Giovanni Paganelli

Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study

BACKGROUND In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favourable effect on quality of life. Results of our previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less. We aimed to update this trial with results from longer follow-up. METHODS Women with breast tumours of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group). Analysis was restricted to patients whose tumour characteristics met eligibility criteria after treatment. The main endpoints were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival. FINDINGS Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; eight of those with negative SLNs were found to have false-negative SLNs. Of the 259 patients in the SLN group, 92 (36%) had a positive SLN, and 167 (65%) had a negative SLN. One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative). After a median follow-up of 79 months (range 15-97), 34 events associated with breast cancer occurred: 18 in the ALND group, and 16 in the SLN group (log-rank p=0.6). The overall 5-year survival of all patients was 96.4% (95% CI 94.1-98.7) in the ALND group and 98.4% (96.9-100) in the SLN group (log-rank p=0.1). INTERPRETATION SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay. The finding that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas eight cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research.

Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study.

Objective:Sentinel node biopsy (SNB) is widely used to stage the axilla in breast cancer. We present 10-year follow-up of our single-institute trial designed to compare outcomes in patients who received no axillary dissection if the sentinel node was negative, with patients who received complete axillary dissection. Methods:From March 1998 to December 1999, 516 patients with primary breast cancer up to 2 cm in pathologic diameter were randomized either to SNB plus complete axillary dissection (AD arm) or to SNB with axillary dissection only if the sentinel node contained metastases (SN arm). Results:The 2 arms were well-balanced for number of sentinel nodes found, proportion of positive sentinel nodes, and all other tumor and patient characteristics. About 8 patients in the AD arm had false-negative SNs on histologic analysis: a similar number (8, 95% CI: 3–15) of patients with axillary involvement was expected in SN arm patients who did not receive axillary dissection; but only 2 cases of overt axillary metastasis occurred. There were 23 breast cancer-related events in the SN arm and 26 in the AD arm (log-rank, P = 0.52), while overall survival was greater in the SN arm (log-rank, P = 0.15). Conclusions:Preservation of healthy lymph nodes may have beneficial consequences. Axillary dissection should not be performed in breast cancer patients without first examining the sentinel node.

Predicting the Risk for Additional Axillary Metastases in Patients With Breast Carcinoma and Positive Sentinel Lymph Node Biopsy

Objective:To assess whether the risk for nonsentinel node metastases may be predicted, thus sparing a subgroup of patients with breast carcinoma and a positive sentinel lymph node (SLN) biopsy completion axillary lymph node dissection (ALND). Summary Background Data:The SLN is the only involved axillary lymph node in the majority of the patients undergoing ALND for a positive SLN biopsy. A model to predict the status of nonsentinel axillary lymph nodes could help tailor surgical therapy to those patients most likely to benefit from completion ALND. Methods:All the axillary sentinel and nonsentinel lymph nodes of 1228 patients were reviewed histologically and reclassified according to the current TNM classification of malignant tumors as bearing isolated tumor cells only, micrometastases, or (macro)metastases. The prevalence of metastases in nonsentinel lymph nodes was correlated to the type of SLN involvement and the size of the metastasis, the number of affected SLNs, and the prospectively collected clinicopathologic variables of the primary tumors. Results:In multivariate analysis, further axillary involvement was significantly associated with the type and size of SLN metastases, the number of affected SLNs, and the occurrence of peritumoral vascular invasion in the primary tumor. A predictive model based on the characteristics most strongly associated with nonsentinel node metastases was able to identify subgroups of patients at significantly different risk for further axillary involvement. Conclusions:Patients with the most favorable combination of predictive factors still have no less than 13% risk for nonsentinel lymph node metastases and should be offered completion ALND outside of clinical trials of SLN biopsy without back-up axillary clearing.

68Ga-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors.

Several authors reported the superiority of 68Ga-DOTANOC PET/CT to conventional imaging (CI) for the assessment of neuroendocrine tumors (NET). However, the detection of a higher number of lesions is not necessarily followed by a modification of disease stage or therapeutic approach. The aim of this study was to assess the impact of 68Ga-DOTANOC PET/CT on the clinical management of NET patients. Methods: The study included 90 patients with pathologic confirmation of NET, CT performed within a month of 68Ga-DOTANOC PET/CT, and a follow-up period of at least 1 y. PET/CT results were compared with CI results. As a standard of reference to finally evaluate PET results, clinical and imaging follow-up data were used. To assess the clinical impact of PET findings, all referring physicians were contacted after PET and asked about how patients were managed. Stage or therapy modifications were independently recorded, and the overall impact was evaluated patient by patient if PET results either affected therapy or caused a change in disease stage. Results: Considering PET/CT and CI concordant cases (47/90 [52.2%]), PET findings affected the therapeutic management in 17 of 47 (36.2%) patients. Although PET did not result in modification of disease stage, 68Ga-DOTANOC detected a higher lesion number in most patients. PET/CT and CI findings were discordant in 42 of 90 (46.7%) patients: PET resulted in a modification of stage in 12 patients (28.6%) and affected the treatment plan in 32 patients (76.2%). PET and CT were both equivocal in 1 patient (1/90). Considering all cases, 68Ga-DOTANOC PET/CT affected either stage or therapy in 50 of 90 (55.5%) patients. The most frequent impact on management (27 patients) was the initiation or continuance of peptide receptor radionuclide therapy, followed by the initiation or continuance of somatostatin analog medical treatment (7 patients) and referral to surgery (6 patients). PET prevented unnecessary surgery in 6 patients and excluded from treatment with somatostatin analogs 2 patients with NET lesions that did not express somatostatin receptors. Less frequent impacts on management included the initiation of radiotherapy (1 patient), further diagnostic investigation (1 patient), and liver transplantation (1 patient). Conclusion: 68Ga-DOTANOC PET/CT either affected stage or caused a therapy modification in more than half the patients, thus confirming the clinical role of PET in the management of NET.

Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours.

Somatostatin receptors are over-expressed in many tumours, mainly of neuroendocrine origin, thus enabling treatment with somatostatin analogues. Almost a decade of clinical experience of receptor radionuclide therapy with the analogue 90Y-[DOTA]0-Tyr3-octreotide [90Y-DOTATOC] has now been obtained at a few centres of excellence. This review reports on the present state of the art of receptor radionuclide therapy and discusses new perspectives.

Sentinel lymph node biopsy as an indicator for axillary dissection in early breast cancer

Sentinel node biopsy (SNB) is a new component of the surgical treatment of breast cancer that accurately predicts axillary status. Although the procedure is still mainly investigational, many patients are requesting SNB to avoid axillary dissection if the sentinel node (SN) is negative. From March 1996 to December 1999, 373 patients with breast carcinoma and clinically negative axillary nodes underwent breast surgery, mainly conservative, and SNB. If the SN was histologically uninvolved no further surgical treatment was given. All patients were informed in detail and signed a consent form. SNB involved injection of labelled albumin particles close to the primary tumour, lymphoscintigraphy and location of the sentinel node with a gamma probe during surgery. 379 SNBs were performed on 373 patients (6 were bilateral). In 94, the SN was positive and complete axillary dissection was performed. In 285 cases (280 patients) the SN was negative and no dissection was performed: these were carefully followed with quarterly clinical examination of the axilla. A total of 343 years at risk were available for evaluation from which seven cases of axillary metastases were expected. No cases of clinically evident axillary node metastasis have occurred. These findings provide further confirmation of the validity of SNB and prompt us to suggest that it should become the method of choice for axillary staging in small-sized breast cancer.

Sentinel node biopsy in early vulvar cancer

Lymph node pathologic status is the most important prognostic factor in vulvar cancer; however, complete inguinofemoral node dissection is associated with significant morbidity. Lymphoscintigraphy associated with gamma-probe guided surgery reliably detects sentinel nodes in melanoma and breast cancer patients. This study evaluates the feasibility of the surgical identification of sentinel groin nodes using lymphoscintigraphy and a gamma-detecting probe in patients with early vulvar cancer. Technetium-99m-labelled colloid human albumin was administered perilesionally in 37 patients with invasive epidermoid vulvar cancer (T1–T2) and lymphoscintigraphy performed the day before surgery. An intraoperative gamma-detecting probe was used to identify sentinel nodes during surgery. A complete inguinofemoral node dissection was then performed. Sentinel nodes were submitted separately to pathologic evaluation. A total of 55 groins were dissected in 37 patients. Localization of the SN was successful in all cases. Eight cases had positive nodes: in all the sentinel node was positive; the sentinel node was the only positive node in five cases. Twenty-nine patients showed negative sentinel nodes: all of them were negative for lymph node metastases. Lymphoscintigraphy and sentinel-node biopsy under gamma-detecting probe guidance proved to be an easy and reliable method for the detection of sentinel node in early vulvar cancer. This technique may represent a true advance in the direction of less aggressive treatments in patients with vulvar cancer.

Expression of the oncofetal ED-B containing fibronectin isoform in hematologic tumors enables ED-B targeted 131I-L19SIP radioimmunotherapy in Hodgkin lymphoma patients

Current treatment of hematologic malignancies involves rather unspecific chemotherapy, frequently resulting in severe adverse events. Thus, modern clinical research focuses on compounds able to discriminate malignant from normal tissues. Being expressed in newly formed blood vessels of solid cancers but not in normal mature tissues, the extradomain B of fibronectin (ED-B FN) is a promising target for selective cancer therapies. Using immunohistology with a new epitope retrieval technique for paraffin-embedded tissues, ED-B FN expression was found in biopsies from more than 200 Hodgkin and non-Hodgkin lymphoma patients of nearly all entities, and in patients with myeloproliferative diseases. ED-B FN expression was nearly absent in normal lymph nodes (n = 10) and bone marrow biopsies (n = 9). The extent of vascular ED-B FN expression in lymphoma tissues was positively correlated with grade of malignancy. ED-B FN expression was enhanced in lymph nodes with severe lymphadenopathy and in some hyperplastic tonsils. The in vivo accessibility of ED-B FN was confirmed in 3 lymphoma patients, in whom the lymphoma lesions were visualized on scintigraphy with (131)I-labeled L19 small immunoprotein ((131)I-L19SIP). In 2 relapsed Hodgkin lymphoma patients(131)I-L19SIP radioimmunotherapy induced a sustained partial response, qualifying ED-B FN as a promising target for antibody-based lymphoma therapies.

Biokinetics and dosimetry in patients administered with 111In-DOTA-Tyr3-octreotide: implications for internal radiotherapy with 90Y-DOTATOC

Abstract. Recent advances in receptor-mediated tumour imaging have resulted in the development of a new somatostatin analogue, DOTA-dPhe1-Tyr3-octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, ease of labelling and stability with yttrium-90 and favourable biodistribution in animal models. The aim of this work was to evaluate the biodistribution and dosimetry of DOTATOC radiolabelled with indium-111, in anticipation of therapy trials with 90Y-DOTATOC in patients. Eighteen patients were injected with DOTATOC (10 µg), labelled with 150–185 MBq of 111In. Blood and urine samples were collected throughout the duration of the study (0–2 days). Planar and single-photon emission tomography images were acquired at 0.5, 3–4, 24 and 48 h and time-activity curves were obtained for organs and tumours. A compartmental model was used to determine the kinetic parameters for each organ. Dose calculations were performed according to the MIRD formalism. Specific activities of >37 GBq/ µmol were routinely achieved. Patients showed no acute or delayed adverse reactions. The residence time for 111In-DOTATOC in blood was 0.9±0.4 h. The injected activity excreted in the urine in the first 24 h was 73%±11%. The agent localized primarily in spleen, kidneys and liver. The residence times in source organs were: 2.2±1.8 h in spleen, 1.7±1.2 h in kidneys, 2.4±1.9 h in liver, 1.5±0.3 h in urinary bladder and 9.4±5.5 h in the remainder of the body; the mean residence time in tumour was 0.47 h (range: 0.03–6.50 h). Based on our findings, the predicted absorbed doses for 90Y-DOTATOC would be 7.6±6.3 (spleen), 3.3±2.2 (kidneys), 0.7±0.6 (liver), 2.2±0.3 (bladder), 0.03±0.01 (red marrow) and 10.1 (range: 1.4–31.0) (tumour) mGy/MBq. These results indicate that high activities of 90Y-DOTATOC can be administered with low risk of myelotoxicity, although with potentially high radiation doses to the spleen and kidneys. Tumour doses were high enough in most cases to make it likely that the disired therapeutic response desired would be obtained.

Pretargeted adjuvant radioimmunotherapy with yttrium-90-biotin in malignant glioma patients: a pilot study.

In a previous study we applied a three-step avidin–biotin pretargeting approach to target 90Y-biotin to the tumour in patients with recurrent high grade glioma. The encouraging results obtained in this phase I–II study prompted us to apply the same approach in an adjuvant setting, to evaluate (i) time to relapse and (ii) overall survival. We enrolled 37 high grade glioma patients, 17 with grade III glioma and 20 with glioblastoma, in a controlled open non-randomized study. All patients received surgery and radiotherapy and were disease-free by neuroradiological examinations. Nineteen patients (treated) received adjuvant treatment with radioimmunotherapy. In the treated glioblastoma patients, median disease-free interval was 28 months (range=9–59); median survival was 33.5 months and one patient is still without evidence of disease. All 12 control glioblastoma patients died after a median survival from diagnosis of 8 months. In the treated grade III glioma patients median disease-free interval was 56 months (range=15–60) and survival cannot be calculated as only two, within this group, died. Three-step radioimmunotherapy promises to have an important role as adjuvant treatment in high grade gliomas, particularly in glioblastoma where it impedes progression, prolonging time to relapse and overall survival. A further randomized trial is justified.