Antonio C. Buzaid

Final Version of 2009 AJCC Melanoma Staging and Classification

PURPOSE To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. METHODS The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. RESULTS Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level. CONCLUSION Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.

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.

Central Venous Catheters Coated with Minocycline and Rifampin for the Prevention of Catheter-Related Colonization and Bloodstream Infections: A Randomized, Double-Blind Trial

See related articles on pp 257-266 and 275-280 and editorial comment on pp 304-306. Central venous catheters are indispensable in the treatment of critically and chronically ill patients, but they are the leading cause of primary nosocomial bloodstream infection [1, 2]. A study of hospitals in the National Nosocomial Infection Surveillance System, conducted between 1986 and 1990, showed that rates of bloodstream infection were substantially higher in patients who were in intensive care units and had intravascular devices than in those who did not have such devices [3]. To decrease the risk for catheter colonization and infection, antiseptic and antibiotic agents have been applied topically at the insertion site [4-6]. More recently, the use of antimicrobial flush solutions has been proposed [7]. However, coating venous catheters with antiseptic or antimicrobial agents may have an even more pronounced protective effect against colonization and infection, particularly if both the external and internal surfaces of the device are coated. Since 1990, several types of antiseptic or antimicrobial vascular catheter coatings have been developed and studied [8, 9]. Maki and colleagues [9] investigated central venous catheters coated with chlorhexidine-silver sulfadiazine; the coated catheters seemed less likely than the uncoated catheters to be associated with bloodstream infections. We recently coated vascular catheters with a combination of minocycline and rifampin after treatment with the tridodecylmethyl-ammonium chloride surfactant. In vitro, these catheters were shown to have broad-spectrum antimicrobial inhibitory activity that was significantly superior to the activity of catheters coated with chlorhexidine-silver sulfadiazine [10, 11]. The catheters coated with minocycline and rifampin were also found to be highly efficacious in preventing catheter colonization and subcutaneous infection in a rabbit model [11]. In a double-blind, randomized clinical trial, we studied the efficacy of catheters that were treated with tridodecylmethyl-ammonium chloride and coated with minocycline and rifampin in preventing catheter colonization and bloodstream infection in hospitalized patients. Methods Study Sample Our study was conducted simultaneously at five university-based hospitals in the Texas Medical Center in Houston: The University of Texas M.D. Anderson Cancer Center (518 beds), Veterans Administration Medical Center (1050 beds), Hermann Hospital (600 beds), Ben Taub General Hospital (580 beds), and The Methodist Hospital (904 beds). The study began on 1 September 1994 and ended on 27 March 1995. Hospitalized patients 18 years of age or older who required a triple-lumen polyurethane central venous catheter at a new insertion site were asked to participate. We excluded pregnant women, patients who were allergic to rifampin or tetracycline, patients with dermatitis or a burn over the insertion site, and patients for whom the anticipated duration of catheterization was less than 3 days. All patients gave informed consent. Randomization All catheters were triple-lumen, polyurethane, 7 French, and 20 cm long (Cook Critical Care, Bloomington, Indiana). The coated catheters were pretreated with tridodecylmethyl-ammonium chloride and then coated, 18 hours later, with minocycline and rifampin. The levels of minocycline and rifampin on the external and internal surfaces of coated catheters before insertion, as determined by high-performance liquid chromatography, were 139.3 g/cm and 13.9 g/cm, respectively. Control catheters were untreated and uncoated. All catheters were gas sterilized and placed in identical trays, and each tray was assigned an identification number. The trays were then randomly assigned into blocks of six: three with coated catheters and three with control catheters. Each block of trays was placed in boxes by Cook Critical Care, and the boxes were shipped to the five hospitals. When a patient was determined to be eligible, a tray was removed from the box (trays were removed one at a time, in sequential order from top to bottom), and that catheter was used for the patient. The catheter identification number was recorded on a data entry form and on the patients medical chart; neither the patient nor the clinician who inserted the device knew which catheter (coated or uncoated) had been used. Catheter Insertion and Care Study catheters were inserted into the subclavian vein, internal jugular vein, or femoral vein of patients who had no other indwelling catheter. Study catheters were not exchanged over guidewires. Maximal sterile barrier precautions were taken, including use of a sterile gown, sterile gloves, full sterile drapes, a mask, and a cap. At the time of catheter insertion and at each dressing change, the insertion site was cleaned with chlorhexidine gluconate (at The Methodist Hospital) or 10% povidone-iodine scrub (at all other hospitals). In each case, the preparation was applied to the skin for 2 minutes before catheter insertion. The insertion site was then covered with sterile gauze and taped securely. The insertion site was inspected every 72 hours (during a dressing change) for evidence of infection, such as erythema, purulence, swelling, or tenderness over the catheter. During follow-up, the following information was obtained for all patients: site of catheter insertion; dates of catheter placement and removal; occurrence of difficulties and violations of aseptic technique during insertion or removal, if any; reason for using the catheter (chemotherapy, total parenteral nutrition, administration of blood products, or a combination of these reasons); type of dressing; and reason for catheter removal. In addition, clinical data were obtained on underlying disease, neutrophil and platelet counts, antibiotic therapy administration, other therapeutic interventions administered during the period of catheterization, and the presence or absence of fever and infection during catheterization. The catheter remained in place until it was no longer needed; until a specific event, such as catheter-related infection, necessitated its removal; or for 28 days, whichever occurred first. Microbiological Methods Quantitative Cultures of Central Venous Catheters The entire catheter was removed aseptically, and 4-cm segments were cut from the catheter tip and the subcutaneous section. These segments were semiquantitatively cultured by using the roll-plate method; the same segment was then quantitatively cultured by using the sonication method [12-14]. Organisms recovered by either method were fully identified according to standard microbiological methods. Coagulase-negative staphylococci were classified as gram-positive cocci in clusters that produced catalase but not coagulase and were categorized according to species by using the Staph-Ident System (Analytab Products, Plainview, New Jersey). All hospitals used the same methods for culture. Skin Cultures To determine whether bacteria became resistant to the antibiotics that coated the study catheters, skin samples obtained from the insertion site were cultured at the time of insertion and within 24 hours after catheter removal, as described elsewhere [15]. Organisms recovered from the insertion site were fully identified by using standard microbiological methods. Antimicrobial Resistance We used the modified Kirby-Bauer technique to test the antimicrobial activity of the catheters coated with minocycline and rifampin against all organisms isolated from indwelling coated catheters at the time of catheter removal [16]. The zones of inhibition against staphylococci cultured from coated catheters were compared with those of uncoated catheters. The minimal inhibitory concentration (MIC) of minocycline hydrochloride (Lederle Laboratories, Pearl River, New York) and rifampin (Ciba-Geigy Corp., Summit, New Jersey) against staphylococcal organisms that colonized the catheter tip, subcutaneous segments, and adjacent skin insertion sites of the coated catheters was determined. A microbroth dilution method was used to determine the MIC in accordance with guidelines established by the National Committee for Clinical Laboratory Standards [17]. Definitions The definitions adopted for our study were proposed by the Centers for Disease Control and Prevention [18]. Colonization of a central venous catheter was defined as 1) the isolation from either the tip or the subcutaneous segment of 15 or more colony-forming units of any organism by the rollplate technique or 2) isolation of more than 1000 colony-forming units of any organism by the sonication technique. Catheter-related bloodstream infection was defined as the isolation of microorganisms from the bloodstream (blood was obtained through venipuncture, not through the catheter) of a patient who had concurrent clinical manifestations of sepsis and no source for the bloodstream infection other than the vascular catheter. In addition, the catheter had to be colonized with the same organism (same species and same antibiogram). To confirm the diagnosis of catheter-related bloodstream infection, DNA molecular typing done using pulse-field gel electrophoresis was performed on organisms that were of the same species, had the same antibiogram, and were isolated from the catheter and blood during the period of catheterization. Patients were considered to have fever if the oral body temperature was greater than 38 C. Neutropenia was defined as a polymorphonuclear count of fewer than 1000 cells/mm3. Thrombocytopenia was defined as a platelet count of fewer than 100 000 cells/mm3. Molecular Typing Molecular typing was performed by using pulse-field gel electrophoresis. Identical organisms with similar DNA profiles that were isolated from a segment of the colonized catheter and from the bloodstream confirmed the diagnosis of catheter-related bloodstream infection. However, a mismatch did not rule out such a diagnosis because catheter coloniza

A new American Joint Committee on Cancer staging system for cutaneous melanoma.

The Melanoma Staging Committee of the AJCC has proposed major revisions of the melanoma TNM and stage grouping criteria. The committee members represent most of the major cooperative groups and cancer centers worldwide with a special interest in melanoma; the committee also collectively has had clinical experience with over 40,000 patients. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include 1) melanoma thickness and ulceration, but not level of invasion, to be used in the T classification; 2) the number of metastatic lymph nodes, rather than their gross dimensions, the delineation of microscopic versus macroscopic lymph node metastases, and presence of ulceration of the primary melanoma to be used in the N classification; 3) the site of distant metastases and the presence of elevated serum LDH, to be used in the M classification; 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 new staging information gained from intraoperative lymphatic mapping and sentinel lymph node biopsy. The AJC Melanoma Staging Committee invites comments and suggestions regarding this proposed staging system before a final recommendation is made.

An evidence-based staging system for cutaneous melanoma.

A completely revised staging system for cutaneous melanoma was implemented in 2003. The changes were validated with a prognostic factors analysis involving 17,600 melanoma patients from prospective databases. This major collaborative study of predicting melanoma outcome was conducted specifically for this project, and the results were used to finalize the criteria for this evidence‐based staging system. In fact, this was the largest prognostic factors analysis of prospectively followed melanoma patients ever conducted. Important results that shaped the staging criteria involved both the tumor‐node‐metastasis (TNM) criteria and stage grouping for all four stages of melanoma. Major changes in the staging include: (1) melanoma thickness and ulceration are the dominant predictors of survival in patients with localized melanoma (Stages I and II); deeper level of invasion (ie, IV and V) was independently associated with reduced survival only in patients with thin or T1 melanomas. (2) The number of metastatic lymph nodes and the tumor burden were the most dominant predictors of survival in patients with Stage III melanoma; patients with metastatic nodes detected by palpation had a shorter survival compared with patients whose nodal metastases were first detected by sentinel node excision of clinically occult or “microscopic” metastases. (3) The site of distant metastases (nonvisceral versus lung versus all other visceral metastatic sites) and the presence of elevated serum lactate dehydrogenase (LDH) were the dominant predictors of outcome in patients with Stage IV or distant metastases. (4) An upstaging was implemented for all patients with Stage I, II, and III disease when a primary melanoma is ulcerated by histopathological criteria. (5) Satellite metastases around a primary melanoma and in‐transit metastases were merged into a single staging entity that is grouped into Stage III disease. (6) A new convention was implemented for defining clinical and pathological staging so as to take into account the new staging information gained from lymphatic mapping and sentinel node biopsy.

Sequential Biochemotherapy Versus Chemotherapy for Metastatic Melanoma: Results From a Phase III Randomized Trial

PURPOSE The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b. PATIENTS AND METHODS Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1 and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25). Biochemotherapy involved CVD with vinblastine reduced 25% plus interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20, and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days 5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks. RESULTS Among 190 patients enrolled, 91 were assessable for biochemotherapy and 92 for chemotherapy. Ten percent of the patients were alive a median of 52 months from start of therapy. Response rates were 48% for biochemotherapy and 25% for chemotherapy (P =.001); six patients given biochemotherapy and two given chemotherapy had complete responses. Median time to progression (TTP) was 4.9 months for biochemotherapy and 2.4 months for chemotherapy (P =.008); median survival was 11.9 and 9.2 months, respectively (P =.06). The influence of treatment on TTP and survival was confirmed in multivariate analyses with other prognostic factors not included in the original stratification. Biochemotherapy produced substantially more constitutional, hemodynamic, and myelosuppressive toxic effects. CONCLUSION Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.

Temozolomide for the Treatment of Brain Metastases Associated With Metastatic Melanoma: A Phase II Study

PURPOSE Temozolomide is a well-tolerated oral alkylating agent with activity in the CNS. A multicenter, open-label, phase II study was conducted to assess the safety and efficacy of temozolomide in patients with brain metastases from metastatic melanoma (MM) who did not require immediate radiotherapy. PATIENTS AND METHODS Eligible patients had histologically confirmed MM to the brain, and no prior radiotherapy or radiosurgery for brain metastases. Previously untreated patients received temozolomide at 200 mg/m(2)/d x 5 days; previously treated patients received 150 mg/m(2)/d x 5 days every 28 days. Treatment continued for 1 year or until disease progression or unacceptable toxicity. RESULTS Of 151 patients enrolled, 117 had received no prior systemic chemotherapy, and 34 had received prior chemotherapy for MM. Among previously untreated patients, 25% had more than four brain lesions, eight (7%) achieved an objective response (one complete and seven partial), and 34 (29%) had stable disease in brain metastases. Median overall survival was 3.5 months. Among previously treated patients, 21% had more than four brain lesions, one had a partial response, and six (18%) had stable disease in brain metastases. Median overall survival was 2.2 months. Temozolomide was well tolerated, with four (3%) patients discontinuing because of adverse events. Grade 3/4 hematologic toxicities included thrombocytopenia (3%), neutropenia (2%), and leukopenia (1%). Headache (9%) and vomiting (8%) were the most common nonhematologic grade 3/4 adverse events. CONCLUSION Temozolomide was well tolerated and demonstrated activity in the treatment of brain metastases from MM. Further evaluation of temozolomide combination therapy is warranted.

Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system.

PURPOSE To critically review the accuracy of the current American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma and propose a more useful staging system. METHODS Retrospective evaluation of the published data as well as a reanalysis of the University of Alabama and Sydney Melanoma Unit (UAB/SMU) data bases (n = 4,568) for patients with primary melanoma was performed to examine specifically the impact of level of invasion and ulceration on the prognostic value of tumor thickness. In addition, an overlay graphic technique was used to compare the Kaplan-Meier survival curves of patients with local recurrences, satellites, in-transit metastases, and nodal metastases reported in the literature. RESULTS Tumor thickness and ulceration remained the most powerful prognostic indicators in patients with stage I and II disease. Level of invasion provided statistically significant prognostic information only in the subgroup of patients with tumor thickness < or = 1 mm, but the absolute 10-year survival differences were small and inconsistent (level II, 95%; level III, 85%; level IV, 89%). The best statistical fit for tumor thickness cutoffs was at 1 versus 2 versus 4 mm. The overlay graphic technique showed that patients who developed satellite lesions or local recurrence had prognoses similar to those of patients with stage III disease. The most important prognostic factor for patients with nodal metastases was number of involved nodes rather than size. CONCLUSION Our analysis showed that the current AJCC staging system has many inaccuracies that should be modified to conform to published data. On the basis of our analysis and review of the literature, we propose a new and more accurate staging system.

Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma.

PURPOSE To evaluate the antitumor activity and toxicity of concurrent biochemotherapy that uses cisplatin, vinblastine, and docarbazine (DTIC) (CVD) in combination with interferon alfa-2a (IFN-alpha) and interleukin-2 (IL-2) in patients with metastatic melanoma. PATIENTS AND METHODS Between October 1992 and October 1993, 53 patients with a documented diagnosis of metastatic melanoma with measurable lesions and an Eastern Oncology Cooperative Group (ECOG) performance status of 2 or less were enrolled onto this study. Patients were required to have no clinically significant cardiac dysfunction and to be free from symptomatic brain metastases. The treatment consisted of cisplatin 20 mg/m2 daily for 4 days; vinblastine 1.6 mg/m2 daily for 4 days; and DTIC 800 mg/m2 intravenously (i.v.) day 1 with IL-2 9 x 10(6) IU/m2 i.v. by continuous infusion daily for 4 days and IFN-alpha 5 x 10(6) U/m2 subcutaneously daily for 5 days, repeated at 21-day intervals. Response was assessed after two cycles and patients who responded were continued on treatment for a total of six cycles. RESULTS Among 53 assessable patients, 11 patients (21%) achieved a complete response (CR) and 23 patients (43%) achieved a partial response (PR), for an overall objective response rate of 64%. The median time to disease progression for all patients was 5 months. The median survival of all patients entered onto the trial was 11.8 months. Among the 11 patients who achieved a CR, five patients (9%) have remained in continuous CR for 50+ to 61+ months. The toxicity of biochemotherapy consisted of severe myelosuppression, significant nausea and vomiting, and moderately severe hypotension that required inpatient hospital care for each 5-day cycle of treatment. There were no treatment-related deaths. CONCLUSION Concurrent biochemotherapy for patients with advanced melanoma is capable of producing high CR and overall response rates and resulted in durable complete remissions in a small fraction of patients. Toxicity, although severe, was manageable in a routine inpatient hospital environment.

Prognostic factors for survival of patients treated systemically for disseminated melanoma

PURPOSE The current American Joint Commission on Cancer (AJCC) staging system distinguishes between soft tissue and visceral metastases in advanced (stage IV) melanoma. We sought to verify these staging criteria and to identify prognostic variables that could be used to evaluate the impact of systemic therapy on long-term survival during the prior decade. PATIENTS AND METHODS We conducted a retrospective study of patients with advanced cutaneous melanoma enrolled in clinical trials between 1979 and 1989 at The University of Texas M.D. Anderson Cancer Center. Pretreatment age, sex, number of organs with metastases, serum levels of lactate dehydrogenase (LDH) and albumin, and period of enrollment were analyzed using a Cox proportional hazards model of survival. RESULTS In univariate and multivariate analyses that involved 318 stage IV patients, normal serum levels of LDH and albumin, soft tissue and/or single visceral organ metastases (especially lung), female sex, and enrollment late in the decade were independent positive predictors for survival. In multivariate analyses, the current AJCC criteria did not significantly predict outcome. Systemic treatment response did not bias these results, and only 4% of patients had a complete response. Patients who lived more than 2 years (11%) had a mix of favorable prognostic characteristics and a high frequency of systemic or surgically induced complete response. CONCLUSION This study supports the use of stratification parameters that reflect the favorable prognostic impact of soft tissue or single visceral organ metastases and normal serum levels of LDH and albumin at time of enrollment in advanced melanoma trials. Improved survival over the prior decade probably reflects advances in diagnostic and palliative interventions.