Showing papers in "Cancer in 2003"

A 5‐decade analysis of 13,715 carcinoid tumors

Abstract: were frequent in conjunction with small intestinal (29.0%), gastric (20.5%), colonic (20.0%), and appendiceal (18.2%) carcinoids. The highest percentages of nonlocalized lesions were noted for cecal (81.5‐ 83.2%) and pancreatic (71.9 ‐ 81.3%) carcinoids, whereas the highest percentage of localized disease was found among rectal (81.7%), gastric (67.5%), and bronchopulmonary (65.4%) carcinoids. The best 5-year survival rates were recorded for patients with rectal (88.3%), bronchopulmonary (73.5%), and appendiceal (71.0%) carcinoids; these tumors exhibited invasive growth or metastatic spread in 3.9%, 27.5%, and 38.8% of patients, respectively. CONCLUSIONS. Carcinoids appear to have increased in overall incidence over the past 30 years; for some sites, this trend has been evident for nearly half a century. Recent marked increases in gastric and rectal carcinoids and a concomitant decrease in appendiceal carcinoid incidence may be due in part to varying rules of registration among the compiled databases examined in this report or to improvements in diagnostic technology; increased awareness of and about carcinoid tumors also may play a significant role. In 12.9% of all patients with carcinoid, distant metastases already were evident at the time of diagnosis; the overall 5-year survival rate for all carcinoid tumors, regardless of site, was 67.2%. These findings bring into question the widely promulgated relative benignity of carcinoid disease. Certain carcinoid tumors, such as those of the rectum, appear to be over-represented among the black and Asian populations within the United States, suggesting the role of genetics in the development of this intriguing disease. Cancer 2003;97: 934 –59. © 2003 American Cancer Society. DOI 10.1002/cncr.11105

Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.

Abstract: BACKGROUND Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug. A large-scale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7% of patients developed doxorubicin-related congestive heart failure (CHF) after a cumulative dose of 550 mg/m2. To assess whether this estimate is reflective of the incidence in the broader clinical oncology setting, the authors evaluated data from three prospective studies to determine both the incidence of doxorubicin-related CHF and the accumulated dose of doxorubicin at which CHF occurs. METHODS A group of 630 patients who were randomized to a doxorubicin-plus-placebo arm of three Phase III studies, two studies in patients with breast carcinoma and one study in patients with small cell lung carcinoma, were included in the analysis. RESULTS Thirty-two of 630 patients had a diagnosis of CHF. Analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin-related CHF at a cumulative dose of 550 mg/m2. Age appeared to be an important risk factor for doxorubicin-related CHF after a cumulative dose of 400 mg/m2, with older patients (age > 65 years) showing a greater incidence of CHF compared with younger patients (age ≤ 65 years). In addition, > 50% of the patients who experienced doxorubicin-related CHF had a reduction < 30% in left ventricular ejection fraction (LVEF) while they were on study. CONCLUSIONS Doxorubicin-related CHF occurs with greater frequency and at a lower cumulative dose than previously reported. These findings further indicate that LVEF is not an accurate predictor of CHF in patients who receive doxorubicin. Cancer 2003;97:2869–79. © 2003 American Cancer Society. DOI 10.1002/cncr.11407

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses

Abstract: BACKGROUND: The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow-up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow-up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months). METHODS: DFS, TTR, CLBC incidence, and safety were assessed in the same patient group as in the first analysis of the ATAC trial. RESULTS: DFS estimates at 4 years remained significantly more favorable (86.9% vs. 84.5%, respectively) for patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76-0.99; P = 0.03). The benefit generated by anastrozole in terms of DFS was even greater in patients with hormone receptor-positive tumors (HR, 0.82; 95% CI, 0.70-0.96; P = 0.014). The HR for TTR also indicated a significant benefit for patients receiving anastrozole compared with those receiving tamoxifen (HR, 0.83; 95% CI, 0.71-0.96; P = 0.015), with additional benefit for patients with hormone receptor-positive tumors (HR, 0.78; 95% CI, 0.65-0.93; P = 0.007). CLBC incidence data also continued to favor anastrozole (odds ratio [OR], 0.62; 95% CI, 0.38-1.02; P = 0.062), and statistical significance was achieved in the hormone receptor-positive subgroup (OR, 0.56; 95% CI, 0.32-0.98; P = 0.042). The updated safety analysis also confirmed the findings of the first analysis, in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group. These results indicated that the safety profile of anastrozole remained consistent. CONCLUSIONS: After an additional follow-up period, anastrozole continues to show superior efficacy, which is most apparent in the clinically relevant hormone receptor-positive population. Furthermore, anastrozole has numerous noteworthy advantages in terms of tolerability compared with tamoxifen. These findings suggest that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer. Copyright 2003 American Cancer Society.

Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial.

Abstract: BACKGROUND The goal of the current study was to compare the long-term (25-month) safety and efficacy of zoledronic acid with pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma. METHODS Patients (n = 1648) were randomized to receive 4 mg or 8 mg (reduced to 4 mg) zoledronic acid as a 15-minute infusion or to receive 90 mg pamidronate as a 2-hour infusion every 3–4 weeks for 24 months. The primary endpoint was the proportion of patients with at least 1 skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate, and multiple-event analysis. Hypercalcemia of malignancy (HCM) was included as an SRE in some secondary analyses. RESULTS After 25 months of follow-up, zoledronic acid reduced the overall proportion of patients with an SRE and reduced the skeletal morbidity rate similar to pamidronate. Compared with pamidronate, zoledronic acid (4 mg) reduced the overall risk of developing skeletal complications (including HCM) by an additional 16% (P = 0.030). In patients with breast carcinoma, zoledronic acid (4 mg) was significantly more effective than pamidronate, reducing the risk of SREs by an additional 20% (P = 0.025) compared with pamidronate and by an additional 30% in patients receiving hormonal therapy (P = 0.009). Zoledronic acid (4 mg) and pamidronate were tolerated equally well. The most common adverse events included bone pain, nausea, and fatigue. CONCLUSIONS Long-term follow-up data confirm that zoledronic acid was more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast carcinoma and was of similar efficacy in patients with multiple myeloma. Cancer 2003. © 2003 American Cancer Society. DOI 10.1002/cncr.11701

Progress in cancer screening practices in the United States: results from the 2000 National Health Interview Survey.

Abstract: BACKGROUND Understanding differences in cancer screening among population groups in 2000 and successes or failures in reducing disparities over time among groups is important for planning a public health strategy to reduce or eliminate health disparities, a major goal of Healthy People 2010 national cancer screening objectives. In 2000, the new cancer control module added to the National Health Interview Survey (NHIS) collected more detailed information on cancer screening compared with previous surveys. METHODS Data from the 2000 NHIS and earlier surveys were analyzed to discern patterns and trends in cancer screening practices, including Pap tests, mammography, prostate specific antigen (PSA) screening, and colorectal screening. The data are reported for population subgroups that were defined by a number of demographic and socioeconomic characteristics. RESULTS Women who were least likely to have had a mammogram within the last 2 years were those with no usual source of health care (61%), women with no health insurance (67%), and women who immigrated to the United States within the last 10 years (61%). Results for Pap tests within the last 3 years were similar. Among both men and women, those least likely to have had a fecal occult blood test or endoscopy within the recommended screening interval had no usual source of care (14% for men and 18% for women), no health insurance (20% for men and 18% for women), or were recent immigrants (20% for men and 18% for women). An analysis of changes in test use since the 1987 survey indicates that the disparities are widening among groups with no usual source of care. CONCLUSIONS No striking improvements have been observed for the groups with greatest need. Although screening use for most groups has increased since 1987, major disparities remain. Some groups, notably individuals with no usual source of care and the uninsured are falling further behind; and, according to the 2000 data, recent immigrants also experience a significant gap in screening utilization. More attention is needed to overcome screening barriers for these groups if the population benefits of cancer screening are to be achieved. Cancer 2003;97:1528–40. Published 2003 by the American Cancer Society. DOI 10.1002/cncr.11208

IARC Handbooks of Cancer Prevention

Abstract: The International Agency for Research on Cancer (IARC) was established in 1965 by the World Health Assembly, as an independently funded organisation within the framework of the World Health Organization. The headquarters of the Agency are in Lyon, France. The Agency conducts a programme of research concentrating particularly on the epidemiology of cancer and the study of potential carcinogens in the human environment. Its field studies are supplemented by biological and chemical research carried out in the Agency's laboratories in Lyon and, through collaborative research agreements, in national research institutions in many countries. The Agency also conducts a programme for the education and training of personnel for cancer research. The publications of the Agency contribute to the dissemination of authoritative information on different aspects of cancer research. Information about IARC publications, and how to order them, is available via the Internet at: http:// The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The authors alone are responsible for the views expressed in this publication.

Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.

Abstract: BACKGROUND The objective of the current study was to develop an algorithm to predict progression to metastases after radical nephrectomy for patients with clinically localized renal cell carcinoma (RCC) to allow stratification of patients for potential adjuvant therapy trials. METHODS The authors identified 1671 sporadic patients with clinically localized, unilateral clear cell RCC who underwent radical nephrectomy between 1970 and 2000. The clinical features examined included age, gender, smoking history, recent onset hypertension, performance status, and presenting symptoms. The pathologic features examined included surgical margins, tumor stage, regional lymph node status, tumor size, nuclear grade, histologic tumor necrosis, sarcomatoid component, cystic architecture, and multifocality. Metastases free survival was estimated using the Kaplan–Meier method. A multivariate Cox proportional hazards regression model was fit to determine associations between the clinical and pathologic features and distant metastases. RESULTS The median follow-up was 5.4 years (range, 0–31 years). Metastases occurred in 479 patients at a median of 1.3 years (range, 0–25 years) after nephrectomy. The estimated metastases free survival rates were 86.9% at 1 year, 77.8% at 3 years, 74.1% at 5 years, 70.8% at 7 years, and 67.1% at 10 years. Multivariate analysis showed that the following features were associated with progression to metastases: tumor stage, regional lymph node status, tumor size, nuclear grade, and histologic tumor necrosis (P < 0.001 for all). CONCLUSIONS In patients with clear cell RCC, tumor stage, regional lymph node status, tumor size, nuclear grade, and histologic tumor necrosis showed statistically significant associations with progression to metastatic RCC. The authors present a scoring algorithm based on these features that can be used to predict disease progression after patients undergo radical nephrectomy for clinically localized clear cell RCC. Cancer 2003;97:1663–71. © 2003 American Cancer Society. DOI 10.1002/cncr.11234

Central nervous system metastases in women who receive trastuzumab‐based therapy for metastatic breast carcinoma

Abstract: BACKGROUND: Women with HER-2 overexpressing metastatic breast carcinoma benefit from trastuzumab-based therapy, but trastuzumab does not cross the blood-brain barrier. The authors characterized central nervous system (CNS) disease in these women. METHODS: Using pharmacy records, the authors retrospectively identified 153 women treated with trastuzumab alone or with chemotherapy for HER-2-positive metastatic breast carcinoma at Dana-Farber Partners Cancer Care from June 1998 to December 2000. A study cohort of 122 patients was identified after excluding patients without adequate clinical follow-up or who had CNS disease before trastuzumab treatment. Central nervous system disease was defined as one or more brain metastases or as leptomeningeal carcinomatosis. The median follow-up of this cohort was 23 months. RESULTS: Central nervous system metastases were identified in 34% of patients (95% confidence interval, 26-44%) at a median of 16 months after diagnosis of metastatic breast carcinoma and 6 months from the beginning of trastuzumab therapy. Ninety-three percent of patients with CNS disease presented with clinical symptoms. Five percent of patients with CNS disease had leptomeningeal involvement alone, although 14% had leptomeningeal involvement and parenchymal brain metastases. Fifty percent of patients were responding or had stable disease while receiving trastuzumab at other disease sites at the time of diagnosis of CNS metastasis. The median survival period after CNS metastases was 13 months. Fifty percent of patients died of progressive CNS disease. Patients receiving trastuzumab as first-line therapy for metastatic disease frequently developed brain metastases while responding to or stable on trastuzumab at other disease sites. CONCLUSIONS: Metastatic breast carcinoma to the CNS is common among patients receiving trastuzumab-based therapy, including patients responding to therapy outside the CNS. This may be due either to predilection for the CNS by HER-2-positive tumor cells and/or poor penetration of the CNS by trastuzumab or to improved visceral disease control leading to a longer life and onset of late tumor spread to the CNS. Efforts to characterize other risk factors for development of CNS disease, optimal screening algorithms, and new treatment strategies may be warranted.

Papillary microcarcinoma of the thyroid—Prognostic significance of lymph node metastasis and multifocality

Abstract: BACKGROUND It is known that patients with papillary microcarcinoma (PMC) of the thyroid gland have a very favorable prognosis. The rising incidence of PMC among papillary thyroid carcinoma (PTC) necessitates the identification of prognostic factors and the formulation of treatment protocols. METHODS The authors conducted a retrospective analysis of 203 patients with PMC who were diagnosed on or before 1999 and were treated at the Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong. RESULTS The cause specific survival, locoregional (LR) failure free survival, and distant metastases failure free survival rates at 10 years were 100%, 92.1%, and 97.1%, respectively. Five patients had lung metastases; 2 patients died of their metastases 12.9 years and 14.8 years after diagnosis, and 3 patients achieved clinical remission after radioiodine (RAI) treatment. Twelve patients had LR recurrences. Patients with LR recurrence were highly salvageable with a combination of surgery, RAI treatment, and external radiotherapy; all but one (who refused treatment) were alive without disease at last follow-up. Multivariate analyses did not reveal any independent prognostic factor for survival. The risk of cervical lymph node (LN) recurrence increased 6.2-fold (P = 0.01) and 5.6-fold (P = 0.02) when LN metastases and multifocal disease were present at diagnosis. RAI ablation reduced the LN recurrence rate to 0.27 (P = 0.04). The presence of LN metastasis increased the rate of distant metastasis 11.2-fold (P = 0.03). Age was not a significant factor in predicting disease recurrence or survival. Subdivision by tumor sizes ≤ 5 mm and > 5 mm did not affect the outcome, but no patient with tumors ≤ 5 mm had mortality related to PMC. CONCLUSIONS Despite the overall excellent prognosis for patients with PMC, PMC was associated with a 1.0% disease-related mortality rate, a 5.0% LN recurrence rate, and a 2.5% distant metastasis rate. Therefore, the treatment of patients with PMC should be no different from the treatment of patients with conventional PTC: i.e., complete surgery with consideration for RAI and/or external radiation therapy if poor prognostic factors are present. Cancer 2003;98:31–40. © 2003 American Cancer Society. DOI 10.1002/cncr.11442

Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy.

Abstract: BACKGROUND Neoadjuvant chemotherapy has shown some success in the treatment of gastric carcinoma, but objective parameters for measuring its effects are lacking. The authors performed the current study to determine which histomorphologic features are correlated with patient prognosis after chemotherapy. METHODS Thirty-six patients with gastric carcinoma were treated with a combination of etoposide, doxorubicin, and cisplatin. The entire tumor beds of the specimens were evaluated histologically and compared with specimens treated with surgery alone. Thirty-four patients were available for survival analysis (follow-up period, 60–130 months). RESULTS None of the 36 patients had complete tumor regression, 4 patients had marked regression (less than 10% viable tumor), 9 patients had regression to 10–50% remaining viable tumor, and 23 patients had more than 50% viable tumor remaining. Currently, 9 patients are still alive (5-year survival rate, 27%). Tumor regression was found to be correlated significantly with survival (P = 0.01), but tumor size (P = 0.002) and lymphatic vessel invasion (P = 0.003) were better predictors of prognosis. CONCLUSIONS Histologic tumor regression grade is an objective measure of the effects of neoadjuvant chemotherapy in patients with gastric carcinoma, but its accuracy may be improved by adding additional staging variables such as tumor size and lymphatic vessel involvement. Cancer 2003;98:1521–30. © 2003 American Cancer Society. DOI 10.1002/cncr.11660

Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients.

Abstract: BACKGROUND Prognostic factors for patients with soft-tissue sarcoma who are treated with conservative surgery and radiation are documented poorly. METHODS The clinicopathologic features and disease outcome for 1225 patients with localized sarcoma who were treated with conservative surgery and radiation were reviewed retrospectively. Actuarial univariate and multivariate statistical methods were used to determine significant prognostic factors for local control, metastatic recurrence, and disease specific survival. RESULTS The median follow-up of surviving patients was 9.5 years. The respective local control rates at 5 years, 10 years, and 15 years were 83%, 80%, and 79%. Factors predictive of local recurrence were positive or uncertain resection margins; tumors located in the head and neck and the deep trunk; presentation with local recurrence; patient age > 64 years; malignant fibrous histiocytoma, neurogenic sarcoma. or epithelioid sarcoma histopathology; tumor measuring > 10 cm in greatest dimension; and high pathologic grade. Freedom from metastasis at 5 years, 10 years, and 15 years was 71%, 68%, and 66%, respectively. Factors that were predictive of metastatic recurrence were high tumor grade; large tumor size (> 5 cm); and leiomyosarcoma, rhabdomyosarcoma, synovial sarcoma, or epithelioid sarcoma. The respective disease specific survival rates at 5 years, 10 years, and 15 years were 73%, 68%, and 65%. Adverse factors for disease specific survival were high tumor grade; large tumor size (> 5 cm); tumors located in the head and neck and deep trunk; rhabdomyosarcoma, epithelioid sarcoma, or clear cell sarcoma; patient age > 64 years; and positive or uncertain resection margins. CONCLUSIONS Soft-tissue sarcoma comprises a heterogeneous group of diseases. Prognostic factors for local recurrence, metastatic recurrence, lymph node recurrence, disease free survival, and disease specific survival are different, and optimal treatment strategies need to take this complexity into account. Cancer 2003;10:2530–43. © 2003 American Cancer Society. DOI 10.1002/cncr.11365

The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis.

Abstract: BACKGROUND Mucositis is a common but poorly studied problem among patients with solid tumors. The authors examined the clinical and economic outcomes of oral and gastrointestinal (GI) mucositis among patients receiving myelosuppressive chemotherapy. METHODS A retrospective, random sample of 599 patients who developed chemotherapy-induced myelosuppression was followed for development of oral or GI mucositis and for development of subsequent episodes of bleeding or infection. Multilevel regression models of the risk of bleeding and infection were fit with chemotherapy cycles nested within patients. RESULTS Mucositis developed during 37% of 1236 cycles of chemotherapy. Episodes of bleeding were significantly more common during cycles with GI mucositis than during cycles without GI mucositis (13% vs. 8%; P = 0.04). Episodes of infection were significantly more common during cycles with mucositis (especially GI mucositis) than during cycles without mucositis (73% vs. 36%; P < 0.0001). The mean durations of hospitalization were 4 days, 6 days, and 12 days during cycles with no mucositis, oral mucositis, and GI mucositis, respectively. After accounting for the depth and duration of myelosuppression and for other predictive factors, GI mucositis was associated with both bleeding (odds ratio [OR], 2.0; P = 0.01) and infection (OR, 2.24; P < 0.0001), whereas oral mucositis was associated with infection only (OR, 2.4; P < 0.0001). CONCLUSIONS Mucositis was clinically and economically significant among patients with solid tumors who were receiving myelosuppressive chemotherapy. New preventive and therapeutic agents are needed. Cancer 2003;98:1531–9. © 2003 American Cancer Society. DOI 10.1002/cncr.11671

Physical activity levels before and after a diagnosis of breast carcinoma: The health, eating, activity, and lifestyle (HEAL) study

Abstract: Background Increased body weight at the time patients are diagnosed with breast carcinoma has been associated with an increased risk of recurrence and reduced survival. Weight gain also is common after diagnosis. Increasing physical activity (PA) after diagnosis may minimize these adverse outcomes. In this population-based study, the authors investigated whether PA levels after diagnosis declined from prediagnosis levels and whether any changes in PA varied by disease stage, adjuvant treatment, patient age, or body mass index (BMI) in 812 patients with incident breast carcinoma (from in situ to Stage IIIa). Methods Types of sports and household activities and their frequency and duration for the year prior to diagnosis and for the month prior to the interview (i.e., 4-12 months postdiagnosis) were assessed during a baseline interview. Results Patients decreased their total PA by an estimated 2.0 hours per week from prediagnosis to postdiagnosis, an 11% decrease (P Conclusions PA levels were reduced significantly after patients were diagnosed with breast carcinoma. Greater decreases in PA observed among heavier patients implied a potential for greater weight gain among women who already were overweight. Randomized, controlled trials are needed to evaluate how PA may improve the prognosis for patients with breast carcinoma.

Cancer-related fatigue: Evolving concepts in evaluation and treatment

Abstract: BACKGROUND Although fatigue is one of the most common complaints of patients with cancer, it went unrecognized or overlooked for many years, until clinicians achieved better control over the more acute symptoms of nausea, emesis, and pain. A number of treatment-related and disease-related factors may contribute to the development of fatigue, but its physiologic basis remains poorly understood, and many proposed interventions have not been studied systematically. The lack of a standard of care for the assessment or treatment of fatigue in patients with cancer has limited research in this field. A critical appraisal of these issues is presented in this review. METHODS The published literature was reviewed for definition, prevalence, causes, and means of managing cancer-related fatigue (CRF). RESULTS Fatigue was reportedly present at the time of diagnosis in approximately 50–75% of cancer patients. The prevalence of CRF increased to 80–96% in patients undergoing chemotherapy and to 60–93% in patients receiving radiotherapy. Two tested interventions that showed consistent effects to alleviate CRF were treatment of cancer-related anemia with erythropoietin agents (recombinant human erythropoietin and darbepotin α) and aerobic exercise. CONCLUSIONS Several lines of research are needed to bridge the specific gaps in the current knowledge of CRF. These involve the pathophysiology of the symptom, the validation of diagnostic criteria, and specific therapeutic interventions. Current practice guidelines are based on a combination of research and expert clinical judgment and should be used to guide care with the expectation that they will evolve to incorporate the results of studies currently underway. Cancer 2003. © 2003 American Cancer Society.

Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America.

Abstract: BACKGROUND Aprepitant is a novel neurokinin 1 (NK1) antagonist that has been shown to improve control of chemotherapy-induced nausea and vomiting (CINV) when added to a standard antiemetic regimen of a 5-hydroxytriptamine-3 antagonist plus a corticosteroid. The authors sought to evaluate further the efficacy and tolerability of aprepitant plus standard therapy in a large clinical trial. METHODS This was a multicenter, randomized, double-blind, placebo-controlled, parallel-groups, Phase III study. Patients with cancer who were scheduled to receive treatment with high-dose cisplatin chemotherapy were randomized to receive 1 of 2 treatment regimens; the standard therapy group received intravenous ondansetron 32 mg and oral dexamethasone 20 mg on Day 1, and oral dexamethasone 8 mg twice daily on Days 2–4. The aprepitant group received oral aprepitant 125 mg, intravenous ondansetron 32 mg, and oral dexamethasone 12 mg on Day 1; oral aprepitant 80 mg and oral dexamethasone 8 mg once daily on Days 2–3; and oral dexamethasone 8 mg on Day 4. Patients recorded episodes of emesis, use of rescue therapy, and severity of nausea in a diary. A modified intent-to-treat approach was used to analyze the efficacy data. The primary endpoint was complete response (no emesis and no rescue therapy) during the 5-day period postcisplatin. Treatment comparisons were made using logistic regression models, and reported adverse events and physical and laboratory assessments were used to assess tolerability. RESULTS A total of 523 patients were evaluated for efficacy, and 568 patients were evaluated for safety. During the 5 days after chemotherapy, the percentages of patients who achieved a complete response were 62.7% in the aprepitant group (163 of 260 patients) versus 43.3% in the standard therapy group (114 of 263 patients; P < 0.001). For Day 1, the complete response rates were 82.8% for the aprepitant group and 68.4% for the standard therapy group (P < 0.001); for Days 2–5, the complete response rates were 67.7% in the aprepitant group and 46.8% in the standard therapy group (P < 0.001). The overall incidence of adverse events was similar between the 2 treatment groups (72.8% in the aprepitant group [206 of 283 patients] and 72.6% in the standard therapy group [207 of 285 patients]) as were rates of serious adverse events, discontinuations due to adverse events, and deaths. CONCLUSIONS In patients with cancer who are receiving high-dose cisplatin-based chemotherapy, therapy consisting of aprepitant (125 mg on Day 1 and 80 mg on Days 2–3) plus a standard regimen of ondansetron and dexamethasone provided superior antiemetic protection compared with standard therapy alone and was generally well tolerated. Cancer 2003;97:3090–8. © 2003 American Cancer Society. DOI 10.1002/cncr.11433

Use of arsenic trioxide (As2O3) in the treatment of patients with acute promyelocytic leukemia: the M. D. Anderson experience.

Abstract: BACKGROUND Approximately 20–30% of patients with acute promyelocytic leukemia (APL) who are treated with all-trans retinoic acid (ATRA) and an anthracycline develop recurrent disease. It has been reported that arsenic trioxide (As2O3) is effective in this setting. The authors report the experience of The M. D. Anderson Cancer Center with As2O3 in the treatment of patients with recurrent APL. METHODS Twelve patients who developed recurrent APL after treatment with ATRA were included. Patients received intravenous As2O3 0.15 mg/kg per day until they achieved a complete remission (CR) or up to a maximum of 60 days. Their median age was 44 years (range, 26–72 years), and the median duration of first remission was 52 weeks (range, 23–292 weeks). RESULTS All 12 patients achieved a CR. The median time to achieve CR was 52 days (range, 27–75 days). Seven of 10 evaluable patients achieved a molecular remission (i.e., polymerase chain reaction [PCR] analysis was negative for the gene encoding fusion of the nuclear receptor for retinoic acid to the PML gene at the time of CR; 70% of patients; 95% confidence interval, 0.35–0.93), and all other patients had negative PCR results after they received postremission therapy. All patients received subsequent therapy: Four patients received As2O3 alone, six patients received As2O3 with other chemotherapeutic agents, and two patients received idarubicin plus ATRA without As2O3. Eight patients continued in CR after a median follow-up of 24 months (range, 9–45 months). Side effects were mild, except for two patients who developed Grade 2 and 3 peripheral neuropathy, respectively; one of those patients required discontinuation of therapy. CONCLUSIONS As2O3 is effective and well tolerated therapy for patients with recurrent APL. Molecular remission may be achieved at the time of CR in the majority of patients, and remissions are durable. Cancer 2003;97:2218–24. © 2003 American Cancer Society. DOI 10.1002/cncr.11314

Levels of Hypoxia-Inducible Factor-1α Independently Predict Prognosis in Patients with Lymph Node Negative Breast Carcinoma

Abstract: BACKGROUND Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF-1α, the O2-regulated subunit of HIF-1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF-1α expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated. METHODS Expression levels of HIF-1α, HER-2/neu, estrogen receptor, and progesterone receptor were analyzed in 150 patients with early-stage breast carcinoma by immunohistochemistry. HER-2/neu gene amplification was investigated with automated fluorescent in situ hybridization. The mitotic activity index, histologic grade, and tumor type were assessed in hematoxylin and eosinstained specimens. Clinical data included disease-free survival, overall survival, lymph node status, and tumor size. The data were analyzed with two-sided univariate and multivariate tests, with P values < 0.05 considered significant. RESULTS High levels of HIF-1α had an association of borderline significance with decreased overall survival (P = 0.059) and disease-free survival (P = 0.110) that was ascribed completely to the subgroup of women with lymph node negative tumors (n = 81 patients; P = 0.008 and P = 0.004, respectively). HER-2/neu immunoreactivity (P < 0.001) and gene amplification (P < 0.001), vascular endothelial growth factor expression (P = 0.016), and Ki-67 expression (P < 0.001) were correlated strongly with HIF-1α positivity, although none of those factors had an independent effect on survival. CONCLUSIONS Increased levels of HIF-1α were associated independently with shortened survival in patients with lymph node negative breast carcinoma. Therefore, the use of immunohistochemical assessment of HIF-1α as a new predictor of poor outcome may improve clinical decision-making regarding adjuvant treatment of patients with lymph node negative breast carcinoma. Cancer 2003;97:1573–81. © 2003 American Cancer Society. DOI 10.1002/cncr.11246

Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms

Abstract: BACKGROUND Cancers and cancer treatments produce multiple symptoms that collectively cause a symptom burden for patients. These symptoms include pain, wasting, fatigue, cognitive impairment, anxiety, and depression, many of which co-occur. There is growing recognition that at least some of these symptoms may share common biologic mechanisms. METHODS In November 2001, basic and clinical scientists met to consider evidence for a cytokine-immunologic model of symptom expression along with directions for future research. RESULTS The characteristics of cytokine-induced sickness behavior in animal models have much in common with those of symptomatic cancer patients. Sickness behavior refers to a set of physiologic and behavioral responses observed in animals after the administration of infectious or inflammatory agents or certain proinflammatory cytokines. In some cases, these responses can be prevented by cytokine antagonists. A combination of animal and human research suggests that several cancer-related symptoms may involve the actions of proinflammatory cytokines. CONCLUSIONS Based on the similarities between cancer symptoms and sickness behavior, the authors discussed approaches to further test the implications of the relationship between inflammatory cytokines and symptoms for both symptom treatment and symptom prevention. Cancer 2003;97:2919–25. © 2003 American Cancer Society. DOI 10.1002/cncr.11382

Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial.

Abstract: BACKGROUND Between 1979–1987, the National Cancer Institute conducted a randomized, prospective study of mastectomy (MT) versus breast conservation therapy (BCT) in the treatment of patients with early-stage breast carcinoma. After a median potential follow-up of 18.4 years, the authors present the updated results. METHODS After informed consent was obtained from each patient, 237 evaluable women with clinical AJCC Stage I and Stage II breast carcinoma were enrolled on an institutionally reviewed protocol and randomly assigned to undergo modified radical MT (116 patients) or BCT (121 patients), which was comprised of lumpectomy, axillary lymph node dissection, and radiation therapy. Negative surgical margins in the lumpectomy arm were not required. The 237 randomized patients were followed for a median potential follow-up of 18.4 years. The primary endpoints were overall survival and disease-free survival. RESULTS At a median follow-up of 18.4 years, there was no detectable difference with regard to overall survival between patients treated with MT and those treated with BCT (58% vs. 54%; P = 0.67 overall). Twenty-seven women in the BCT arm (22%) experienced an in-breast event. After censoring in-breast events in the BCT arm that were salvaged successfully by MT, disease-free survival also was found to be statistically similar (67% in the MT arm vs. 63% in the BCT arm; P = 0.64 overall). There was no statistically significant difference with regard to contralateral breast carcinoma between the two treatment arms (P = 0.70). CONCLUSIONS After nearly 20 years of follow-up, there was no detectable difference in overall survival or disease-free survival in patients with early-stage breast carcinoma who were treated with MT compared with those treated with BCT. For BCT patients, long-term in-breast failures continued to occur throughout the duration of follow-up. There was no statistically significant difference in the incidence of contralateral breast carcinoma between the two treatment groups. Cancer 2003;98:697–702. Published 2003 by the American Cancer Society. DOI 10.1002/cncr.11580

CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression.

Abstract: BACKGROUND Active suppression by CD4+CD25+ regulatory T cells plays an important role in the down-regulation of the response of T cells to foreign and self antigens. Experimental tumor models in mice revealed that regulatory T cells inhibit antitumor immune responses. The purpose of the current study was to demonstrate the possible involvement of CD4+CD25+ regulatory T cells in immune system impairment in patients with gastrointestinal malignancies. METHODS The phenotypes of lymphocytes, particularly those of CD4+CD25+ T cells, were analyzed in peripheral blood in 149 patients with gastrointestinal malignancies and in ascites in 7 patients with peritoneal dissemination. In addition, cytokine production after in vitro stimulation was examined in CD4+CD25+ and CD4+CD25− T cells isolated from patients with malignant disease. RESULTS Compared with healthy volunteers, patients with gastrointestinal malignancies had a higher proportion of CD4+CD25+ T cells in peripheral blood, due to the presence of a drastically smaller number of CD4+CD25− T cells. Among patients with gastric carcinoma, those with higher percentages of CD4+CD25+ T cells had a poorer prognosis than did those with lower percentages. CD4+CD25+ T cells also were present in greater proportions in ascites from patients who had advanced-stage disease with peritoneal dissemination. Isolated CD4+CD25+ T cells from patients with malignant disease produced interleukin (IL)-4 and IL-10 but not IL-2 or interferon-γ; these cells also inhibited cytokine production by CD4+CD25− T cells after in vitro stimulation. CONCLUSIONS The relative increase in CD4+CD25+ regulatory T cells may be related to immunosuppression and tumor progression in patients with gastrointestinal malignancies. This finding suggests that the use of immunomodulatory therapy to treat patients with gastrointestinal malignancies may be an effective strategy. Cancer 2003;98:1089–99. © 2003 American Cancer Society. DOI 10.1002/cncr.11618

Evaluation of an internet support group for women with primary breast cancer.

Abstract: BACKGROUND Women with breast carcinoma commonly experience psychologic distress following their diagnosis Women who participate in breast cancer support groups have reported significant reduction in their psychologic distress and pain and improvement in the quality of their lives Web-based breast cancer social support groups are widely used, but little is known of their effectiveness Preliminary evidence suggests that women benefit from their participation in web-based support groups METHODS Seventy-two women with primary breast carcinoma were assigned randomly to a 12-week, web-based, social support group (Bosom Buddies) The group was semistructured, moderated by a health care professional, and delivered in an asynchronous newsgroup format RESULTS The results indicate that a web-based support group can be useful in reducing depression and cancer-related trauma, as well as perceived stress, among women with primary breast carcinoma The effect sizes ranged from 038 to 054 Participants perceived a variety of benefits and high satisfaction from their participation in the intervention CONCLUSIONS This study demonstrated that the web-based program, Bosom Buddies, was effective in reducing participants' scores on depression, perceived stress, and cancer-related trauma measures The effect size of the intervention was in the moderate range Although web-based social support groups offer many advantages, this delivery mechanism presents a number of ethical issues that need to be addressed Cancer 2003;97:1164–73 © 2003 American Cancer Society DOI 101002/cncr11174

Pathology and classification of ovarian tumors.

Abstract: *This article is a US Government work and, as such, is in the public domain of the United States of America. Knowledge of the embryology and microscopic anatomy of the ovary is fundamental to the understanding of the various cancer types that originate in this organ. A complete description of the embryology and anatomy of the ovary is beyond the scope of this monograph; however, comprehensive reviews are available for those who seek more detail. The current discussion focuses on key developmental events and anatomic features that shed light on the natural history of ovarian cancers. At approximately five weeks of gestation, thickenings of the lining of the posterior embryonic body cavity, the coelomic epithelium, form the genital ridges. Continued proliferation of the coelomic epithelium into the underlying primitive connective tissue, known as the mesenchyme, leads to the formation of the primordial indifferent gonads. Cells from adjacent transient embryonic structures, known as mesonephros, concurrently invade the mesenchyme, and the primordial germ cells arrive after a long journey that starts at their place of origin in the yolk sac and takes the cells along the distal embryonic intestine and the posterior wall of the embryonic body cavity. The different tumor types that arise in the ovary are linked to the different cell types that are present at this stage of development: coelomic epithelial, mesenchymal, mesonephric, and germ cells. Ovaries and testes develop in similar fashion until approximately the fourth month of embryonic life. This finding explains the origin of tumors that are commonly associated with testicular tissue but appear in the ovaries and vice versa. At two months gestation, the primitive gonad is recognized as an ovary because of the lack of development of the well-defined testicular sex cords. Instead, mesonephric cells and germ cells remain closely associated, forming illdefined ovarian sex cords embedded in the primitive mesenchyme. The coelomic epithelium remains at the periphery, enwrapping the developing ovary. In the adult, the ovaries are flat, nodular, oval structures that measure between 3 and 5 cm in their greatest dimension and weigh between 2 and 4 g. They are suspended by peritoneal folds and ligaments on either side of the uterus and attached to the back of the broad ligament of the uterus, behind and below the uterine tubes. A single layer of cells, the surface epithelium, which is derived from the coelomic epithelium, lines their external surface. A dense, fibrous tissue, the stroma, which is derived from the mesenchyme, makes up most of their internal substance. The germ cells, also known as oocytes, are located near the periphery of the stroma. The granulosa cells, specialized cells of probable mesonephric origin that are derived from the sex cords, surround the germinal cells that form the follicles. The stroma immediately surrounding the follicles differentiates into plum elongated cells known as theca cells. When stimulated, theca 2631

Improved survival in women with BRCA-associated ovarian carcinoma.

Abstract: BACKGROUND The objective of this study was to determine the clinical characteristics, treatment response, and frequency of p53 overexpression in Ashkenazi Jewish women with hereditary ovarian carcinoma. METHODS Seventy-one Jewish women with epithelial ovarian carcinoma (EOC) were tested for the three BRCA founder mutations using single-strand conformation polymorphism analysis, heteroduplex analysis, and protein truncation testing. Clinical and histopathologic data were reviewed retrospectively. In vitro chemoresistance was analyzed in 32 patients. Mutations of p53 were studied using immunohistochemical detection of p53 overexpression. RESULTS Thirty-four of 71 Jewish patients with EOC (48%) had germline BRCA mutations (BRCA heterozygotes), including 22 BRCA1 mutations and 12 BRCA2 mutations. BRCA heterozygotes were younger compared with Jewish patients who had EOC without mutations (sporadic carcinoma; 50 years vs. 59 years, respectively; P = 0.01). BRCA1 heterozygotes were younger compared with BRCA2 heterozygotes (48 years vs. 57 years, respectively; P = 0.01). Histopathologic tumor features were similar; however, tumors with low malignant potential were seen only in women with sporadic carcinoma. Both groups had equivalent rates of surgical cytoreduction and similar median follow-up (72 months). BRCA heterozygotes had higher response rates to primary therapy compared with patients who had sporadic disease (P = 0.01). In vitro chemoresistance predicted tumor response to platinum chemotherapy correctly in BRCA heterozygotes (P = 0.0096). BRCA heterozygotes with advance-stage disease had improved survival compared with patients who had advanced stage sporadic carcinoma (91 months vs. 54 months, respectively; P = 0.046) and had a longer disease free interval (49 months vs. 19 months, respectively; P = 0.16). p53 overexpression was common in BRCA heterozygotes (80%). CONCLUSIONS BRCA1 heterozygotes developed EOC at a younger age compared with BRCA2 heterozygotes and women who had sporadic ovarian carcinoma. BRCA heterozygotes had a better response to platinum chemotherapy compared with women who had sporadic disease, which may have contributed to their improved prognosis. Cancer 2003;97:2187–95. © 2003 American Cancer Society. DOI 10.1002/cncr.11310

Cancer in Fanconi anemia, 1927–2001

Abstract: BACKGROUND Fanconi anemia (FA) is an autosomal recessive disease associated with an abnormal response to DNA damage. Although FA is well known for the association of aplastic anemia and characteristic birth defects, leukemia and solid tumors also occur at a high rate in this group of patients. A review of all reported cases is informative with regard to the specific types of cancer, the ages at which they occur, and the cumulative probability of their development. METHODS Medline and bibliographies of publications were searched for articles containing “Fanconi's anemia” or “aplastic anemia” and all cases of FA from 1927 through 2001 were included in the database. Cancer cases were identified within these reports. Descriptive statistical analyses were performed using Stata7 software. RESULTS One thousand three hundred cases of FA were identified. Nine percent had leukemia (primarily acute myeloid leukemia), 7% had myelodysplastic syndrome, 5% had solid tumors, and 3% had liver tumors. Patients with cancer were older than the cancer-free patients at the time of diagnosis of FA. The median age for cancer (including leukemia) was 16, compared with 68 in the general population. The most frequent solid tumors were aerodigestive and gynecological carcinomas. In approximately 25% of patients with cancer, the malignancy preceded the diagnosis of FA. CONCLUSIONS If the competing risks of aplastic anemia and leukemia could be removed, the estimated cumulative probability of development of a solid tumor in FA patients is 76% by the age of 45 years. Carcinogenic pathways and cancer prevention, surveillance, and treatment can be studied to advantage in this genetic model of human cancer. Cancer 2003;97:425–40. Published 2003 by the American Cancer Society. DOI 10.1002/cncr.11046

Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies.

Abstract: BACKGROUND Current approaches to adjuvant treatment after resection of gallbladder carcinoma (GBCA) and hilar cholangiocarcinoma (HCCA) are based on an incomplete understanding of the recurrence patterns of these diseases. Through an in-depth analysis of the sites of initial recurrence after resection of GBCA and HCCA, the current study aimed to highlight differences in the biology of these tumors and to provide further insight for adjuvant therapeutic strategies. METHODS Patients with either GBCA or HCCA who underwent a potentially curative resection were identified prospectively from a maintained database. Specific sites of initial disease recurrence were identified retrospectively and categorized as locoregional (resection margin, porta hepatis, or retroperitoneal lymph nodes) or distant (peritoneal, extraabdominal, or discontiguous liver metastases). Differences in disease recurrence patterns, time to disease recurrence, and overall and site-specific survival were analyzed. RESULTS Between May 1990 and August 2001, 177 patients underwent potentially curative resection, 97 for GBCA and 80 for HCCA. Disease recurrence and follow-up data were available for 156 patients (80 with GBCA and 76 with HCCA). The median time to disease recurrence was shorter for patients with GBCA compared with patients with HCCA (11.5 vs. 20.3 months; P = 0.007). Overall, 52 (68%) patients with HCCA and 53 (66%) patients with GBCA had disease recurrene at a median follow-up of 24 months. Of those who developed disease recurrence, isolated locoregional disease as the first site of failure occurred in 15% of patients with GBCA compared with 59% of patients with HCCA (P < 0.001). By contrast, an initial GBCA recurrence involving a distant site, with or without concomitant locoregional recurrence, occurred in 85% of patients compared with 41% of patients with HCCA (P < 0.001). This pattern of disease recurrence was diagnosis specific and did not change significantly when patients were stratified by several clinicopathologic factors, including disease stage and its component variables. Using multivariate analysis, diagnosis was an independent predictor of the site of disease recurrence. Among patients who experienced disease recurrence, survival was greater among the patients with HCCA compared with patients with GBCA (29 months vs. 20.6 months, respectively; P = 0.037). For both tumors, the site of initial disease recurrence had no apparent impact on survival time. CONCLUSIONS After resection, recurrent GBCA is much more likely than recurrent HCCA to involve a distant site. GBCA is also associated with a much shorter time to recurrence and a shorter survival period after recurrence. The results demonstrated significant differences in the clinical behavior of these tumors and suggested that an adjuvant therapeutic strategy targeting locoregional disease, such as radiotherapy, is unlikely to have a significant impact in the overall management of GBCA. Conversely, there is at least some rationale for such an approach in patients with HCCA based on the pattern of initial recurrence. Cancer 2003. © 2003 American Cancer Society. DOI 10.1002/cncr.11699

Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron.

Abstract: BACKGROUND. Palonosetron, a highly selective and potent 5-HT3 receptor antagonist with a strong binding affinity and a long plasma elimination half-life (approximately 40 hours), has shown efficacy in Phase II trials in preventing chemotherapy-induced nausea and vomiting (CINV) resulting from highly emetogenic chemotherapy. The current Phase III trial evaluated the efficacy and safety of palonosetron in preventing acute and delayed CINV after moderately emetogenic chemotherapy. METHODS. In the current study, 592 patients were randomized to receive a single, intravenous dose of palonosetron 0.25 mg, palonosetron 0.75 mg, or dolasetron 100 mg, 30 minutes before receiving moderately emetogenic chemotherapy. The primary efficacy endpoint was the proportion of patients with a complete response (CR; defined as no emetic episodes and no rescue medication) during the first 24 hours after chemotherapy. Secondary endpoints included assessment of prevention of delayed emesis (2–5 days postchemotherapy). RESULTS. In the current study, 569 patients received study medication and were included in the intent-to-treat efficacy analyses. CR rates during the first 24 hours were 63.0% for palonosetron 0.25 mg, 57.1% for palonosetron 0.75 mg, and 52.9% for dolasetron 100 mg. CR rates during the delayed period (24 –120 hours after chemotherapy) were superior for palonosetron compared with dolasetron. Adverse events (AEs) were mostly mild to moderate and not related to study medication, with similar incidences among groups. There were no serious drug-related AEs. CONCLUSIONS. A single dose of palonosetron is as effective as a single dose of dolasetron in preventing acute CINV and superior to dolasetron in preventing delayed CINV after moderately emetogenic chemotherapy, with a comparable safety profile for all treatment groups. Cancer 2003;98:2473– 82. © 2003 American Cancer Society.

Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center.

Abstract: BACKGROUND The current study was performed to determine whether tumor mitotic rate (TMR) is a useful, independent prognostic factor in patients with localized cutaneous melanoma. METHODS From the Sydney Melanoma Unit database, 3661 patients with complete clinical information and details of primary tumor thickness, ulcerative state, and TMR were studied. TMR was expressed as mitoses per mm2 in the dermal part of the tumor in which most mitoses were seen, as recommended in the 1982 revision of the 1972 Sydney classification of malignant melanoma. To determine which was the more prognostically useful method of grouping TMR, two separate methods (A and B) were used. Factors predicting melanoma-specific survival were analyzed using the Cox proportional hazards regression model. RESULTS Patients with a TMR of 0 mitoses/mm2 had a significantly better survival than those with 1 mitosis/mm2 (P < 0.0001) but no significant survival differences were recorded for the stepwise increases from 1–2, 2–3, 3–4, and 4–5/mm2. Tumor thickness, ulceration, and TMR were closely correlated, whether TMR was grouped using Method A (0, 1–4, 5–10, and ≥ 11 mitoses/mm2) or Method B (0–1, 2–4, and ≥ 5 mitoses/mm2). However, Cox regression analysis indicated that the TMR was a highly significant independent prognostic factor, particularly when grouped according to Method A, in which it was second only to tumor thickness as the most powerful predictor of survival (P < 0.0001). CONCLUSIONS TMR is an important independent predictor of survival for melanoma patients. If confirmed by studies from other centers, it has the potential to further improve the accuracy of melanoma staging, as well as to define more rigidly the risk categories for patients entering clinical trials. Cancer 2003;97:1488–98. © 2003 American Cancer Society. DOI 10.1002/cncr.11196

Insights into the mechanisms of lymph node metastasis.

Abstract: The mechanisms by which malignant tumors leave the primary tumor site, invade lymphatics, and metastasize to regional lymph nodes (RLNs) are complex and interrelated. Although the phenomenon of lymph node metastasis has been recognized for over 200 years, the exact mechanisms have only recently been the subject of intense interest and sophisticated experimentation. Sentinel lymph node biopsy has rapidly entered the clinical mainstream for melanoma and breast carcinoma, and this technique has provided confirmation of the orderly anatomic progression of tumor cells from primary site to the RLNs through lymphatic capillaries and trunks. Exciting studies involving the pathophysiology of interstitial fluid pressure in tumors and the peritumoral extracellular matrix have focused on lymphatic flow and tumor microenvironment and microcirculation. Molecular techniques have led to the definition of unique markers found on lymphatic endothelial cells. These markers have enabled scientists to identify peritumoral and intratumoral lymphatics and to visualize the ingrowth of tumor cells into the lumena of lymphatic capillaries. Tumor-secreted cytokines, such as vascular endothelial growth factors (VEGF)-C and -D, bind to VEGF receptors on lymphatic endothelial cells and induce proliferation and growth of new lymphatic capillaries; this process is similar to the well-known mechanism of angiogenesis, which results from the proliferation of new blood vessel capillaries. Lymphangiogenesis is associated with an increased incidence of RLN metastasis, and it is possible that this step is essential to the metastatic process. Directional movement toward lymphatics and lymph nodes appears to follow a chemokine gradient, and it is likely that some tumor cells that express certain types of chemokine receptors are more likely to metastasize to the RLNs. In contrast, tumor cells that do not express specific receptors that are responsive to lymphatic chemokines may not metastasize. New knowledge regarding the molecules involved in these processes should enable improvements in prognostic and possibly therapeutic approaches to the management of malignant tumors.

A Phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases

Abstract: BACKGROUND Osteoprotegerin (OPG) is a decoy receptor for OPG ligand (OPGL), or receptor activator of NF-κB ligand (RANKL) RANKL/RANK interaction is important in terminal differentiation and activation of osteoclasts In binding to RANKL, OPG blocks differentiation and activation of osteoclasts AMGN-0007 is a recombinant OPG construct developed as a potential therapeutic agent in the treatment of bone disease METHODS A randomized, double-blind, double-dummy, active-controlled, single-dose, dose escalation study was conducted to determine the safety and effect on bone resorption of AMGN-0007 in patients with multiple myeloma (n = 28) or breast carcinoma (n = 26) with radiologically confirmed lytic bone lesions Patients were randomized (3:1 ratio) to receive a single dose of either AMGN-0007 (subcutaneously [SC]) or pamidronate (90 mg intravenously) and were followed for 56 days Medications or other diseases affecting bone metabolism and chemotherapy within 28 days of dosing were exclusion criteria Biologic activity of AMGN-0007 was assessed by measurement of the surrogate marker of bone resorption, urinary N-telopeptide of collagen (NTX) RESULTS AMGN-0007 caused a rapid, sustained, dose-dependent decrease in NTX/creatinine levels, which was at least comparable to the profile observed with pamidronate Four serious adverse events were reported, three in breast carcinoma patients: a fracture in the left femur (pamidronate, considered unrelated), extreme fatigue (03 mg/kg AMGN-0007, considered unrelated), and congestive heart failure (10 mg/kg AMGN-0007, considered by the investigator to be probably related to doxorubicin and radiation therapy); one event occurred in a multiple myeloma patient: Herpes zoster (pamidronate, considered unrelated) Two multiple myeloma patients (10 mg/kg AMGN-0007) had albumin-adjusted serum calcium levels of 19 mmol/L on Day 8 but without clinical symptoms CONCLUSIONS A single SC dose of AMGN-0007 suppressed bone resorption as indicated by a rapid, sustained, and profound decrease of urinary NTX/creatinine in multiple myeloma and breast carcinoma patients Changes were comparable to those with pamidronate AMGN-0007 was well tolerated Cancer 2003;97(3 Suppl):887–92 © 2003 American Cancer Society DOI 101002/cncr11138

Pattern of recurrence following complete resection of esophageal carcinoma and factors predictive of recurrent disease

Abstract: BACKGROUND Despite increasingly radical surgery for esophageal carcinoma, a large number of patients still experience recurrent disease soon after operation. The current study was undertaken to evaluate the pattern of recurrence after curative esophagectomy for cancer of the thoracic esophagus and to identify factors predictive of recurrent disease. METHODS A total of 439 consecutive patients discharged from the authors' institution following R0 resection between January 1982 and July 2002 were followed for evidence of recurrence over a mean interval of 37.3 (range, 1–207) months. RESULTS Overall 1-, 3- and 5-years survival rates were 91%, 54%, and 41%, respectively. Some 230 patients (52.4%) developed proven recurrence, of whom 24 were alive and 206 were dead at the time of writing. The median time to recurrence was 12.0 (range, 6–96) months, with a median survival thereafter of 7.0 (range, 0–83) months. The pattern of recurrence was local in 12.1%, regional in 20.5% (cervical 3.6%, mediastinal 14.8%, and abdominal 2.1%), and distant in 19.8%, respectively. The overall pattern of dissemination was significantly different according to the histologic subtype (P = 0.021). One hundred five (45.7%) of all recurrences occurred within 12 months of surgery, with local, regional, and distant recurrence occurring at a median of 14.0 (range, 6–77), 13.5 (range, 6–73), and 11.0 (range, 6–96) months, respectively; A factor predictive of recurrent disease was histologic tumor depth invasion (P = 0.001). CONCLUSIONS Depth of tumor invasion should be used to identify patients who will have recurrence within 12 months of operation, so that these patients may be either entered into trials of multimodality treatment or offered nonsurgical palliation. Cancer 2003;97:1616–23. © 2003 American Cancer Society. DOI 10.1002/cncr.11228