group demonstrated significantly better survival in comparison with CLND. CONCLUSION The study demonstrates no survival benefit from SLB with subsequent radical regional LND in malignant melanoma patients with lymph node metastases.

Neoadjuvant treatment for unresectable rectal cancer: an interim analysis of a multicentre randomized study.

PURPOSE To present an interim analysis of the trial comparing two neoadjuvant therapies for unresectable rectal cancer. METHODS Patients with fixed cT3 or cT4 or locally recurrent rectal cancer without distant metastases were randomized to either 5 × 5 Gy and 3 courses of FOLFOX4 (schedule I) or 50.4 Gy delivered in 28 fractions given simultaneously with 5-Fu, leucovorin and oxaliplatin (schedule II). Surgery in both groups was performed 12 weeks after the beginning of radiation and 6 weeks after neoadjuvant treatment. RESULTS 49 patients were treated according to schedule I and 48 according to schedule II. Grade III+ acute toxicity was observed in 26% of patients in group I and in 25% in group II. There were two toxic deaths, both in group II. The microscopically radical resection (primary endpoint) rate was 73% in group I and 71% in group II. Overall and severe postoperative complications were recorded in 27% and 9% of patients vs. 16% and 7%, respectively. Pathological complete response was observed in 21% of the patients in group I and in 9% in group II. CONCLUSIONS The interim analysis revealed no major differences in acute toxicity and local efficacy between the two evaluated strategies.

Initial Direct Comparison of 99mTc-TOC and 99mTc-TATE in Identifying Sites of Disease in Patients with Proven GEP NETs

The imaging of neuroendocrine tumors has become one of the most significant areas in nuclear oncology. In an attempt to provide high-quality imaging and possible sensitivity at a reduced cost, time, and radiation dose, several 99mTc agents have been proposed. The aim of this initial study was to compare the tumor uptake and biodistribution of 2 new 6-hydrazinopyridine-3-carboxylic acid (HYNIC)–derivatized Tyr3-octreotide analogs, 99mTc-[HYNIC,Tyr3]octreotide (99mTc-TOC) and 99mTc-[HYNIC,Tyr3,Thr8]octreotide (99mTc-TATE), in patients with somatostatin receptor–expressing tumors. Methods: Each of 12 patients with proven gastrointestinal pancreatic neuroendocrine tumors received a mean activity of 520 MBq of 99mTc-TOC and 99mTc-TATE. Scintigraphy with both tracers was performed 3–4 h after their injection using standard whole-body and SPECT imaging. The images were reviewed subjectively by 2 readers, who reported tumor uptake lesion by lesion. Results: Both radiotracers demonstrated concordance between the results in 7 patients (58%). In total, 110 sites of disease were identified with 99mTc-TOC, compared with 115 with 99mTc-TATE. There was 1 case in which 99mTc-TOC identified sites of disease not seen on 99mTc-TATE imaging but 4 cases in which some sites of disease were seen with 99mTc-TATE and not 99mTc-TOC. Conclusion: In this initial study, both tracers seem to show similar sites of tumor, with 99mTc-TATE having a slight edge in the total number of lesions seen, especially in lymph node metastases.

Neuroendocrine neoplasms of the small intestine and the appendix — management guidelines (recommended by the Polish Network of Neuroendocrine Tumours)

We present revised Polish guidelines regarding the management of patients harbouring neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common origin of these neoplasms. Most of them are well differentiated with slow growth. Rarely, they are less differentiated, growing fast with a poor prognosis. Since symptoms can be atypical, the diagnosis is often accidental. Typical symptoms of carcinoid syndrome occur in less than 10% of patients. The most useful laboratory marker is chromogranin A; 5-hydroxyindoleacetic acid is helpful in the monitoring of carcinoid syndrome. Ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, balloon enteroscopy and somatostatin receptors scintigraphy are used in the visualisation. A histological report is crucial for the proper diagnostics and therapy of NENs, and it has been extensively described. The treatment of choice is surgery, either radical or palliative. Somatostatin analogues are crucial in the pharmacological treatment of the hormonally active and non-active small intestine NENs and NENs of the appendix. Radioisotope therapy is possible in patients with a good expression of somatostatin receptors. Chemotherapy is not effective in general. Everolimus therapy can be applied in patients with generalised NENs of the small intestine in progression and where there has been a failure or an inability to use other treatment options. Finally, we make recommendations regarding the monitoring of patients with NENs of the small intestine and appendix.

Diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours)

An increased interest in gastro-entero-pancreatic neuroendocrine neoplasms (GEP NENs) has recently been observed. These are rare neoplasms and their detection in recent years has improved. Over 50% of GEP NENs are carcinoids, and they are usually found incidentally during surgery in the small intestine and appendix and at diagnosis in distant metastases, mainly to the liver. There is a need for co-operation between specialists in various disciplines of medicine in order to work out the diagnostic and therapeutic guidelines. In this publication, we present general recommendations of the Polish Network of Neuroendocrine Tumours for the management of patients with GEP NENs, developed at the Consensus Conference which took place in Kamień Śląski in April 2013. Members of the guidelines working groups were assigned sections of the 2008 guidance to update. In the subsequent parts of this publication, we present the rules of diagnostic and therapeutic management of: - neuroendocrine neoplasms of the stomach and duodenum (including gastrinoma); - pancreatic neuroendocrine neoplasms; - neuroendocrine neoplasms of the small intestine and the appendix; - colorectal neuroendocrine neoplasms. The proposed recommendations by Polish and foreign experts representing different fields of medicine (endocrinology, gastroenterology, surgery, oncology, nuclear medicine and pathology) will be helpful in the diagnosis and treatment of GEP NENs patients.