David R. Byrd

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.

Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells

Adoptive T cell therapy, involving the ex vivo selection and expansion of antigen-specific T cell clones, provides a means of augmenting antigen-specific immunity without the in vivo constraints that can accompany vaccine-based strategies. A phase I study was performed to evaluate the safety, in vivo persistence, and efficacy of adoptively transferred CD8+ T cell clones targeting the tumor-associated antigens, MART1/MelanA and gp100 for the treatment of patients with metastatic melanoma. Four infusions of autologous T cell clones were administered, the first without IL-2 and subsequent infusions with low-dose IL-2 (at 0.25, 0.50, and 1.0 × 106 units/m2 twice daily for the second, third, and fourth infusions, respectively). Forty-three infusions of MART1/MelanA-specific or gp100-specific CD8+ T cell clones were administered to 10 patients. No serious toxicity was observed. We demonstrate that the adoptively transferred T cell clones persist in vivo in response to low-dose IL-2, preferentially localize to tumor sites and mediate an antigen-specific immune response characterized by the elimination of antigen-positive tumor cells, regression of individual metastases, and minor, mixed or stable responses in 8 of 10 patients with refractory, metastatic disease for up to 21 mo.

Sentinel Lymph Node Surgery After Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer The ACOSOG Z1071 (Alliance) Clinical Trial

IMPORTANCE Sentinel lymph node (SLN) surgery provides reliable nodal staging information with less morbidity than axillary lymph node dissection (ALND) for patients with clinically node-negative (cN0) breast cancer. The application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer is unclear because of high false-negative results reported in previous studies. OBJECTIVE To determine the false-negative rate (FNR) for SLN surgery following chemotherapy in women initially presenting with biopsy-proven cN1 breast cancer. DESIGN, SETTING, AND PATIENTS The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial enrolled women from 136 institutions from July 2009 to June 2011 who had clinical T0 through T4, N1 through N2, M0 breast cancer and received neoadjuvant chemotherapy. Following chemotherapy, patients underwent both SLN surgery and ALND. Sentinel lymph node surgery using both blue dye (isosulfan blue or methylene blue) and a radiolabeled colloid mapping agent was encouraged. MAIN OUTCOMES AND MEASURES The primary end point was the FNR of SLN surgery after chemotherapy in women who presented with cN1 disease. We evaluated the likelihood that the FNR in patients with 2 or more SLNs examined was greater than 10%, the rate expected for women undergoing SLN surgery who present with cN0 disease. RESULTS Seven hundred fifty-six women were enrolled in the study. Of 663 evaluable patients with cN1 disease, 649 underwent chemotherapy followed by both SLN surgery and ALND. An SLN could not be identified in 46 patients (7.1%). Only 1 SLN was excised in 78 patients (12.0%). Of the remaining 525 patients with 2 or more SLNs removed, no cancer was identified in the axillary lymph nodes of 215 patients, yielding a pathological complete nodal response of 41.0% (95% CI, 36.7%-45.3%). In 39 patients, cancer was not identified in the SLNs but was found in lymph nodes obtained with ALND, resulting in an FNR of 12.6% (90% Bayesian credible interval, 9.85%-16.05%). CONCLUSIONS AND RELEVANCE Among women with cN1 breast cancer receiving neoadjuvant chemotherapy who had 2 or more SLNs examined, the FNR was not found to be 10% or less. Given this FNR threshold, changes in approach and patient selection that result in greater sensitivity would be necessary to support the use of SLN surgery as an alternative to ALND. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00881361.

Colon and Rectum

In the sixth edition, Stage II was subdivided into IIA and IIB on the basis of whether the primary tumor was T3N0 or T4N0, respectively, and Stage III was subdivided into IIIA (T1-2N1M0), IIIB (T3-4N1M0), or IIIC (any TN2M0). In the seventh edition, further substaging of Stage II and III has been accomplished, based on survival and relapse data that was not available for the prior edition

Early Diagnosis and Treatment of Pancreatic Dysplasia in Patients with a Family History of Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer death in the United States, and its incidence is increasing. At the time of diagnosis, 96% to 99% of patients are incurable and have a median survival of less than 1 year (1-3). Hereditary predisposition accounts for at least 10% of cases of pancreatic cancer (4). Some inherited syndromes that confer a high risk for pancreatic cancer include familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, cystic fibrosis, and hereditary pancreatitis. However, patients who inherit pancreatic cancer in an autosomal dominant fashion (familial pancreatic cancer) are at the highest risk, which can approach 50% (4, 5). Management of patients with a family history of pancreatic cancer has not been prospectively studied. Theoretically, the poor prognosis of patients with pancreatic cancer could be improved if a method for detecting precancerous, or dysplastic, changes in the pancreas was available. Current methods for evaluating patients with suspected pancreatic adenocarcinoma include endoscopic retrograde cholangiopancreatography (ERCP), abdominal computed tomography, transabdominal and endoscopic ultrasonography, and serum tumor markers. These methods of diagnosis are usually used after pancreatic cancer has developed. No prospective studies to detect precancerous lesions in the pancreas have previously been performed. We sought to determine whether laboratory, radiologic, or endoscopic findings aid in the diagnosis of early precancerous conditions of the pancreas in patients with a strong family history of pancreatic cancer. Methods Patients Fourteen patients were drawn from three separate, consecutive, unrelated kindreds (families X, Y, and Z) that had two or more members in at least two generations with pancreatic cancer (Figure 1). Primary care physicians referred the probands from the kindreds to the gastroenterology clinic at the University of Washington for pancreatic evaluation because of the strong family history of pancreatic cancer. All family members were eligible for evaluation if they were between 18 and 80 years of age and were willing to have imaging studies done and be assessed by the authors. The cohort included 8 of 20 eligible members of family X, 1 of 10 eligible members of family Y, and 5 of 6 eligible members of family Z. Patients were interviewed to ascertain the presence of diarrhea, abdominal or back pain, weight loss, and diabetes (Table 1). Eleven symptomatic patients and 3 asymptomatic patients were evaluated. The institutional review board of the University of Washington approved any K- ras analysis and genetic testing. Informed consent was obtained from all patients for all tests and procedures. Figure 1. Families X, Y, and Z. Table 1. Patient History Family X is a large pedigree of 75 members spanning five generations (Figure 1) (5). Nine family members have died of adenocarcinoma of the pancreas. Two patients in generation II and all patients in generation III had pathologic confirmation of their diagnosis. No other types of cancer are present in the family. Family X was previously tested for the hereditary pancreatitis gene, hereditary nonpolyposis colon cancer genes, and the p16 gene; no evidence of mutation was found (unpublished data). Members of this family frequently develop pancreatic endocrine or exocrine insufficiency before cancer is diagnosed; this fact can be used as a clinical marker for family members who are at greatest risk for pancreatic cancer. Eight members of family X were evaluated (Table 1). Four family members (patients X.III.2, X.III.12, X.III.17, and X.IV.30) had frequent diarrhea (one to five loose stools per day), and 1 family member (patient X.III.1) had occasional diarrhea (loose stools a few times per month). One family member with frequent diarrhea (patient X.III.17) also had chronic lower abdominal pain. Four family members had diabetes (patients X.III.1, X.III.2, X.III.12, and X.III.14), and 1 family member had a history of lightheadedness associated with hypoglycemia (patient X.IV.28). One family member was asymptomatic (patient X.IV.29). Family Y includes more than 39 members, 2 of whom died of pancreatic cancer (patients Y.III.2 and Y.IV.9); other types of cancer in the family include breast cancer, oropharyngeal cancer, and bladder cancer (Figure 1). Five family members had diabetes, including 4 who did not develop pancreatic cancer (patients Y.II.2, Y.III.3, Y.III.5, and Y.V.19) and 1 who developed cancer several months after diabetes was diagnosed (patient Y.III.20). One family member (patient Y.IV.5) with recurrent epigastric pain and frequent diarrhea was evaluated. Family Z consists of 29 members (Figure 1). Three members died of pancreatic cancer (patients Z.II.5, Z.III.7, and Z.IV.5), which was present in both sides of the family; however, the maternal lineage seemed to develop cancer at an earlier age than the paternal lineage (45 years compared with 63 years). Prostate, stomach, and breast cancer were present in paternal family members, and diabetes and suspected liver cancer were present in maternal family members (the diagnosis of liver cancer is uncertain because objective medical information was not available). Five family members were available for evaluation (Table 1). One patient (patient Z.IV.1) had frequent loose stools, and two patients (patient Z.IV.2 and Z.V.3) had occasional loose stools (Table 1). Patients Z.IV.1 and Z.V.3 also had intermittent abdominal pain. Two family members were asymptomatic (patients Z.III.6 and Z.IV.4). Patient Z.III.6 was the link between two generations with pancreatic cancer: her mother (patient Z.II.5) and her son (patient Z.IV.5). Interventions Diagnostic Tests Laboratory tests consisted of carcinoma embryonic antigen analysis, CA19-9 analysis, and, when possible, a 3-hour glucose tolerance test (unless the patient was already known to have diabetes). Analysis for the K -ras mutation was performed in patients who underwent ERCP if sufficient pancreatic juice could be obtained. Exon 1 of the K -ras oncogene was amplified by polymerase chain reaction, and products were directly sequenced as previously described (5, 6). Imaging studies included spiral computed tomography, endoscopic ultrasonography, and ERCP. Endoscopic ultrasonography was done after conscious sedation with a mechanical radial scanning ultrasonography endoscope (Olympus UM-20, Olympus Optical Co., Tokyo, Japan). Images were recorded as prints and were videotaped. Videotapes were reviewed after examinations were done to confirm the findings. Findings on endoscopic ultrasonography and ERCP were examined by the same observer to avoid interobserver variation. Computed tomography with dual-phase and helical technique was performed by using intravenous contrast, negative oral contrast, and intravenous glucagon to maximize distention of the duodenum. Thin collimation of 3 mm was used for initial noncontrast images and for the arterial and delay phases. Needle biopsies guided by computed tomography were not done for histologic evaluation because of the risk for pancreatitis and the high risk for sampling error (most patients had no focal lesions to target). Surgery Seven patients were referred for surgery because they had abnormal findings on endoscopic ultrasonography and ERCP. They received pneumococcal, influenza, and meningococcal vaccines approximately 3 weeks before surgery in anticipation of splenectomy and subsequently had abdominal exploration and en bloc total pancreaticoduodenectomy and splenectomy to remove all pancreatic tissue. Total pancreatectomy rather than partial pancreatectomy was performed because of concerns that cancer could develop in any pancreatic remnant left in situ. Reconstruction was done by using duodenojejunostomy followed by end-side choledochojejunostomy using an antecolic jejunal limb. A feeding jejunostomy tube was placed to allow early postoperative enteral nutrition. Postoperative therapy included H2-blockers or proton-pump inhibitors as prophylaxis against marginal ulcers. One patient required segmental jejunal resection for an intramural mass found to contain a pancreatic rest on histologic examination. Results Fourteen patients were evaluated for evidence of pancreatic abnormalities, and 7 were referred for pancreatectomy on the basis of ERCP findings and family history. All 7 patients were found to have widespread dysplasia throughout the pancreas; 6 of these patients were from family X, and 1 was from family Z (Table 2). Table 2. Endoscopic, Radiologic, and Histologic Findings Diagnostic Tests Initial history showed that 6 of the 14 patients had frequent symptoms of pancreatic endocrine or exocrine insufficiency, 3 patients had occasional diarrhea, 1 patient had weight loss, 1 patient had lightheadedness associated with hypoglycemia, and 3 patients were asymptomatic. Of the patients found to have dysplasia, 6 had symptoms and 1 was asymptomatic. Of the 7 patients who did not undergo surgery, 5 had symptoms and 2 were asymptomatic (Table 1). Physical examinations were noncontributory. Laboratory analysis showed diabetes or glucose intolerance in half of the patients (7 of 14); however, most of these patients (6 of 7) were from family X, in which diabetes is a phenotypic component of the hereditary syndrome. Carcinoembryonic antigen and CA19-9 levels were tested in 8 of the 14 patients and found to be normal in all patients except patient X.III.17, who had an elevated carcinoembryonic antigen level of 10.6 g/L (normal range<5.0 g/L) but a normal CA19-9 level of 34 U/mL (normal range<35 U/mL). Analysis for the K- ras mutation was performed on pancreatic juice obtained on ERCP in 4 of the 7 patients who were subsequently found to have dysplasia. Three patients (patients X.III.1, X.III.2, and X.III.17) were positive for the K- ras mutation, and 1 patient (patient X.III.14) had no detectable mutation. Endoscopic ultrasonography was perfo

Multivariate Analysis of Prognostic Factors Among 2,313 Patients With Stage III Melanoma: Comparison of Nodal Micrometastases Versus Macrometastases

PURPOSE To determine the survival rates and independent predictors of survival using a contemporary international cohort of patients with stage III melanoma. PATIENTS AND METHODS Complete clinicopathologic and follow-up data were available for 2,313 patients with stage III disease in an updated and expanded American Joint Committee on Cancer (AJCC) melanoma staging database. Kaplan-Meier and Cox multivariate survival analyses were performed. RESULTS Among all 2,313 patients with stage III disease, 81% had micrometastases, and 19% had clinically detectable macrometastases. The 5-year overall survival was 63%; it was 67% for patients with nodal micrometastases, and it was 43% for those with nodal macrometastases (P < .001). Tremendous heterogeneity in survival was observed, particularly in the microscopically detected nodal metastasis subset (from 23% to 87% for 5-year survival). Multivariate analysis demonstrated that in patients with nodal micrometastases, number of tumor-containing lymph nodes, primary tumor thickness, patient age, ulceration, and anatomic site of the primary independently predicted survival (all P < .01). When added to the model, primary tumor mitotic rate was the second-most powerful predictor of survival after the number of tumor-containing nodes. In contrast, for patients with nodal macrometastases, the number of tumor-containing nodes, primary ulceration, and patient age independently predicted survival (P < .01). CONCLUSION In this multi-institutional analysis, we demonstrated remarkable heterogeneity of prognosis among patients with stage III melanoma, especially among those with nodal micrometastases. These results should be incorporated into the design and interpretation of future clinical trials involving patients with stage III melanoma.

Prognostic Significance of Mitotic Rate in Localized Primary Cutaneous Melanoma: An Analysis of Patients in the Multi-Institutional American Joint Committee on Cancer Melanoma Staging Database

PURPOSE The aim of this study was to assess the independent prognostic value of primary tumor mitotic rate compared with other clinical and pathologic features of stages I and II melanoma. METHODS From the American Joint Committee on Cancer (AJCC) melanoma staging database, information was extracted for 13,296 patients with stages I and II disease who had mitotic rate data available. RESULTS Survival times declined as mitotic rate increased. Ten-year survival ranged from 93% for patients whose tumors had 0 mitosis/mm(2) to 48% for those with ≥ 20/mm(2) (P < .001). Mean number of mitoses/mm(2) increased as the primary melanomas became thicker (1.0 for melanomas ≤ 1 mm, 3.5 for 1.01 to 2.0 mm, 7.3 for 3.01 to 4.0 mm, and 9.6 for > 8 mm). Ulceration was also associated with a higher mitotic rate; 59% of ulcerated melanomas had ≥ 5 mitoses/mm(2) compared with 16% of nonulcerated melanomas (P < .001). In a multivariate analysis of 10,233 patients, the independent predictive factors for survival in order of statistical significance were as follows: tumor thickness (χ(2) = 104.9; P < .001), mitotic rate (χ(2) = 67.0; P < .001), patient age (χ(2) = 48.2; P < .001), ulceration (χ(2) = 46.4; P < .001), anatomic site (χ(2) = 34.6; P < .001), and patient sex (χ(2) = 33.9; P < .001). Clark level of invasion was not an independent predictor of survival (χ(2) = 3.2; P = .37). CONCLUSION A high mitotic rate in a primary melanoma is associated with a lower survival probability. Among the independent predictors of melanoma-specific survival, mitotic rate was the strongest prognostic factor after tumor thickness.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma

BACKGROUND Sentinel‐lymph‐node biopsy is associated with increased melanoma‐specific survival (i.e., survival until death from melanoma) among patients with node‐positive intermediate‐thickness melanomas (1.2 to 3.5 mm). The value of completion lymph‐node dissection for patients with sentinel‐node metastases is not clear. METHODS In an international trial, we randomly assigned patients with sentinel‐node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph‐node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma‐specific survival. Secondary end points included disease‐free survival and the cumulative rate of nonsentinel‐node metastasis. RESULTS Immediate completion lymph‐node dissection was not associated with increased melanoma‐specific survival among 1934 patients with data that could be evaluated in an intention‐to‐treat analysis or among 1755 patients in the per‐protocol analysis. In the per‐protocol analysis, the mean (±SE) 3‐year rate of melanoma‐specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log‐rank test) at a median follow‐up of 43 months. The rate of disease‐free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log‐rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log‐rank test); these results must be interpreted with caution. Nonsentinel‐node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS Immediate completion lymph‐node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma‐specific survival among patients with melanoma and sentinel‐node metastases. (Funded by the National Cancer Institute and others; MSLT‐II ClinicalTrials.gov number, NCT00297895.)

A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: Creation and rationale for inclusion of tumor (T) characteristics

BACKGROUND The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. Although most patients achieve complete remission with surgical treatment, those with advanced disease have a poor prognosis. The American Joint Committee on Cancer (AJCC) is responsible for the staging criteria for all cancers. For the past 20 years, the AJCC cancer staging manual has grouped all nonmelanoma skin cancers, including cSCC, together for the purposes of staging. However, based on new evidence, the AJCC has determined that cSCC should have a separate staging system in the 7th edition AJCC staging manual. OBJECTIVE We sought to present the rationale for and characteristics of the new AJCC staging system specific to cSCC tumor characteristics (T). METHODS The Nonmelanoma Skin Cancer Task Force of AJCC reviewed relevant data and reached expert consensus in creating the 7th edition AJCC staging system for cSCC. Emphasis was placed on prospectively accumulated data and multivariate analyses. Concordance with head and neck cancer staging system was also achieved. RESULTS A new AJCC cSCC T classification is presented. The T classification is determined by tumor diameter, invasion into cranial bone, and high-risk features, including anatomic location, tumor thickness and level, differentiation, and perineural invasion. LIMITATIONS The data available for analysis are still suboptimal, with limited prospective outcomes trials and few multivariate analyses. CONCLUSIONS The new AJCC staging system for cSCC incorporates tumor-specific (T) staging features and will encourage coordinated, consistent collection of data that will be the basis of improved prognostic systems in the future.

The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging

The American Joint Committee on Cancer (AJCC) staging manual has become the benchmark for classifying patients with cancer, defining prognosis, and determining the best treatment approaches. Many view the primary role of the tumor, lymph node, metastasis (TNM) system as that of a standardized classification system for evaluating cancer at a population level in terms of the extent of disease, both at initial presentation and after surgical treatment, and the overall impact of improvements in cancer treatment. The rapid evolution of knowledge in cancer biology and the discovery and validation of biologic factors that predict cancer outcome and response to treatment with better accuracy have led some cancer experts to question the utility of a TNM‐based approach in clinical care at an individualized patient level. In the Eighth Edition of the AJCC Cancer Staging Manual, the goal of including relevant, nonanatomic (including molecular) factors has been foremost, although changes are made only when there is strong evidence for inclusion. The editorial board viewed this iteration as a proactive effort to continue to build the important bridge from a “population‐based” to a more “personalized” approach to patient classification, one that forms the conceptual framework and foundation of cancer staging in the era of precision molecular oncology. The AJCC promulgates best staging practices through each new edition in an effort to provide cancer care providers with a powerful, knowledge‐based resource for the battle against cancer. In this commentary, the authors highlight the overall organizational and structural changes as well as “whats new” in the Eighth Edition. It is hoped that this information will provide the reader with a better understanding of the rationale behind the aggregate proposed changes and the exciting developments in the upcoming edition. CA Cancer J Clin 2017;67:93–99.