Bin B. R. Kroon

Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas: The cumulative multicenter European experience

OBJECTIVE The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible. SUMMARY BACKGROUND DATA To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation. METHODS In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP. RESULTS A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths. CONCLUSIONS In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.

Lymphatic Drainage Patterns From the Breast

Objectives:The aim of this study was to describe the lymphatic drainage patterns from the 5 “quadrants” of the breast. Summary Background Data:Lymphatic mapping has provided techniques to visualize and harvest sentinel nodes in various locations and has generated renewed interest in nodes outside the axilla. Methods:Between January 1997 and June 2002, 700 sentinel node procedures were performed in patients with cN0 breast cancer. Preoperative lymphoscintigraphy was performed after injection of 99mTc-nanocolloid into the tumor in a volume of 0.2 mL and a mean dose of 107.7 MBq (2.8 mCi). Intraoperatively, the sentinel node was pursued with the aid of a gamma-ray detection probe and patent blue dye (1.0 mL, into the lesion). The patients were divided into 5 groups according to the location of the primary breast cancer. In each group, a distinction was made between palpable and nonpalpable lesions of the breast. Results:Drainage to either an axillary or an extra-axillary basin was observed in 678 patients. Both palpable and nonpalpable lesions may drain toward the internal mammary chain, although the latter more frequently, regardless of the quadrant. Drainage was also observed to supraclavicular, infraclavicular, interpectoral, and intramammary sentinel nodes. Conclusion:In each quadrant, a breast cancer may drain to sentinel nodes in various locations. There is a distinct difference in drainage patterns between palpable and nonpalpable lesions. These findings may improve the assessment of lymphatic dissemination in invasive breast cancer.

Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: Results of a multicenter randomized phase III trial

PURPOSE Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival. PATIENTS AND METHODS A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm. RESULTS Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP. CONCLUSION Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.

Anatomy and physiology of lymphatic drainage of the breast from the perspective of sentinel node biopsy

Knowledge of the anatomy and physiology of the lymphatic system is helpful when considering a particular sentinel node biopsy technique. The delicate balance between internal and external pressures in a lymphatic channel can be influenced by the injection volume and by massage in a negative or positive way. The narrow openings in the interendothelial junctions determine the speed of clearance of particles with a certain size, and this has implications for the timing of lymphoscintigraphy and surgery. Tracer uptake and lymph flow are highly variable and depend on a number of factors, some of which are beyond our control. The lymphatic anatomy is not completely understood despite numerous studies since the end of the 18th century. Several topics have been elucidated in more recent studies and through experience with sentinel node biopsy. First, although axillary drainage is the principal lymphatic path of the breast, any drainage pattern from any quadrant of the breast can occur. Second, most lymph from the breast flows to the nodal basins with a direct course, not passing through the subareolar plexus. Another relevant point is that gentle massage encourages lymph flow and facilitates sentinel node detection. What problems do we still face in clinical practice? The optimum size and number of labeled colloid particles remain to be established. The optimum volume of the tracer also remains to be determined. But the main controversy concerns the injection site. Although the intradermal injection technique has attractive practical features, there is currently insufficient certainty that drainage of tracer injected anywhere in or underneath the skin of the breast reflects drainage from the cancer. Connections between collecting lymphatic vessels from the tumor site and the collecting vessels from the skin and subdermal lymphatics can explain the concordance between intraparenchymal and superficial injections in most patients. To determine the technique that yields the best sentinel node identification rate with the lowest possible false-negative rate would require a large randomized trial with all patients undergoing a complete lymph node dissection and evaluation of all other axillary lymph nodes with serial sections and immunohistochemistry. Current knowledge about sensitivity is based on examination of the other axillary nodes with hematoxylin and eosin staining and not with immunohistochemistry, with the exception of two studies. (33,76) In addition, a complete level I to III dissection may not have been done in all patients, and it is not certain that pathologists removed and examined all the nodes from the specimens. The proposed study seems impossible now that routine axillary node dissection has been abandoned by the larger centers around the world. Choosing the most attractive approach requires determining the aim of lymphatic mapping. A superficial injection technique may be adequate when the purpose is to spare patients without lymph node metastases in the axilla an unnecessary axillary node dissection. An intraparenchymal injection technique should be used when the additional purpose is to determine the stage as accurately as possible and to identify sentinel nodes elsewhere.

The definition of a sentinel node.

Lymphatic mapping with sentinel node biopsy is one of the most interesting recent developments in surgical oncology. This approach allows patients with lymph node metastasis to be treated in an early phase without submitting other patients to unnecessary regional lymph node dissection. The urologist Ramon Cabañas 1 was one of the first persons to use the name “sentinel lymph node.” In 1977, he suggested that squamous cell carcinoma of the penis initially drains to a particular lymph node in the groin that is defined by its constant anatomic position. For penile cancer this assumption appears plausible, because penile cancer is always located in the exact same part of the body, quite unlike the situation in breast cancer and in melanoma. In the late 1980s, Donald L. Morton, surgeon at the John Wayne Cancer Center in Santa Monica, and his pathologist Alistair J. Cochran (from UCLA) proposed the innovative concept of “lymphatic mapping with sentinel lymph node biopsy” for melanoma. 2 They suggested that the node to receive direct drainage from a melanoma could be any one node in a particular lymph node field, depending on the location of the primary lesion and with certain individual variability. By suggesting that other lymph nodes would become involved in a later phase, they revived William S. Halsted’s (1852– 1922) concept of sequential lymphatic dissemination. 3

Frozen section investigation of the sentinel node in malignant melanoma and breast cancer.

Background: Intraoperative frozen section investigation allows immediate regional lymph node dissection when the sentinel node contains tumor. The purpose of this study was to determine the sensitivity of frozen section diagnosis of the sentinel node in melanoma and breast cancer patients.Methods: A total of 177 sentinel nodes from 99 melanoma patients and 444 lymph nodes from 262 breast cancer patients were assessed by frozen section investigation. Nodes were bisected, and a complete cross-section was obtained for frozen section. Step sections at three levels were made of the remaining lymphatic tissue and were stained with hematoxylin and eosin and S100/HMB45 (melanoma) or CAM5.2 (breast cancer) to obtain a final pathological diagnosis.Results: Frozen section investigation revealed metastases in 8 of 17 node-positive melanoma patients (47%). Seventy-one of 96 breast cancer patients (74%) with lymph node metastases were identified with frozen section. The specificity was 100% and 99%, respectively.Conclusion: The sensitivity of intraoperative frozen section investigation of sentinel nodes was 47% in melanoma patients and 74% in breast cancer patients. Frozen section examination allows immediate axillary lymph node dissection in the majority of node-positive breast cancer patients. Frozen section analysis is not recommended in patients with melanoma.

Ultrasonography and Fine-Needle Aspiration Cytology Can Spare Breast Cancer Patients Unnecessary Sentinel Lymph Node Biopsy

BackgroundSome 30% to 40% of the breast cancer patients scheduled for sentinel node biopsy have axillary metastasis. Pilot studies suggest that ultrasonography is useful in the preoperative detection of such nodes. The aims of this study were to evaluate the sensitivity of preoperative ultrasonography and fine-needle aspiration cytology for detecting axillary metastases and to assess how often sentinel node biopsy could be avoided.MethodsBetween October 1999 and December 2003, 726 patients with clinically negative lymph nodes were eligible for sentinel node biopsy. A total of 732 axillae were examined. Preoperative ultrasonography with subsequent fine-needle aspiration cytology in case of suspicious lymph nodes was performed in all patients. The sentinel node procedure was omitted in patients with tumor-positive axillary lymph nodes in lieu of axillary lymph node dissection.ResultsUltrasound and fine-needle aspiration cytology established axillary metastases in 58 (8%) of the 726 patients. These 58 were 21% of the total of 271 patients who were proven to have axillary metastasis in the end. Of the patients with ultrasonographically suspicious lymph nodes and negative cytology, 31% had tumor-positive sentinel nodes. Patients with preoperatively established metastases by ultrasonography and fine-needle aspiration cytology had more tumor-positive lymph nodes (P < .001) than patients with metastases established later on.ConclusionsThe sensitivity of ultrasonography and fine-needle aspiration cytology is 21%, and unnecessary sentinel node biopsy is avoided in 8% of the patients. This approach improves the selection of patients eligible for sentinel node biopsy.

Localizing the sentinel node in cutaneous melanoma: gamma probe detection versus blue dye

AbstractBackground: Sentinel node (SN) biopsy can be used to select patients with melanoma for therapeutic lymphadenectomy. We investigated the value of two methods to locate the SN: patent blue dye (PBD) and gamma probe detection of99mTc-nanocolloid. Methods: One hundred ten patients with cutaneous melanoma were studied. Lymphoscintigraphy with99mTc-nanocolloid was performed to determine the position of the SN. Before operation, PBD was injected at the same site as the radiopharmaceutical. When a blue node was identified intraoperatively, its radioactivity level was measured with the probe. In the absence of blue coloration, the probe was used to trace the SN. Results: Scintigrams visualized a total of 219 SNs in 141 basins. Eight SNs were not explored. One SN was not found. The remaining 210 and 27 additional intraoperatively identified SNs were excised. From the total of 237 removed SNs, 200 (84%) were found using PBD only. All 37 nodes that were not found with the PBD were localized with the probe so that the probe combined with PBD identified 99.5% of all SNs. In 23 patients the SN contained tumor. In three patients the SN was false-negative for metastasis. Conclusion: The gamma probe together with PBD can identify more SNs (99.5%) than lymphatic mapping with PBD alone (84%).

Lymphatic mapping and sentinel lymph node biopsy in breast cancer

Abstract. Lymphatic mapping with selective lymphadenectomy is an attractive approach in breast-cancer patients. It uses existing technology to exploit logical anatomic and physiological principles to identify occult regional lymph-node metastases. The lymphatic flow is visualized and the first (sentinel) lymph node on a direct drainage pathway from the primary tumour is identified. This is the node at greatest risk of harbouring metastatic deposits. Retrieving this node requires a concerted effort from the nuclear medicine physician, surgeon and pathologist. Lymphoscintigraphy can indicate the number of sentinel nodes and their location. The surgeon can use two techniques to find the node. A vital dye injected at the tumour site will stain the lymphatic duct as well as the sentinel node and allow their visual identification. Alternatively, a lymph-node-seeking radiopharmaceutical will also migrate from the tumour site to the sentinel node and will enable its retrieval with the use of a gamma detection probe. The pathologist has a number of techniques to identify tumour deposits in the lymph node. A review of the literature shows that the sentinel node can be found in more than 90% of the patients. With experience, the false-negative rate can be kept down to about 5%. This novel approach of lymphatic mapping with selective lymphadenectomy may lead to a substantial reduction in the need for axillary node dissection in patients with breast cancer without compromising survival and regional control, and without loss of prognostic and staging information. This development will translate into a great reduction in patient morbidity and medical expenses.

Axillary recurrence after a tumour-negative sentinel node biopsy in breast cancer patients: A systematic review and meta-analysis of the literature

BACKGROUND Sentinel node biopsy became the standard of care before consensus on the technique was reached and without randomized studies having shown a similar or decreased axillary recurrence rate. The purpose of this study was to evaluate studies reporting on patients with a negative sentinel node biopsy. METHODS We performed a systematic review and meta-analysis of the literature for studies concerning clinically node-negative breast cancer patients with a tumour-negative sentinel node biopsy and no subsequent axillary node dissection. The axillary recurrence rate was determined, as well as the sensitivity of the sentinel node procedure and the differences in lymphatic mapping techniques. RESULTS Forty-eight studies concerning 14 959 sentinel node-negative breast cancer patients followed for a median of 34 months were selected. Sixty-seven patients developed an axillary recurrence, resulting in a recurrence rate of 0.3%. The sensitivity of the sentinel node biopsy was 100%. Uni- and multivariable variable analyses showed that the lowest recurrence rates were reported in studies performed in cancer centres, in studies that described the use of (99m)Tc-sulphur colloid, and also when investigators used the superficial injection technique or evaluated the harvested sentinel nodes with haematoxylin-eosin and immunohistochemistry staining (p<0.01). CONCLUSIONS In this systematic literature review, the axillary recurrence rate in sentinel node-negative patients is 0.3%, which is well within the desired range. The median sensitivity of the procedure appears to be as high as 100%. The recurrence rate is influenced by the differences in the lymphatic mapping technique.