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Journal of Clinical Oncology, Vol 24, No 19 (July 1), 2006: pp. 3157-3163
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.04.5344
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Phase II Multicenter Study of Neoadjuvant Biochemotherapy for Patients With Stage III Malignant Melanoma

Karl D. Lewis, William A. Robinson, Martin McCarter, Nathan Pearlman, Steven J. O'Day, Clay Anderson, Thomas T. Amatruda, Anna Baron, Chan Zeng, Maude Becker, Susan Dollarhide, Karen Matijevich, Rene Gonzalez

From the University of Colorado Health Sciences Center, Aurora, CO; The Angeles Clinic and Research Institute, Santa Monica, CA; Ellis Fischel Cancer Center, University of Missouri, Columbia, MO; North Memorial Health Care, Hubert H. Humphrey Cancer Center, Robbinsdale, MN

Address reprint requests to Rene Gonzalez, MD, Anschutz Cancer Pavilion, Mail Stop F703, 1635 N Ursula St, PO Box 6510, Aurora, CO 80045; e-mail: rene.gonzalez{at}uchsc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
PURPOSE: To determine the relapse-free survival, overall survival, and response rate of patients with stage III melanoma treated with neoadjuvant biochemotherapy in a multicenter setting.

PATIENTS AND METHODS: Patients with pathologically proven stage III melanoma, either via clinical detection or sentinel lymph node positivity, were eligible for enrollment. Patients received two cycles of preoperative biochemotherapy followed by complete regional lymphadenectomy and two postoperative courses of biochemotherapy. The biochemotherapy regimen consisted of the following: cisplatin 20 mg/m2 on days 1 to 4, dacarbazine 800 mg/m2 on day 1 only, vinblastine 1.6 mg/m2 on days 1 to 4, interleukin-2 total dose of 36 MU/m2 during 4 days, and interferon alfa 5 MU/m2 on days 1 to 5. Growth factor support was administered with each cycle.

RESULTS: Ninety-two patients were eligible for the study. At a median follow-up of 40.4 months, relapse-free survival and overall survival are 64% and 78%, respectively. There was a lower relapse rate and improved survival for patients with a positive sentinel lymph node compared with patients with clinically detected lymph nodes, although this difference did not reach statistical significance. Of the 50 patients with measurable disease, the overall response rate was 26%. Toxicity of the biochemotherapy was high but generally manageable.

CONCLUSION: The current study has expanded the preliminary evidence on neoadjuvant biochemotherapy for stage III melanoma.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Melanoma is a major health problem, with more than 59,000 new cases and 8,000 deaths expected in 2005.1 When discovered early and fully excised, melanoma is highly curable. However, once metastatic disease develops, treatment options are limited and survival is generally measured in months. Patients with stage III melanoma (involvement of regional lymph nodes) have a 5-year survival of approximately 50%.2 The only US Food and Drug Administration–approved adjuvant treatment for stage III disease is interferon alfa (IFN-{alpha}). Although the relapse-free survival (RFS) is significantly improved with 1 year of high-dose IFN-{alpha} (HDI), the effect on overall survival (OS) is less clear.3 Therefore, better adjuvant options are needed for this high-risk population. Most studies of adjuvant IFN-{alpha} were performed before the widespread use of sentinel lymph node (SLN) biopsies, which has dramatically changed our ability to identify patients with occult metastases. When SLN biopsy is performed on patients with primary melanoma ≥ 1 mm thickness, approximately 20% will have a positive SLN.4 Furthermore, it has been shown that regardless of tumor thickness, the presence of a positive SLN portends a poor prognosis.5-8

Biochemotherapy, the use of cytotoxic drugs combined with IFN and interleukin-2 (IL-2), has response rates of approximately 50% in patients with metastatic melanoma.9 It was these encouraging data that led investigators to study biochemotherapy in the neoadjuvant treatment of patients with stage III melanoma. The initial study by Buzaid et al10 showed a pathologic response rate of 50% in patients with measurable disease. A subsequent study by our group showed similarly encouraging results with an overall clinical response rate of 39% and a 65% RFS at 31 months.11

Here we report the results of a multicenter, phase II study evaluating neoadjuvant biochemotherapy in patients with stage III melanoma. Unlike the previous studies, the current study includes a significant percentage of SLN-positive patients. The first two cycles of biochemotherapy were administered before completion lymphadenectomy to allow for evaluation of clinical response in patients with measurable disease. The primary objective was to evaluate RFS and OS in a larger cohort of patients than previously reported. A secondary objective was to determine any differences in RFS or OS in patients with clinically detectable disease versus SLN-positive patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Patient Selection
Patients were required to have pathologically proven stage III melanoma either by biopsy or cytologic evaluation of an enlarged lymph node or via a pathologically documented positive SLN. Patients had an Eastern Cooperative Oncology Group performance status of ≤ 2 and adequate end-organ function. Patients of child-bearing age must have agreed to use adequate birth control. The study was approved by each centers' institutional review board and patients were required to give written informed consent before treatment.

Patients were excluded if they tested positive for the HIV antibody, were pregnant or lactating, had organ allografts, or would require corticosteroids for intercurrent illness. Patients must not have received prior 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC), cisplatin, vinblastine, or IL-2.

Treatment
Pretreatment staging consisted of history and physical examination. Computed tomography scan of the chest, abdomen, and pelvis; magnetic resonance imaging of the brain; and baseline laboratory data including CBC with differential, serum chemistries, liver function studies, and lactate dehydrogenase level were performed.

Two cycles of induction biochemotherapy (preoperative) were followed by reimaging and complete regional lymphadenectomy. Surgery was done within 3 to 4 weeks of completing the second course of biochemotherapy or when all toxicities related to treatment had resolved. This was followed by two cycles of postoperative biochemotherapy. Cycle 3 of biochemotherapy was begun within 42 days of lymphadenectomy.

The biochemotherapy regimen consisted of cisplatin 20 mg/m2 intravenously (IV) during 1 hour on days 1 to 4, DTIC 800 mg/m2 IV during 1 hour on day 1 only, vinblastine 1.6 mg/m2 IV push on days 1 to 4, IL-2 total dose of 36 MU/m2 administered by continuous infusion or via a decrescendo schedule during 4 days, and IFN-{alpha} 5 MU/m2 subcutaneously days 1 to 5. Hematopoietic growth factor support with granulocyte colony-stimulating factor 5 µg/kg subcutaneously was started day 6 and continued until WBC ≥ 10 x 109/L. Patients received at least 1 L of normal saline before cisplatin (followed by additional adequate hydration). No specific antiemetic regimen was required; although the following was recommended: ondansetron 20 mg IV before chemotherapy on day 1 followed by 8 mg orally every 8 hours on days 2 to 5; prochlorperazine 10 mg orally every 8 hours on days 1 to 5; and lorazepam 1 mg IV every 6 hours as needed. Corticosteroidal antiemetics were not allowed. Dopamine 3 µg/kg/min was started on day 1 with the IL-2 infusion and continued through conclusion of the IL-2. The dopamine was titrated to a maximum of 5 µg/kg/min if patient's systolic blood pressure decreased below 90 mmHg and did not respond to an appropriate fluid bolus. Constitutional symptoms, such as myalgias, fever, and rigors, were treated with naproxen 375 mg orally every 12 hours as needed. Patients could also receive acetaminophen 500 mg orally every 4 hours as needed. For rigors, meperidine 50 mg IV every 4 hours as needed was administered.

Dose Reductions
Dose reductions were based on the following criteria. Patients with an absolute neutrophil count less than 1.5 x 109/L and/or platelets less than 75 x 109/L on day 19 had therapy withheld 1 week. If, on day 26, the values remained below the minimal acceptable levels, treatment was withheld a second week. If, at day 33, the WBC and platelets were not at the prescribed level, continuation on the study was discussed with the principal investigator.

Patients experiencing grade 4 febrile neutropenia and/or thrombocytopenia had their DTIC and vinblastine dose reduced 25% in subsequent cycles if the investigator deemed appropriate. Patients who continued to experience grade 4 toxicity were allowed to receive a second 25% dose reduction of DTIC and vinblastine in subsequent cycles. Patients who continued to have grade 4 febrile neutropenia and/or thrombocytopenia were removed from study.

Vinblastine was modified for hepatic dysfunction based on the following criteria. If the bilirubin was more than 1.5 but ≤ 3.0 mg/dL, a 50% dose reduction was performed. If the bilirubin was more than 3.0 but ≤ 5.0 mg/dL, a 75% dose reduction was performed. If the bilirubin was more than 5.0 mg/dL, vinblastine was withheld. Cisplatin was modified for renal dysfunction based on the following criteria. If creatinine clearance was 50 to 59 mL/min, cisplatin was reduced 25%; if creatinine clearance was 40 to 49 mL/min, cisplatin was reduced 50%; and if creatinine clearance was less than 40 mL/min, cisplatin was withheld. Intravenous hydration was administered to maximize the creatinine clearance and up to 24-hour delay in treatment was allowed to accomplish this. For grade 4 paresthesias, vinblastine was stopped and the dose of cisplatin was reduced 50%.

Clinical Assessments
Initial radiologic studies were required within 30 days of study initiation. For patients with measurable disease (defined either as a lymph node on imaging with at least one diameter > 0.5 cm or as a palpable lesion with both diameters ≥ 2 cm), computed tomography of the involved lymph node basin was repeated after the second course of biochemotherapy before lymphadenectomy to assess response. Complete response was defined as disappearance of all measurable lesions and no disease related symptoms. Partial response was defined as ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable lesions, and no new lesions. A physical examination was performed before each cycle of biochemotherapy. CBC and electrolytes were monitored on days 1, 3, 5, 8, 10, and 19. After completion of treatment, patients were evaluated every 3 months for 1 year and then every 6 months thereafter.

Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0.

Statistical Analysis
The Kaplan-Meier estimate was applied for OS and RFS as calculated from the start of biochemotherapy. The log-rank test and the Cox regression model were applied to examine differences in survival for clinical variables such as sex, age, number of lymph nodes, and SLN status.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Patients
A total of 102 patients from four institutions were registered between May 1999 and August 2002. Seven patients were excluded because they were found subsequently to have metastatic disease, two patients were ineligible because they had surgery before receiving biochemotherapy, and one patient was withdrawn secondary to insurance reasons. The characteristics of the 92 eligible patients are shown in Table 1. Overall survival is based on 91 patients because one patient received surgery after the fourth cycle of biochemotherapy, in violation of protocol. RFS is based on 90 patients because one patient, who had received only 1 day of biochemotherapy secondary to toxicity, was lost to follow-up; however, survival data were available for that patient.


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  		Table 1. Patient Characteristics

 
There were 60 males (65%) and 32 females (35%), with a median age of 43 years (range, 17 to 76 years). The majority of primary melanomas were located on the trunk and extremities, although 16% had head/neck primaries and 15% had unknown primaries. Fifty-seven patients (62%) had clinically detected lymph node–positive disease, whereas 35 patients (38%) were SLN positive. For the SLN-positive patients, the median number of SLNs harvested was 2.1 (range, one to five SLNs) and the median number of positive SLNs was 1.4 (range, one to three SLNs). Eighteen patients (20%) had previous treatment, including 10 patients (11%) who had received previous IFN.

Treatment
Seventy-three patients (79.3%) completed all cycles of biochemotherapy. Eight patients received only one cycle of therapy: four secondary to toxicity, two secondary to disease progression, and two withdrew consent. Seven patients received only two cycles of treatment: four withdrew consent, one secondary to toxicity, one secondary to progressive disease, and one patient was found to have lymphoma involving the lymph node basin on dissection. This patient was believed to have two primary tumors with simultaneous lymph node involvement and subsequently underwent chemotherapy for lymphoma. In total 326 cycles of biochemotherapy were administered (89% of the planned cycles).

Of the patients with a positive SLN, 71% did not have additional evidence of lymph node involvement on dissection (Table 2). Five patients (14.3%) had a single additional node involved, whereas only one patient (2.9%) had at least two additional lymph nodes involved. In total, 47.8% of patients had no additional lymph nodes involved, 21.7% had one additional lymph node involved, 10.9% had two to four lymph nodes involved, and 6.5% had more than four lymph nodes involved at the time of lymphadenectomy. Ten patients did not undergo lymphadenectomy as planned per the protocol: three secondary to disease progression, four secondary to toxicity from biochemotherapy, two withdrew consent, and one was a protocol violation because the treating physician performed surgery after four cycles of biochemotherapy. However, of these 10 patients, seven ultimately did undergo surgery off protocol. Of the three patients who did not have surgery, two developed progressive systemic disease and surgery was considered inappropriate, and one was medically unfit after having a myocardial infarction during cycle 1 of biochemotherapy.


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  		Table 2. Extent of Lymph Node Disease at Time of Lymphadenectomy for Patients With a Positive Sentinel Lymph Node Initially and All Study Patients

 
Efficacy
Table 3 summarizes the clinical response. Overall, 50 patients (54%) had measurable disease. A complete response was seen in two patients (4%) and a partial response was seen in 11 patients (22%). The overall response rate was 26%. Twenty-five patients (50%) had stable disease and four patients (8%) had progressive disease. At the time of surgery, 13 (26%) of the 50 patients with measurable disease before treatment had no melanoma detected in their lymph nodes pathologically.


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  		Table 3. Response After Two Cycles of Biochemotherapy in the 50 Patients With Measurable Disease

 
At a median follow-up of 40.4 months (range, 3.9 to 67.5 months), 58 patients (64%) remain free of disease. RFS is shown in Figure 1. Median RFS has yet to be reached. There was a lower relapse rate in patients with a positive SLN compared with those with clinically positive disease, although this did not reach statistical significance (Fig 2). For patients with a positive SLN, RFS at 36 months was 80.3% (95% CI, 60.9% to 90.8%) compared with 59.7% (95% CI, 45.5% to 71.4%) for patients with clinical disease. There was no statistically significant difference in RFS survival with regard to age, sex, or previous treatment (data not shown).


Figure 1
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  		Fig 1. Kaplan-Meier estimate of relapse-free survival (n=90).

 

Figure 2
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  		Fig 2. Relapse-free survival (RFS) by lymph node status. The difference in RFS between patients with clinically positive lymph nodes and patients with sentinel lymph nodes positive at the time of diagnosis did not reach statistical significance (P = .053).

 
Overall survival is shown in Figure 3. As of the current follow-up, median survival has yet to be reached and 71 patients (78%) remain alive. Figure 4 shows the OS by SLN status. Although there is a trend toward improved survival for patients in the SLN group, this did not reach statistical significance (P = .085). Similar to RFS, there was no difference in OS with regard to sex or previous treatment (data not shown).


Figure 3
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  		Fig 3. Kaplan-Meier estimate of overall survival.

 

Figure 4
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  		Fig 4. Overall survival (OS) by lymph node status. The difference in OS between patients with clinically positive lymph nodes and patients with sentinel lymph node–positive disease did not reach statistical significance (P = .085).

 
Toxicity
Toxicity was high but manageable. Treatment was administered in the inpatient setting and all patients required blood pressure support with dopamine during the administration of IL-2, per protocol. Fever and chills were noted in all patients and were most prevalent on the first day. Virtually all patients developed constitutional toxicities of anorexia, fatigue, and other flu-like symptoms. In total, 35 patients required dose reductions. Thirty-five patients also had treatment delays; this was secondary to patient request in nine instances and postoperative complications in three instances. Table 4 lists the grade 3 and 4 toxicities. Grades 3 and 4 neutropenia were rather common, as was grade 3 thrombocytopenia. Electrolyte abnormalities were frequent; however, few grade 4 electrolyte abnormalities occurred.


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  		Table 4. Frequency of the Common Toxicities Associated With Biochemotherapy

 
One patient developed a non–Q-wave myocardial infarction on day 1 of cycle 1. A second patient developed symptomatic bradycardia with syncope on day 3 of cycle 1. Biochemotherapy was stopped and no additional cycles were administered. In total, eight patients, including the two patients described, had the biochemotherapy stopped secondary to toxicity. An additional eight patients withdrew consent, mainly secondary to constitutional toxicities.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
The treatment of stage III melanoma is a difficult problem. This patient population is at high risk of developing systemic disease and subsequent death. Many previous studies using various agents, such as IFN or vaccines, have shown limited benefit in this setting. Preliminary studies of biochemotherapy in metastatic melanoma have shown promising results and subsequently prompted the use of this regimen in the adjuvant setting. Advantages of administering the treatment neoadjuvantly are that it allows for assessment of clinical response, potentially improves resectability, and allows for measurements of surrogate end points of activity, such as circulating tumor cells. We performed serial measurements of circulating tumor cells using real-time quantitative polymerase chain reaction on a subset of patients treated on this trial; these results are the subject of a separate report.12 In addition to our trial, another recent study has evaluated neoadjuvant HDI in patients with stage III melanoma.13

Buzaid et al10 studied neoadjuvant biochemotherapy in 64 patients with locoregional metastases. Their results showed a clinical response rate of 44% and, with a median follow-up of 27 months, 44% of patients remained disease free and 58% were alive. A previous phase II study of neoadjuvant biochemotherapy from our group evaluated 48 patients with stage III melanoma.11 We showed an overall response rate of 39%, with a complete pathologic response of 11%. At a median follow-up of 31 months, 79% of the patients were alive and 65% were disease free.

The purpose of this study was to evaluate neoadjuvant biochemotherapy in a larger patient population in a multicenter setting. The overall clinical response rate was 26%. However, at a median follow-up of more than 40 months, the median RFS and OS have not been reached. Seventy-eight percent of patients remain alive and 64% remain free of disease. These results are similar to those in our previous study.

The current study differs from the previous study in that a larger number of SLN-positive patients were enrolled. Thirty-eight percent of patients in this study were SLN positive compared with 12.5% in our previous trial. However, many studies have shown that patients with a positive SLN have high-risk disease, with a 5-year relapse rate of approximately 45% to 60%.5-8 In fact, this study did not demonstrate a significant difference in RFS or OS for patients with clinically positive disease compared with those with SLN-positive disease. In this regard, a major difficulty in interpreting the results of this study is that patients with stage III melanoma have a wide range of outcomes depending on factors such as tumor burden in the lymph node basin and ulceration of the primary lesion.2 Unfortunately, ulceration status was not captured in the current study. In addition, because the treatment was administered neoadjuvantly, it is impossible to classify the patients definitively according to the American Joint Committee on Cancer staging criteria, given that the treatment may have affected the number of lymph nodes involved at time of surgery. With this said, however, studies have demonstrated consistently that patients with stage III melanoma are at an overall high risk of death,14,15 and additional treatment options need to be explored in this population.

Like all studies of biochemotherapy, toxicity was high but manageable. All patients experienced flu-like symptoms and hypotension requiring blood pressure support. The majority of toxicities resolved within several weeks of completing therapy. However, 35 patients required dose reductions at some point during treatment.

The current study has expanded the preliminary evidence that neoadjuvant biochemotherapy may be an effective regimen with tolerable toxicities for patients with stage III melanoma. Since this study began accrual, a randomized trial of biochemotherapy versus cisplatin, vinblastine, and DTIC alone in stage IV patients has been completed and reported in abstract form.16 That trial did not show a benefit to biochemotherapy in stage IV patients, which raises a number of issues that cannot be addressed completely until the results are reported in full. The results of the current study could simply be the consequence of patient selection in a nonrandomized trial. However, other factors, such as the experience of the treatment centers with this regimen and the dose-intensity of the biochemotherapy, may have played a role. In addition, the use of this and similar regimens in stage III disease with minimal tumor burden could also be a contributing factor to greater efficacy. This approach warrants additional investigation in a randomized trial. A National Intergroup trial (Southwest Oncology Group trial 0008) currently is evaluating a similar regimen of three postoperative courses of biochemotherapy versus HDI in patients with two or more positive nodes. It is hoped that this trial will clarify the role of biochemotherapy in stage III melanoma.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
Author Contributions
 REFERENCES
 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other
Steven J. O'Day Berlex (C); Chiron (C); Schering-Plough (C)
Clay Anderson Schering Oncology (A); Chiron (A) Schering Oncology (A); Chiron (A)
Rene Gonzalez Schering-Plough (A); Amgen (A); Chiron (A) Amgen (B) Schering-Plough (A); Amgen (A); Chiron (A) Schering-Plough (A); Amgen (A); Chiron (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) ≥ $100,000 (N/R) Not Required


   Author Contributions
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
REFERENCES
 

Conception and design: Rene Gonzalez

Administrative support: Maude Becker, Susan Dollarhide, Karen Matijevich

Provision of study materials or patients: William A. Robinson, Martin McCarter, Nathan Pearlman, Steven J. O'Day, Clay Anderson, Thomas T. Amatruda, Rene Gonzalez

Collection and assembly of data: Karl D. Lewis, Steven J. O'Day, Clay Anderson, Thomas T. Amatruda, Maude Becker, Susan Dollarhide, Karen Matijevich, Rene Gonzalez

Data analysis and interpretation: Karl D. Lewis, William A. Robinson, Martin McCarter, Anna Baron, Chan Zeng, Rene Gonzalez

Manuscript writing: Karl D. Lewis, William A. Robinson, Martin McCarter, Rene Gonzalez

Final approval of manuscript: Karl D. Lewis, William A. Robinson, Martin McCarter, Nathan Pearlman, Steven J. O'Day, Rene Gonzalez

 


   NOTES
 
Supported by Grants from Chiron, Amgen, and Schering-Plough, and by University of Colorado Cancer Center core Grant P30 CA046934.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005[Abstract/Free Full Text]

2. Balch CM, Buzaid AC, Soong SJ, et al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635-3648, 2001[Abstract/Free Full Text]

3. Kirkwood JM, Manola J, Ibrahim J, et al: A pooled analysis of Eastern Cooperative Oncology Group and Intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 10:1670-1677, 2004[Abstract/Free Full Text]

4. Morton DL, Thompson JF, Essner R, et al: Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: A multicenter trial—Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 230:453-463, 1999[CrossRef][Medline]

5. Gershenwald JE, Thompson W, Mansfield PF, et al: Multi-institutional melanoma lymphatic mapping experience: The prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17:976-983, 1999[Abstract/Free Full Text]

6. Statius Muller MG, van Leeuwen PAM, de Lange-de Klerk ESM, et al: The sentinel lymph node status is an important factor for predicting clinical outcome in patients with stage I or II cutaneous melanoma. Cancer 91:2401-2408, 2001

7. Vuylsteke RJCLM, van Leeuwen PAM, Statius Muller MG, et al: Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection: Long-term follow-up results. J Clin Oncol 21:1057-1065, 2003[Abstract/Free Full Text]

8. Berk DR, Johnson DL, Uzieblo A, et al: Sentinel lymph node biopsy for cutaneous melanoma: The Stanford experience, 1997-2004. Arch Dermatol 141:1016-1022, 2005[Abstract/Free Full Text]

9. Keilholz U, Gore ME: Biochemotherapy for advanced melanoma. Semin Oncol 29:456-461, 2002[Medline]

10. Buzaid AC, Colome M, Bedikian A, et al: Phase II study of neoadjuvant concurrent biochemotherapy in melanoma patients with local-regional metastases. Melanoma Res 8:549-556, 1998[Medline]

11. Gibbs P, Anderson C, Pearlman N, et al: A phase II study of neoadjuvant biochemotherapy for stage III melanoma. Cancer 94:470-476, 2002[CrossRef][Medline]

12. Koyanagi K, O'Day SJ, Gonzalez R, et al: Serial monitoring of circulating melanoma cells during neoadjuvant biochemotherapy for stage III melanoma: Outcome prediction in a multicenter trial. J Clin Oncol 23:8057-8064, 2005[Abstract/Free Full Text]

13. Moschos SJ, Edington HD, Rao UN, et al: High dose interferon-a2b (HDI): Toxicity, response, and predictive markers in a neoadjuvant trial for regional lymph node metastatic melanoma. J Clin Oncol 23:714s, 2005 (suppl; abstr 7517)

14. Gimotty PA, Botbyl J, Soong SJ, et al: A population-based validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 23:8065-8075, 2005[Abstract/Free Full Text]

15. Ben-Porat L, Panageas KS, Hanlon C, et al: Estimates of stage-specific survival are altered by changes in the 2002 American Joint Committee on Cancer staging system for melanoma. Cancer 106:163-171, 2006[CrossRef][Medline]

16. Atkins MB, Lee S, Flaherty LE, et al: A prospective randomized phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with metastatic melanoma (E3695): An ECOG-coordinated intergroup trial. Proc Am Soc Clin Oncol 22:708, 2003 (abstr 2847)

Submitted October 10, 2005; accepted April 27, 2006.





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