Final trial report of sentinel-node biopsy versus nodal observation in melanoma.

BACKGROUND: Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial. METHODS: We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (± SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3 ± 1.8% vs. 64.7 ± 2.3%; hazard ratio for recurrence or metastasis, 0.76; P=0.01), and those with thick melanomas, defined as >3.50 mm (50.7 ± 4.0% vs. 40.5 ± 4.7%; hazard ratio, 0.70; P=0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1 ± 4.8% among those with metastasis versus 85.1 ± 1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P<0.001); among patients with thick melanomas, the respective rates were 48.0 ± 7.0% and 64.6 ± 4.9% (hazard ratio, 1.75; P=0.03). Biopsy-based management improved the 10-year rate of distant disease-free survival (hazard ratio for distant metastasis, 0.62; P=0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P=0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted. CONCLUSIONS: Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.).

Metastasectomy for distant metastatic melanoma: analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).

BACKGROUND: For stage IV melanoma, systemic medical therapy (SMT) is used most frequently; surgery is considered an adjunct in selected patients. We retrospectively compared survival after surgery with or without SMT versus SMT alone for melanoma patients developing distant metastases while enrolled in the first Multicenter Selective Lymphadenectomy Trial. METHODS: Patients were randomized to wide excision and sentinel node biopsy, or wide excision and nodal observation. We evaluated recurrence site, therapy (selected by treating clinician), and survival after stage IV diagnosis. RESULTS: Of 291 patients with complete data for stage IV recurrence, 161 (55 %) underwent surgery with or without SMT. Median survival was 15.8 versus 6.9 months, and 4-year survival was 20.8 versus 7.0 % for patients receiving surgery with or without SMT versus SMT alone (p < 0.0001; hazard ratio 0.406). Surgery with or without SMT conferred a survival advantage for patients with M1a (median > 60 months vs. 12.4 months; 4-year survival 69.3 % vs. 0; p = 0.0106), M1b (median 17.9 vs. 9.1 months; 4-year survival 24.1 vs. 14.3 %; p = 0.1143), and M1c (median 15.0 vs. 6.3 months; 4-year survival 10.5 vs. 4.6 %; p = 0.0001) disease. Patients with multiple metastases treated surgically had a survival advantage, and number of operations did not reduce survival in the 67 patients (42 %) who had multiple surgeries for distant melanoma. CONCLUSIONS: Our findings suggest that over half of stage IV patients are candidates for resection and exhibit improved survival over patients receiving SMT alone, regardless of site and number of metastases. We have begun a multicenter randomized phase III trial comparing surgery versus SMT as initial treatment for resectable distant melanoma.

The impact on morbidity and length of stay of early versus delayed complete lymphadenectomy in melanoma: results of the Multicenter Selective Lymphadenectomy Trial (I).

BACKGROUND: Complete lymph node dissection, the current standard treatment for nodal metastasis in melanoma, carries the risk of significant morbidity. Clinically apparent nodal tumor is likely to impact both preoperative lymphatic function and extent of soft tissue dissection required to clear the basin. We hypothesized that early dissection would be associated with less morbidity than delayed dissection at the time of clinical recurrence. MATERIALS AND METHODS: The Multicenter Selective Lymphadenectomy Trial I randomized patients to wide excision of a primary melanoma with or without sentinel lymph node biopsy. Immediate completion lymph node dissection (early CLND) was performed when indicated in the SLN arm, while therapeutic dissection (delayed CLND) was performed at the time of clinical recurrence in the wide excision-alone arm. Acute and chronic morbidities were prospectively monitored. RESULTS: Early CLND was performed in 225 patients, and in the wide excision-alone arm 132 have undergone delayed CLND. The 2 groups were similar for primary tumor features, body mass index, basin location, and demographics except age, which were higher for delayed CLND. The number of nodes evaluated and the number of positive nodes was greater for delayed CLND. There was no significant difference in acute morbidity, but lymphedema was significantly higher in the delayed CLND group (20.4% vs. 12.4%, P = .04). Length of inpatient hospitalization was also longer for delayed CLND. CONCLUSION: Immediate nodal treatment provides critical prognostic information and a likely therapeutic effect for those patients with nodal involvement. These data show that early CLND is also less likely to result in lymphedema.

Refinements of surgical technique in soft tissue sarcomas.

The primary modality of treatment for a localized soft tissue sarcoma is surgical resection. Adjuvant or neoadjuvant radiation helps reduce the rate of local recurrence. The rate of limb preserving resection is 94% in our series. Local recurrence can be re-excised in 95% of the patients, with limb preservation in 90%. Retroperitoneal sarcomas present difficulties in resection but with optimal techniques the complete resectability rate approaches 95% with 5- and 10-year survivals rates of 65% and 56%.

Cutdowns for totally implantable access ports to central veins.

For insertion of totally implantable access ports, with the catheter end in the superior vena cava, the percutaneous (Seldinger) technique is commonly used. Of cutdowns, the cephalic vein cutdown is the most popular one (success rate about 80%), followed by the external jugular vein cutdown. Our preliminary experience suggests that internal jugular vein and basilic vein cutdowns have the anatomic features to prove both of them superior to the cephalic vein cutdown.

Large gaps of midline abdominal incisions and their management.

The operative management of midline full-thickness abdominal wall gaps is difficult, often requires several surgical procedures and is associated with significant short- and long-term complications. A rectus abdominis-posterior sheath (RAPS) flap with skin grafting provides a tension-free one-step repair which was used in three patients successfully with midline abdominal wall (including the skin) gaps who had multiple previous operations related to intra-abdominal malignancy. No complications occurred in these patients in relation to this procedure.

Desmoplastic small round cell tumor of the pleura.

Desmoplastic small round cell tumor (DSRCT) is a rare neoplasm with aggressive behavior. Usually it presents as a peritoneal mass, although other cases in various locations have been described. Since less than 10 cases of primary DSRCT in the pleura have been described, it is of interest to report a pediatric case arising from the pleura. The diagnosis was confirmed by molecular detection of the EWS/WT-1 fusion gene product. Multidisciplinary treatment with chemotherapy, radiotherapy, and surgical resection resulted in a progression-free survival time above the median survival, suggesting that this conventional approach could prove effective for this rare and very aggressive malignancy.

Modified anterior compartment resection of the thigh.

For large soft tissue sarcomas of the anterior thigh, an anterior compartment resection is often performed. This may leave the patient with the inability to extend the knee. In our practice, we find that it is usually possible to preserve one of the heads of the quadriceps, usually the vastus medialis, with intact innervation, and thus preserve significant extension function of the knee joint, while the requirements for a radical oncologic procedure are being met. The modified anterior compartment resection preserves one or more heads of the quadriceps and requires a thorough knowledge of the course and distribution of the branches of the femoral nerve from the level of the inguinal ligament to their termination at the individual heads of the quadriceps femoris.

Sentinel-node biopsy or nodal observation in melanoma.

BACKGROUND: We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma. METHODS: Patients with a primary cutaneous melanoma were randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy. RESULTS: Among 1269 patients with an intermediate-thickness primary melanoma, the mean (+/-SE) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6% in the biopsy group and 73.1+/-2.1% in the observation group (hazard ratio for recurrence[corrected], 0.74; 95% confidence interval [CI], 0.59 to 0.93; P=0.009). Five-year melanoma-specific survival rates were similar in the two groups (87.1+/-1.3% and 86.6+/-1.6%, respectively). In the biopsy group, the presence of metastases in the sentinel node was the most important prognostic factor; the 5-year survival rate was 72.3+/-4.6% among patients with tumor-positive sentinel nodes and 90.2+/-1.3% among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95% CI, 1.54 to 3.98; P<0.001). The incidence of sentinel-node micrometastases was 16.0% (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6% (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group (P<0.001), indicating disease progression during observation. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3+/-4.6% vs. 52.4+/-5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P=0.004). CONCLUSIONS: The staging of intermediate-thickness (1.2 to 3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy. (ClinicalTrials.gov number, NCT00275496 [ClinicalTrials.gov].).

Surgical procedures and lymphedema of the upper and lower extremity.

BACKGROUND: Lymphedema occurs in the upper and lower extremity, in a minority of patients, following axillary and groin dissections, respectively. Several technical operative factors have been implicated through the years whose relative significance remains unknown. METHODS: Retrospective review of the author's personal experience with axillary and groin dissections and review of the articles and results written on the author's series of patients. The results, specifically lymphedema, are reported in relation to components of each surgical procedure and the presence or absence of additional surgical procedures, e.g., wide excision of the primary site when performed in the distal leg. RESULTS: In the axilla, skeletonization of the axillary vein, dissection up to and including Level III nodes, removal of the fat and nodes above the level of the axillary vein (exposing the brachial plexus), removal of pectoralis minor and all the axillary fat, exposing thus serratus anterior, latissimus dorsi and subscapularis are all technical components which do not cause lymphedema. It seems excessively thin flaps in axillary dissections may be the most likely cause for upper extremity lymphedema. The incidence of upper extremity lymphedema, in our experience, after axillary dissection is low (2%). For the lower extremity, skeletonization of the femoral and iliac vessels, in continuity dissection of the femoral and deep nodes (iliac and obturator), do not cause in themselves lymphedema (which occurs in 30% of the patients). The incidence of lymphedema increases with making thin flaps, with wide resection of a primary melanoma below the knee, postoperative incidence of cellulites, failure to follow a prophylactic regimen of leg elevation and compression stockings, and obesity. CONCLUSIONS: Lymphedema in the upper and lower extremity may be caused by making thin flaps during node dissection, the additional wide excision of primary sites in the distal half of the extremity, postoperative cellulitis, and failure to follow an antilymphedema regimen.

Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial.

OBJECTIVE: The objective of this study was to evaluate, in an international multicenter phase III trial, the accuracy, use, and morbidity of intraoperative lymphatic mapping and sentinel node biopsy (LM/SNB) for staging the regional nodal basin of patients with early-stage melanoma. SUMMARY BACKGROUND DATA: Since our introduction of LM/SNB in 1990, this technique has been widely adopted and has become part of the American Joint Committee on Cancer (AJCC) staging system. Eleven years ago, the authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT-I) to compare 2 treatment approaches: wide excision (WE) plus LM/SNB with immediate complete lymphadenectomy (CLND) for sentinel node (SN) metastases, and WE plus postoperative observation with CLND delayed until the subsequent development of clinically evident nodal metastases. METHODS: After each center achieved 85% accuracy of SN identification during a 30-case learning phase, patients with primary cutaneous melanoma (> or =1 mm with Clark level > or =III, or any thickness with Clark level > or =IV) were randomly assigned in a 4:6 ratio to WE plus observation (WEO) with delayed CLND for nodal recurrence, or to WE plus LM/SNB with immediate CLND for SN metastasis. The accuracy of LM/SNB was determined by comparing the rates of SN identification and the incidence of SN metastases in the LM/SNB group versus the subsequent development of nodal metastases in the regional nodal basin of those patients with tumor-negative SNs. Early morbidity of LM/SNB was evaluated by comparing complication rates between the 2 treatment groups. Trial accrual was completed on March 31, 2002, after enrollment of 2001 patients. RESULTS: Initial SN identification rate was 95.3% overall: 99.3% for the groin, 95.3% for the axilla, and 84.5% for the neck basins. The rate of false-negative LM/SNB during the trial phase, as measured by nodal recurrence in a tumor-negative dissected SN basin, decreased with increasing case volume at each center: 10.3% for the first 25 cases versus 5.2% after 25 cases. There were no operative mortalities. The low (10.1%) complication rate after LM/SNB increased to 37.2% with the addition of CLND; CLND also increased the severity of complications. CONCLUSIONS: LM/SNB is a safe, low-morbidity procedure for staging the regional nodal basin in early melanoma. Even after a 30-case learning phase and 25 additional LM/SNB cases, the accuracy of LM/SNB continues to increase with a center's experience. LM/SNB should become standard care for staging the regional lymph nodes of patients with primary cutaneous melanoma.

Internal packing in the control of hemorrhage from large retroperitoneal veins.

BACKGROUND: Hemorrhage from large retroperitoneal veins is usually controlled by suturing the venous tear. Infrequently, the extent and location of the tear and amount of hemorrhage preclude successful suturing. METHODS: In seven patients with severe hemorrhage from large retroperitoneal veins encountered in association with resection of retroperitoneal sarcoma (6) or repair of a ruptured abdominal aortic aneurysm (1), packing of the area with sufficient amounts of Surgicel (Ethicon, Johnson & Johnson, Somerville, NJ) and pressure for one half hour was used. RESULTS: All seven patients did not show any bleeding postoperatively and no clinical sequelae developed, with the exception of one patient who developed an abscess requiring drainage. CONCLUSION: Internal packing with Surgicel appears to be reliable in controlling venous hemorrhage not manageable by the standard methods and may be preferable to roll gauze packing.

Cytokines and chemokines are expressed at different levels in small and large murine colon-26 tumors following intratumoral injections of CpG ODN.

Direct tumor injections of (CpG ODN) into murine colon tumor 26 (CT-26) tumors can induce a potent antitumor response. Tumor size at the beginning of treatment determines the final therapeutic outcome, with smaller tumors responding favorably to CpG ODN therapy whereas large tumors do not. CpG ODN injections in small tumors resulted in tumor necrosis and extensive inflammatory cell infiltration, with average survival that is significantly higher (48.1 +/- 34 days) when compared to control ODN-treated mice (16.1 +/- 3.5 days). Cytokines and chemokines are expressed at different levels in small and large CT-26 tumors following intratumoral injections of CpG ODN. We observed that granulocyte-macrophage colony-stimulating factor and interleukin (IL) 6 are the major cytokines that were overexpressed in CpG ODN-treated small tumors but not in large tumors. Similarly, several chemokines (CXCL1, CCL2, and CCL3) were also significantly higher in CpG ODN-treated small tumors compared to control ODN-treated tumors.

Surgical treatment of locally progressive stage IIIB carcinoma of the cervix: use of the inverted "T" incision.

Stage III carcinoma of the cervix is treated usually, and often effectively, with the combination of radiation and chemotherapy. For tumors locally recurring, without evidence of distant lymphatic or hematogenous spread, the option of pelvic exenteration rises. The described surgical technique derives from soft tissue sarcoma pelvic surgery. It is a lower midline incision extending transversely at its lower end ("reverse T"), which improves the exposure and hence resectability of some of these tumors.

Technique of forequarter (interscapulothoracic) amputation.

In the anterior approach to forequarter amputation, a segment of clavicle is removed and early dissection and division of the subclavian vessels are done. In the posterior approach after division of the trapezius and muscles attached to the vertebral border of the scapula, the trunks of the brachial plexus and the subclavian vessels are serially ligated and divided, while the pectoral muscles are intact. In both approaches, the dissection around the subclavian vessels can be slow and tedious to avoid bleeding, which could be difficult to control because the vessels have not been cleared circumferentially for application of a vascular clamp. Our technique combines an anterior and a posterior approach, which rapidly divides all the relevant muscles and clavicle, and leaves at the end the division of the nerves and subclavian vessels as the extremity is gently supported to avoid undue traction on the vessels. The trunks of the brachial plexus are divided posteriorly and the subclavian vessels at the thoracic inlet, allowing a greater proximal margin than that achieved by the anterior or posterior approach. When extra skin has to be removed from the axilla because of tumor involvement, a fasciocutaneous deltoid flap may provide coverage of the defect.