Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial.

Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB-IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58-0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30-0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8+ density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB-IVM1a melanoma.

Correction to: Neurologically asymptomatic cerebral oligometastatic prostate carcinoma metastasis identified on [Ga]Ga-THP-PSMA PET/CT.

An amendment to this paper has been published and can be accessed via the original article.

Neurologically asymptomatic cerebral oligometastatic prostate carcinoma metastasis identified on [Ga]Ga-THP-PSMA PET/CT.

BACKGROUND: Brain metastases from prostate cancer are rare and usually only occur in the context of widespread systemic disease. This is the first case report of a solitary brain oligometastasis, in a neurologically intact prostate cancer patient with no other systemic disease, detected using [68Ga]Ga-THP-PSMA PET/CT and only the second one using a PSMA-based radiopharmaceutical. CASE PRESENTATION: We report the case of a prostate cancer patient presenting 5 years after robot-assisted laparoscopic prostatectomy with biochemical recurrence, no neurological symptoms, and in the absence of metastatic lesions in the body on conventional imaging. A solitary cerebral metastasis was detected using [68Ga]Ga-THP-PSMA PET/CT, surgically resected, leading to a drop in serum PSA and a good recovery. CONCLUSION: In this case, [68Ga]Ga-THP-PSMA PET/CT resulted in a major change in clinical management and avoided additional morbidity associated with delayed diagnosis and treatment. This report demonstrates the importance of considering the presence of metastatic disease outside the conventional locations of prostate cancer spread, as well as the importance of ensuring comprehensive [68Ga]Ga-PSMA PET/CT coverage from vertex to upper thighs.

Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma.

BACKGROUND: Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. METHODS: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. RESULTS: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). CONCLUSIONS: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.

Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results: Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions: Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

Is surviving enough? Coping and impact on activities of daily living among melanoma patients with lymphoedema.

We assessed the impact of lymphoedema (defined as ≥ 10% limb volume change) on quality of life (QOL), ability to perform activities of daily living (ADLs) and coping in 277 melanoma patients. Limb volume was measured prospectively, pre-operatively and every 3-6 months for 18 months post-operatively using a perometer. Three questionnaires were administered to measure QOL, coping and impact on ADLs. Statistical analyses were conducted using longitudinal logistic regression models. At 18 months, the cumulative incidence of lymphoedema was 31% in patients with upper extremity nodal basin treatment and 40% in lower extremity nodal basin treatment patients. Patients with lower extremity lymphoedema reported lower QOL scores than those with upper extremity lymphoedema. Over 18 months, both groups with mild and moderate lymphoedema showed improvement in coping [odds ratio (OR): 6.67, 95% confidence interval (CI): 3.30-13.47] and performance of ADLs (OR: 7.46, CI: 3.38-16.47). Over the course of 18 months, men were found to have poorer coping scores than women (OR: 2.91, CI: 1.35-6.27). Lymphoedema was associated with improvement in coping over time (P = 0.08) and a higher reported interference with ADLs (OR: 2.53, CI: 1.29-4.97). Patient education about lymphoedema at the time of surgical consent may improve self-efficacy and coping ability. Effective management of lymphoedema may improve patient QOL and reduce interference with ADLs.

Safety and feasibility of adjunctive regadenoson injection at peak exercise during exercise myocardial perfusion imaging: The Both Exercise and Regadenoson Stress Test (BERST) trial.

BACKGROUND: The data existing in the literature regarding the safety of using regadenoson with symptom-limited exercise are limited, which motivated the authors to undertake this randomized study. METHODS: We offered patients scheduled to undergo vasodilator stress nuclear myocardial perfusion imaging the opportunity to exercise instead. Patients who failed to reach target heart rate (THR) were randomized to (1) receive regadenoson at peak exercise or (2) stop exercise and receive regadenoson at rest. Patients who reached THR received a standard Tc-99m sestamibi injection with no regadenoson. RESULTS: 200 patients were included (66% male, mean age 52.5 ± 13.6). 125 patients (62%) reached THR with exercise alone. All stress protocols were well tolerated, and there were no significant adverse events. There were no statistically significant differences in the extent of perfusion abnormalities, image quality, or rate of referral to cardiac catheterization within 60 days between the groups. In fully adjusted logistic regression models, beta-blocker use and diabetes remained significant univariate predictors of failure to reach THR (OR 0.21, 95% CI 0.1-0.5, P < .0001, OR 0.34, 95% CI 0.2-0.7, P = .004, respectively). CONCLUSIONS: A protocol combining regadenoson at peak exercise in patients unable to reach THR with exercise is feasible, well-tolerated, and yields comparable imaging results to a standard regadenoson injection at rest. In addition, pharmacologic stress testing may be over-ordered in current clinical practice, as patients referred for such testing were often able to exercise.

Phase II trial of imatinib mesylate in patients with metastatic melanoma.

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Future directions in regional treatment strategies for melanoma and sarcoma.

Hyperthermic isolated limb perfusion (HILP) with melphalan and more recently isolated limb infusion (ILI) with melphalan +/- dactinomycin are common treatment modalities for both in-transit melanoma of the extremity and advanced extremity sarcoma. In order to further optimize treatment, future research should focus on selection of appropriate patients, verification of a technique that produces consistent results while maintaining acceptable toxicity, and development of novel strategies and agents. Development of these novel agents and strategies has potential to not only improve the efficacy of regional chemotherapy but may also help guide future strategies for systemic treatment.

Recommendations for sentinel lymph node processing in breast cancer.

The status of the sentinel lymph node (SLN) has been shown to accurately reflect the presence or absence of metastases in the axilla in patients with breast cancer. This study was designed to determine the optimal protocol for SLN processing. A total of 173 SLNs from 96 breast cancer patients who had successful SLN localization and underwent completion axillary node dissection were identified. All SLNs were negative for metastases by initial routine histologic evaluation. The nodes were submitted in a total of 300 blocks. Each block was serially sectioned to produce 10 levels. Pan-cytokeratin stain was performed on levels 3 and 8. All other levels were stained with hematoxylin and eosin. Metastases were identified in 22 SLNs from 19 patients by examining all 10 levels. The first two hematoxylin and eosin- or the first cytokeratin-stained levels were positive for metastases in 21 (95.5%) of the 22 positive SLNs. Two additional hematoxylin and eosin-stained and one cytokeratin-stained levels of each SLN correctly identified the status of the node in 94 (97.9%) of 96 patients. Therefore, we recommend that after an initial hematoxylin and eosin-stained section, two additional hematoxylin and eosin-stained sections and one cytokeratin-stained section should be evaluated.

Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy.

BACKGROUND: Adrenal abnormalities are often identified on imaging studies performed during the staging of patients presenting with a new malignancy or restaging of patients with a history of a malignancy. METHODS: We reviewed the records of patients who underwent surgical resection of an adrenal mass identified in the setting of previously or newly diagnosed extra-adrenal malignancy. RESULTS: Eighty-one patients with an adrenal mass and recently diagnosed malignancy (n = 24) or history of a malignancy (n = 57) underwent adrenalectomy. In 42 patients (52%) the adrenal mass was a metastasis. In 39 patients (48%) the adrenal mass was an additional primary adrenal tumor process: 19 pheochromocytomas, (14 syndrome-associated, 5 sporadic), 13 cortical adenomas, 3 adrenocortical carcinomas, 2 ganglioneuromas, and 2 cases of nodular hyperplasia. CONCLUSIONS: In this series nearly half of the patients with cancer and an adrenal mass had adrenal pathologic condition independent of their primary malignancy. Despite the presence of a newly diagnosed malignancy or history of malignancy, all patients with an adrenal mass should undergo a standard hormone evaluation to confirm that the mass is not a functional neoplasm. An assumption that the adrenal mass is metastatic disease will be wrong in up to 50% of such patients.

Anaphylactic reactions to isosulfan blue dye during sentinel lymph node biopsy for breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is an alternative to axillary dissection for many breast cancer patients. Cases of anaphylactic reaction to the isosulfan blue dye used during SLNB have recently been reported. No study on the incidence of serious anaphylactic reactions during SLNB for breast cancer has been reported. METHODS: We reviewed 639 consecutive SLNBs for breast cancer performed at our institution. Sentinel lymph node biopsy was performed using both isosulfan blue dye and technetium-99m sulfur colloid. Cases of anaphylaxis were reviewed in detail. RESULTS: Overall, 1.1% of patients had severe anaphylactic reactions to isosulfan blue requiring vigorous resuscitation. No deaths or permanent disability occurred. In patients with anaphylaxis, hospital stay was prolonged by a mean of 1.6 days. In 1 patient, the anaphylactic reaction required termination of the operation. CONCLUSIONS: Prompt recognition and aggressive treatment of anaphylactic reactions to isosulfan blue are critical to prevent an adverse outcome. Lymphatic mapping with blue dye should be performed in a setting where personnel are trained to recognize and treat anaphylaxis.

Sentinel node dissection in early-stage breast cancer: ongoing prospective randomized trials in the USA.

One of the most important advances in the surgical treatment of early-stage breast cancer has been the introduction of sentinel lymph node dissection as an alternative to routine axillary node dissection. This minimally invasive procedure may reduce the morbidity of surgical treatment and improve staging of the axillary lymph node basin. Over the last 5 to 7 years, numerous institutions have published their sentinel node identification rates, false-negative events, optimal techniques, and learning curves. Many of these issues need confirmation in a prospective multicentered fashion and other issues such as survival and comparative toxicities require prospective randomized trials. Two prospective randomized trials using sentinel node biopsy have been implemented in the United States: the NSABP B-32 trial and the ACOSOG Z0010/Z0011 trials. Design, hypotheses, and rationale for these trials are discussed.

Relationship of sentinel and axillary level I-II lymph nodes to tangential fields used in breast irradiation.

PURPOSE: To evaluate the volume of nodal irradiation associated with breast-conserving therapy, we defined the anatomic relationship of sentinel lymph nodes and axillary level I and II lymph nodes in patients receiving tangential breast irradiation. METHODS AND MATERIALS: A retrospective analysis of 65 simulation fields in women with breast cancer treated with sentinel lymph node surgery and 39 women in whom radiopaque clips demarcated the extent of axillary lymph node dissection was performed. We measured the relationship of the surgical clips to the anatomic landmarks and calculated the percentage of prescribed dose delivered to the sentinel lymph node region. RESULTS: A cranial field edge 2.0 cm below the humeral head the sentinel lymph node region was included or at the field edge in 95% of the cases and the entire extent of axillary I and II dissection in 43% of the axillary dissection cases. In the remaining 57%, this field border encompassed an average of 80% of cranial/caudal extent of axillary level I and II dissection. In 98.5% of the cases, all sentinel lymph nodes were anterior to the deep field edge and 71% were anterior to the chest wall-interface, whereas 61% of the axillary dissection cohort had extension deep to the chest wall-lung interface. If the deep field edge had been set 2 cm below the chest wall-lung interface, the entire axillary dissection would have been included in 82% of the cases, and the entire sentinel lymph node would have been covered with a 0.5-cm margin. The median dose to the sentinel lymph node region was 98% of the prescribed dose. CONCLUSIONS: By extending the cranial border to 2 cm below the humeral head and 2 cm deep to the chest wall-lung interface, the radiotherapy fields used to treat the breast can include the sentinel lymph node region and most of axillary levels I and II.

Breast conservation therapy as a treatment option for the elderly. The M. D. Anderson experience.

BACKGROUND: Although almost half of all incidents of breast carcinoma occur in women age > or = 65 years, not enough is known about appropriate care for patients in this age group. The objective of the current study was to evaluate the role of breast conservation therapy in the management of breast carcinoma in women age > or = 65 years. METHODS: From 1970 to 1994, 1325 patients with carcinoma of the breast were treated with breast conservation therapy (segmental mastectomy and radiation therapy with or without axillary lymph node dissection) at The University of Texas M. D. Anderson Cancer Center. From this patient group, the authors identified 184 elderly women (> or = 65 years) with Stage 0-III disease at the time of diagnosis. RESULTS: The median patient age was 70 years (range, 65-88 years). The distribution of disease by stage among the women was Stage 0 disease in 12 patients (7%), Stage I disease in 107 patients (58%), Stage II disease in 63 patients (34%), and Stage III disease in 2 patients (1%). Comorbid conditions that may have influenced treatment planning were reported in 91 patients (50%). An axillary lymph node dissection was performed in 135 patients (73%), with positive axillary lymph nodes found in 30 patients (22%). Adjuvant chemotherapy was given to 10 patients (5%), and tamoxifen therapy was given to 63 patients (34%). Complications from treatment were reported in 24 patients (13%). With a median follow-up of 7.3 years (range, 0.25-23.5 years), 9 patients developed locoregional disease recurrence (5%), 10 patients developed contralateral breast carcinoma (5%), and 21 patients developed distant metastasis (11%). At last follow-up, 113 patients (61%) were alive, 15 patients (8%) were dead of disease, and 56 patients (30%) were dead of other causes. The 5-year and 10-year disease specific survival rates were 96% and 91%, respectively. CONCLUSIONS: Breast conservation therapy with segmental mastectomy and postoperative radiation therapy with or without axillary lymph node dissection provides excellent local control and disease free survival in elderly women with breast carcinoma. This treatment should be considered as the standard of care for elderly patients without severe comorbid disease.

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma.

BACKGROUND: This analysis was performed to identify prognostic factors that are predictive of sentinel lymph node (SLN) metastasis in melanoma. METHODS: Analysis was performed of a multi-institutional, prospective, randomized trial of SLN biopsy for melanoma. Eligibility criteria included age 18 to 70 years, Breslow thickness of 1.0 mm or more, and clinically negative regional lymph nodes. SLNs were evaluated by serial sectioning and immunohistochemistry for S100. Univariate chi-square and multivariate logistic regression analyses were performed to assess factors predictive of the presence of a positive SLN. Probability values of less than.05 were considered significant. RESULTS: SLNs were identified in 99.7% of patients. A total of 1058 patients were evaluated; 961 patients had complete data and were included in the statistical analysis. SLNs were positive for tumor in 208 of 961 patients (22%). Breslow thickness, Clark level, ulceration, and patient age were factors that were found to be independently predictive of the presence of SLN metastasis. CONCLUSIONS: Increasing Breslow thickness, Clark level of more than III, the presence of ulceration, and patient age of 60 years or less are the most important independent prognostic factors associated with the finding of positive SLN in patients with melanoma.

Adverse prognostic significance of infraclavicular lymph nodes detected by ultrasonography in patients with locally advanced breast cancer.

BACKGROUND: Ultrasonography is increasingly used to evaluate the nodal status of breast cancer patients and specialized positioning permits assessment of the infraclavicular fossa. However, the incidence and significance of infraclavicular (level III) adenopathy detected sonographically in locally advanced breast cancer (LABC) has not been defined. METHODS: The study population consisted of 146 LABC patients registered in a prospective trial of induction chemotherapy between 1991 and 1996. All patients underwent ultrasound imaging before and after chemotherapy. Median follow-up was 32 months. RESULTS: Forty-two of 146 patients (29%) had suspicious infraclavicular adenopathy; all 42 had additional positive axillary lymph nodes by ultrasound. Disease-free and overall survival for the patients with suspicious infraclavicular adenopathy was significantly worse compared with patients without this feature; disease-free survival 50% versus 68% (P = 0.112); overall survival 58% versus 83% (P = 0.026). CONCLUSIONS: Nearly one third of LABC patients will have infraclavicular lymph node involvement by ultrasound imaging; this finding is a significant adverse prognostic feature, and we recommend that infraclavicular nodal evaluation become a routine component of the sonographic workup of breast cancer patients, particularly if lower axillary lymph nodes appear involved.

Sentinel lymph node biopsy for melanoma: controversy despite widespread agreement.

Although sentinel lymph node (SLN) biopsy for melanoma has been adopted throughout the United States and abroad as a standard method of determining the pathologic status of the regional lymph nodes, some controversy still exists regarding the validity and utility of this procedure. SLN biopsy is a minimally invasive procedure, performed on an outpatient basis at the time of wide local excision of the melanoma, with little morbidity. Numerous studies have documented the accuracy of this procedure for identifying nodal metastases. There are four major reasons to perform SLN biopsy. First, SLN biopsy improves the accuracy of staging and provides valuable prognostic information for patients and physicians to guide subsequent treatment decisions. Second, SLN biopsy facilitates early therapeutic lymph node dissection for those patients with nodal metastases. Third, SLN biopsy identifies patients who are candidates for adjuvant therapy with interferon alfa-2b. Fourth, SLN biopsy identifies homogeneous patient populations for entry onto clinical trials of novel adjuvant therapy agents. Overall, the benefit of accurate nodal staging obtained by SLN biopsy far outweighs the risks and has important implications for patient management.