Marshall M. Urist

Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger

OBJECTIVE A prospective multi-institutional randomized surgical trial involving 740 stage I and II melanoma patients was conducted by the Intergroup Melanoma Surgical Program to determine whether elective (immediate) lymph node dissection (ELND) for intermediate-thickness melanoma (1-4 mm) improves survival rates compared with clinical observation of the lymph nodes. A second objective was to define subgroups of melanoma patients who would have a higher survival with ELND. METHODS The eligible patients were stratified according to tumor thickness, anatomic site, and ulceration, and then were prerandomized to either ELND or nodal observation. Femoral, axillary, or modified neck dissections were performed using standardized surgical guidelines. RESULTS The median follow-up was 7.4 years. A multifactorial (Cox regression) analysis showed that the following factors independently influenced survival: tumor ulceration, trunk site, tumor thickness, and patient age. Surgical treatment results were first compared based on randomized intent. Overall 5-year survival was not significantly different for patients who received ELND or nodal observation. However, the 552 patients 60 years of age or younger (75% of total group) with ELND has a significantly better 5-year survival. Among these patients, 5-year survival was better with ELND versus nodal observation for the 335 patients with tumors 1 to 2 mm thick, the 403 patients without tumor ulceration, and the 284 patients with tumors 1 to 2 mm thick and no ulceration. In contrast, patients older than 60 years of age who had ELND actually had a lower survival trend than those who had nodal observation. When survival rates were compared based on treatment actually received (i.e., including crossover patients), the patients with significantly improved 5-year survival rates after ELND included those with tumors 1 to 2 mm thick, those without tumor ulceration, and those 60 years of age or younger with tumors 1 to 2 mm thick or without ulceration. CONCLUSION This is the first randomized study to prove the value of surgical treatment for clinically occult regional metastases. Patients 60 years or age or younger with intermediate-thickness melanomas, especially with nonulcerative melanoma and those with tumors 1 to 2 mm thick, may benefit from ELND. However, because some patients still are developing distant disease, these results should be considered an interim analysis.

Thin Stage I Primary Cutaneous Malignant Melanoma

Although wide surgical excision is the accepted treatment for thin malignant melanomas, there is reason to believe that narrower margins may be adequate. We conducted a randomized prospective study to assess the efficacy of narrow excision (excision with 1-cm margins) for primary melanomas no thicker than 2 mm. Narrow excision was performed in 305 patients, and wide excision (margins of 3 cm or more) was performed in 307 patients. The major prognostic criteria were well balanced in the two groups. The mean thickness of melanomas was 0.99 mm in the narrow-excision group and 1.02 mm in the wide-excision group. The subsequent development of metastatic disease involving regional nodes and distant organs was not different in the two groups (4.6 and 2.3 percent, respectively, in the narrow-excision group, as compared with 6.5 and 2.6 percent in the wide-excision group). Disease-free survival rates and overall survival rates (mean follow-up period, 55 months) were also similar in the two groups. Only three patients had a local recurrence as a first relapse. All had undergone narrow excision, and each had a primary melanoma with a thickness of 1 mm or more. The absence of local recurrence in the group of patients with a primary melanoma thinner than 1 mm and the very low rate of local recurrences indicate that narrow excision is a safe and effective procedure for such patients.

Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial.

BACKGROUND A prospective, multi-institutional, randomized surgical trial involving 486 localized melanoma patients was conducted to determine whether excision margins for intermediate-thickness melanomas (1.0 to 4.0 mm) could be safely reduced from the standard 4-cm radius. METHODS Patients with 1- to 4-mm-thick melanomas on the trunk or proximal extremities were randomly assigned to receive either a 2- or 4-cm surgical margin. RESULTS The median follow-up time was 6 years. The local recurrence rate was 0.8% for 2-cm margins and 1.7% for 4-cm margins (p value not significant [NS]). The rates of in-transit metastases were 2.1% and 2.5%, respectively (p = NS). Of the six patients with local recurrences, five have died. Recurrence rates did not correlate with surgical margins, even among stratified thickness groups. The overall 5-year survival rate was 79.5% for the 2-cm margin patients and 83.7% for the 4-cm margin patients (p = NS). The need for skin grafting was reduced from 46% with 4-cm surgical margins to 11% with 2-cm surgical margins (p < 0.001). The hospital stay was shortened from 7.0 days for patients receiving 4-cm surgical margins to 5.2 days for those receiving 2-cm margins (p = 0.0001). This reduction was largely due to reduced need for skin grafting, since the hospital stay for those who had a skin graft was 2.5 days longer than that for those who had a primary wound closure (p < 0.01). CONCLUSION Margins of excision can be safely reduced to 2 cm for patients with intermediate-thickness melanomas. The narrower margins significantly reduced the need for skin grafting and shortened the hospital stay.

Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm)

BACKGROUND: Ten- to 15-year survival results were analyzed from a prospective multi-institutional randomized surgical trial that involved 740 stages I and II melanoma patients with intermediate thickness melanomas (1.0 to 4.0 mm) and compared elective (immediate) lymph node dissection (ELND) with clinical observation of the lymph nodes as well as prognostic factors that independently predict outcomes. METHODS: Eligible patients were stratified according to tumor thickness, anatomical site, and ulceration, and then prerandomized to either ELND or nodal observation. By using Cox stepwise multivariate regression analysis, the independent predictors of outcome were tumor thickness (P < .001), the presence of tumor ulceration (P < .001), trunk site (P = .003), and patient age more than 60 years (P = .01). RESULTS: Overall 10-year survival was not significantly different for patients who received ELND or nodal observation (77% vs. 73%; P = .12). Among the prospectively stratified subgroups of patients, 10-year survival rates favored those patients with ELND, with a 30% reduction in mortality rate for the 543 patients with nonulcerated melanomas (84% vs. 77%; P = .03), a 30% reduction in mortality rate for the 446 patients with tumor thickness of 1.0 to 2.0 mm (86% vs. 80%; P = .03), and a 27% reduction in mortality rate for 385 patients with limb melanomas (84% vs. 78%; P = .05). Of these subgroups, the presence or absence of ulceration should be the key factor for making treatment recommendations with regard to ELND for patients with intermediate thickness melanomas. CONCLUSIONS: These long-term survival rates from patients treated at 77 institutions demonstrate that ulceration and tumor thickness are dominant predictive factors that should be used in the staging of stages I and II melanomas, and confer a survival advantage for these subgroups of prospectively defined melanoma patients.

Multimodality Treatment of Merkel Cell Carcinoma: Case Series and Literature Review of 1024 Cases

Background: Merkel cell carcinoma (MCC) is an unusual and potentially aggressive cancer of the skin. There is no consensus regarding the optimal therapeutic approach, and the relative roles of surgery, radiotherapy, and chemotherapy still are controversial The aim of this study is to analyze the roles of these therapeutic options.Methods: The medical records of 16 patients with a diagnosis of localized, primary MCC treated at the University of Alabama at Birmingham were reviewed. An extensive review of the English-language literature also was performed. The Kaplan-Meier method was used to develop the survival curves. Comparisons were made using Fisher’s exact test. Significance was defined as P < .05.Results: MCC presented primarily in Caucasians (98.3%) with a median age of 69 years. Immunosuppressive therapy appeared to play a role in the development of this cancer. In the UAB experience, 3-year actuarial survival was 31%. The only factor significantly associated with overall survival was the stage of disease at presentation: median survivals were 97 vs. 15 months for stages I and II, respectively (log-rank, P = .02). From the literature review, adjuvant radiotherapy was associated with a reduced risk of local recurrence (P < .00001).Conclusions: MCC is an aggressive cancer, with a high tendency for local recurrence and distant spread. Surgery and adjuvant radiotherapy appear to provide optimal local control. The role of chemotherapy remains to be defined.

Resection of the liver for colorectal carcinoma metastases. A multi-institutional study of long-term survivors.

In this review of a collected series of patients undergoing hepatic resection for colorectal metastases, 100 patients were found to have survived greater than five years from the time of resection. Of these 100 long-term survivors, 71 remain disease-free through the last follow-up, 19 recurred prior to five years, and ten recurred after five years. Patient characteristics that may have contributed to survival were examined. Procedures performed included five trisegmentectomies, 32 lobectomies, 16 left lateral segmentectomies, and 45 wedge resections. The margin of resection was recorded in 27 patients, one of whom had a positive margin, nine of whom had a less than or equal to 1-cm margin, and 17 of whom had a greater than 1-cm margin. Eighty-one patients had a solitary metastasis to the liver, 11 patients had two metastases, one patient had three metastases, and four patients had four metastases. Thirty patients had Stage C primary carcinoma, 40 had Stage B primary carcinoma, and one had Stage A primarycarcinoma. The disease-free interval from the time of colon resection to the time of liver resection was less than one year in 65 patients, and greater than one year in 34 patients. Three patients had bilobar metastases. Four of the patients had extrahepatic disease resected simultaneously with the liver resection. Though several contraindications to hepatic resection have been proposed in the past, five-year survival has been found in patients with extrahepatic disease resected simultaneously, patients with bilobar metastases, patients with multiple metastases, and patients with positive margins. Five-year disease-free survivors are also present in each of these subsets. It is concluded that five-year survival is possible in the presence of reported contraindications to resection, and therefore that the decision to resect the liver must be individualized.

Conventional TRAM flap versus free microsurgical TRAM flap for immediate breast reconstruction.

Immediate breast reconstruction using the transverse abdominal myocutaneous island (TRAM) flap was performed in 54 patients over the past 3 years at our institution. This represented approximately 59 percent of patients undergoing all types of immediate breast reconstruction. In 10 patients, the abdominal island flap was transferred as a free flap based on the deep inferior epigastric pedicle. These patients were compared with the other 44 patients, in whom the flap was transferred using the conventional technique. The TRAM flap is well suited for immediate breast reconstruction because the procedure can be carried out simultaneously with mastectomy using separate operating teams and instruments. The operation is safe and relatively free of complications. The free TRAM group compared favorably with the conventional group in terms of complications, operating time, estimated blood loss, hospitalization, and return to functional baseline. The free TRAM flap appears to be as safe as the conventional technique with the advantages of a more limited rectus muscle harvest, improved medial contour of the breast due to the lack of tunneling, and perhaps a healthier flap because of the large donor vessels.

Factors Associated With Local Recurrence After Skin-Sparing Mastectomy and Immediate Breast Reconstruction for Invasive Breast Cancer

ObjectiveTo examine the incidence of local recurrence (LR) and factors associated with it in a population of patients who underwent skin-sparing mastectomy (SSM) and immediate reconstruction for invasive carcinoma. Summary Background DataThe efficacy of SSM has been challenged by concerns about increased risks of LR. MethodsA consecutive series of 173 patients (176 cancers) with invasive carcinoma underwent SSM and immediate breast reconstruction (June 1986 to December 1997). Data were analyzed by the Kaplan-Meier method, the log-rank statistic test, and the Cox proportional hazards model. ResultsMean patient age was 47 ± 9 years (27% were 40 or younger). The AJCC stages were 1 = 43%, 2 = 52%, and 3 = 5%. Thirty percent of tumors were poorly differentiated. With a median follow-up of 73 months, the LR rate was 4.5%. The mean local relapse-free interval was 26 months. Seventy-five percent of patients who presented with LR developed distant metastases and died of disease within a mean of 21 months. On univariate analysis, factors associated with higher LR rate were tumor stage 2 or 3, tumor size larger than 2 cm, node-positive disease, and poor tumor differentiation. Actuarial 1-, 3-, and 5-year overall survival rates were 98%, 94%, and 88%, respectively. On multivariate analysis, factors associated with decreased survival were advanced stage, presence of LR, and absence of hormone therapy. LR was a highly significant predictor of tumor-related death. ConclusionsThere is a low incidence of LR after SSM, and it is associated with advanced disease at presentation. LR is an independent risk factor for tumor-related death.

A prospective phase II clinical trial of continuous FUDR regional chemotherapy for colorectal metastases to the liver using a totally implantable drug infusion pump.

A prospective phase II evaluation of regional FUDR chemotherapy using a totally implantable drug infusion pump was conducted in 81 patients with colorectal metastases to the liven. The survival results were compared to a historical control group of 129 patients with isolated liver metastases. The two groups were comparable with respect to their dominant prognostic factors. The pump patients received their continuous chemotherapy on an outpatient basis and had an 88% response rate, as evidenced by a fall in their serum CEA levels by one-third or greater after two cycles of chemotherapy. By four criteria, the regional chemotherapy patients had an improved survival rate compared to the control series. First, the 1 year survival and median survival was better for the entire group of pump patients vs. controls (82% vs. 36%, 26 months vs. 8 months, p<0.0001). The survival for the regional chemotherapy patients was not influenced by the extent of tumor involvement, whether previous systemic 5-FU was given, or whether the patient had symptomatic disease. Second, the entire group of regional chemotherapy patients (including nonresponders) had a greater 1 year survival compared to the most favorable subgroup of control patients with the following characteristics: normal liver function tests, no symptoms, and only one lobe involved (82% vs. 66%, p = 0.009). Third, a subgroup of 49 pump patients, whose initial treatment for metastatic disease was regional chemotherapy (within 3 months of diagnosis) had a better 1 year survival than an exactly matched group of 49 control patients (67% vs. 30%, p = 0.000003). Fourth, the actuarial survival for all 81 pump patients was significantly better than predicted by a mathematical model constructed to predict the patients clinical course based upon the seven dominant prognostic variables identified in a multifactorial analysis (82% survival at 1 year vs. 33% predicted survival). While liver metastases could be controlled in most patients, the major cause of death was tumor progression in extrahepatic sites, particularly lung metastases and abdominal carcinomatosis. Although it appears that regional chemotherapy with an implantable pump appears to prolong life by 12 to 18 months more than matched historical controls, these results must be confirmed by a randomized (phase III) prospective clinical trial.

Local recurrence in malignant melanoma: Long-term results of the multiinstitutional randomized surgical trial

AbstractBackground: In the past, radical margins of excision were prescribed for cutaneous melanoma based on preconceived notions rather than on hard clinical evidence. Methods: In a prospective study of 742 patients with intermediate-thickness melanoma (1–4 mm), 470 patients with trunk or proximal extremity lesions were randomized into a 2-or 4-cm margin. Patients with distal extremity or head and neck lesions (n=272) received uniformly a 2-cm margin. Results: The overall rate of local recurrence was 3.8%. This rate in the randomized portion (n=470) was 2.1% for the 2-cm margin and 2.6% for the 4-cm margin (p=0.72). A progressive increase in local recurrence rates was observed with thickness: 2.3% for lesions 1.0–2.0 mm, 4.2% for those 2.01–3.0 mm, and 11.7% for those 3.01–4.0 mm thick (p=0.001). Local recurrence occurred in 1.5% of those without ulceration and in 10.6% of those with ulceration of the primary lesion (p=0.001). The local recurrence rate was not significantly affected by the margin of resection even among the thicker or ulcerated lesions. It also was not affected significantly by the method of closure of the primary site or management of the regional nodes, or the age or gender of the patients. Conclusions: A 2-cm margin is as effective as a 4-cm margin in local control and survival of intermediate-thickness melanomas. The local recurrence rate is significantly affected by the thickness of the primary lesion and the presence or not of ulceration.