BETHESDA, MarylandNewly released data show that the nation’s mortality rate for all cancers combined, which declined between 1994 and 1998, remained stable from 1998 through 2000. However, the mortality rate for the four leading malignancies in the United Stateslung, female breast, prostate, and colorectalcontinued to decline in the late 1990s, according to the "Annual Report to the Nation on the Status of Cancer, 1975-2000."

Mortality for cancer of the lung and bronchus dropped 25% for both sexes of all ages and races in the 5-year span 1996 to 2000, followed by prostate (19.8%), breast (17.6%), and colorectal (11.8%). Death rates for the four cancers declined in most states as well as nationally.

The overall cancer incidence essentially continued to plateau at the level reached in the mid-1990s, although a slight increase occurred between 1995 and 2000 that was not statistically significant. The newest data show that an increase in breast cancer incidence among women and prostate cancer in men offset a continuing long-term decrease in the incidence of male lung cancer.

The annual report on cancer statistics is a collaborative effort of the American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute, and the North American Association of Central Cancer Registries. The 2003 report includes incidence data from 34 statewide cancer registries that cover 68% of the US population, up from 55% in 2002. Mortality data came from state vital statistics offices consolidated by CDC’s National Vital Statistics System.

Each year, the report highlights the cancer statistics related to the four major cancers, which account for about 50% of the nation’s cancer burden. Findings include:

 Mortality continued to decrease among men, and the rate of increase slowed among women.

 Death rates continued to decline in spite of a gradual increase in the rate of new diagnoses. The decline is attributed, at least in part, to the increase in screening mammography and improved access to treatment. However, death rates remained substantially lower for white women than for black women. The highest rate of increase in breast cancer incidence since the late 1970s has occurred in the 65 to 74 age group.

 Mortality has declined since 1994. However, incidence has risen since 1995as the result of an increase in the diagnosis of localized diseaseat an annual rate of 3.0% for white men and 2.3% for black men. The incidence of other stages of prostate cancer has continued to drop.

 Death rates began declining for both whites and blacks in the 1970s, and in the mid-1980s the decrease accelerated. However, white men and women continued to show a greater decrease in mortality than black men and women. Incidence rates have remained stable since 1996 for all men and women.

The incidence of other cancers between 1995 through 2000for both sexes and all ages and racesincluded declines in oral cavity and pharynx (9.3%), leukemia (7.3%), cervix (6.0%), corpus and uterus (4.9%), non-Hodgkin’s lymphoma (4.8%), pancreas (4.1%), stomach (3.4%), ovary (1.9%), and brain (0.8%). Cancer with increased incidence for the same period included melanoma (4.4%) and urinary bladder (4.5%).

While most cancers showed a drop in mortality, the rate for pancreatic cancer rose 7.3%.

Both incidence and mortality rates varied considerably among racial and ethnic groups. For example, lung cancer incidence and mortality rates per 100,000, respectively, were 63.2 and 56.7 for whites; 81.2 and 66.4 for blacks; 43.2 and 28.5 for Asians and Pacific Islanders; 33.1 and 37.2 for American Indians and Alaskan Natives; and 33.2 and 25.8 for Hispanics.

For female breast cancer, incidence ranged from 140.8 for whites to 58.0 for American Indians and Alaska Natives, and mortality ranged from 35.9 for blacks to 12.5 for Asians and Pacific Islanders.

Prostate cancer incidence ranged from 272.1 for blacks down to 53.6 in American Indians and Alaska Natives, while mortality ranged from 73.0 in blacks to 13.9 in Asians and Pacific Islanders.

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BETHESDA, Maryland&#151;Newly released data show that the nation’s mortality rate for all cancers combined, which declined between 1994 and 1998, remained stable from 1998 through 2000. However, the mortality rate for the four leading malignancies in the United States&#151;lung, female breast, prostate, and colorectal&#151;continued to decline in the late 1990s, according to the "Annual Report to the Nation on the Status of Cancer, 1975-2000."

Mortality Rates for the Big Four Cancers Continue to Decline

WASHINGTONCommon over-the-counter pain relievers such as ibuprofen and aspirin, taken two or more times per week, may cause a significant reduction in the risk of breast cancer, according to a presentation at the 94th Annual Meeting of the American Association for Cancer Research (AACR abstract 4893).

The conclusions were inferred from data drawn from the National Cancer Institute’s Women’s Health Initiative (WHI) Observational Study, a 15-year prospective epidemiological initiative designed to reduce the incidence of breast cancer, colorectal cancer, coronary heart disease, and osteoporotic fractures in postmenopausal women.

"These data confirm numerous other studies that also demonstrate a reduction of breast cancer risk by NSAIDs [nonsteroidal anti-inflammatory drugs]. Our findings indicate that a significant chemoprotective effect exists, even for women at relatively high risk for breast cancer," said Randall E. Harris, MD, principal investigator of the study and director of the Center for Molecular Epidemiology and Environmental Health, Ohio State University.

In order for NSAID usage guidelines to be developed, he said, "we require further studies, involving randomized prospective double-blinded trials, that will allow us to better assess the doses and duration of NSAID use that provide a significant protective impact."

The WHI study population included 80,741 postmenopausal women between 50 and 79 years of age, who reported no history of cancer, other than nonmela-noma skin cancer. Participants completed a personal baseline interview, providing comprehensive health information that allowed the assessment of breast cancer risk factors, as well as the degree of NSAID use.

Breast cancer cases were identified through biannual contact with the study enrollees, in accordance with the WHI protocol, and the breast cancer diagnoses were confirmed by WHI physicians, using pathology reports.

Average follow-up was 43 months. Among the enrollees in the WHI study, 1,392 were later diagnosed with breast cancer.

Regular NSAID use (defined operationally as two or more tablets per week), for 5 to 9 years, was associated with a 21% reduction in breast cancer risk, while regular use for 10 or more years resulted in a 28% risk reduction, Dr. Harris reported. This improvement reflects a statistically significant inverse linear trend of breast cancer incidence with duration of NSAID use (

Ibuprofen (200 mg) proved more effective than regular (325 mg) aspirin (49% vs 21% risk reduction), while use of low-dose aspirin (less than 100 mg) or acetaminophen, an analgesic with little or no anti-inflammatory activity, showed no effect.

These conclusions were not altered when subgroup analyses were performed to control for several known breast cancer risk factors, including body mass index, estrogen use, family history, nulliparity or late parity, and amount of exercise.

"We believe that the most likely explanation for the protective effects of NSAIDs is through their inhibition of the COX-2 [cyclo-oxygenase-2] enzyme," Dr. Harris told 

COX-2 is an inducible enzyme that is a key mediator of inflammation, through its role in prostaglandin synthesis, he said. It is overexpressed in most breast cancers, as well as in other cancers such as colorectal cancer.

COX-2 has been implicated in promoting a variety of cellular processes of direct relevance to cancer, including cell proliferation, angiogenesis, metastasis, and overexpression of the HER-2/neu oncogene, itself a predisposing factor for breast cancer. In addition, inhibition of COX-2 may promote apoptosis of cancer cells.

There are many preclinical studies indicating that COX-2 inhibition can reduce the incidence of tumors and, in the case of existing tumors, can cause them to regress, Dr. Harris said. "We find it most interesting that ibuprofen, which is superior to aspirin in blocking COX-2, also exerts a greater chemoprotective effect, while acetaminophen, which does not block COX-2 at all, is ineffective," he noted.

In addition to inhibition of COX-2, classical NSAIDs also block the related enzyme COX-1, an effect that is associated with an increased incidence of gastric ulcers, including perforations. Dr. Harris indicated that further studies will be directed to examine the anticancer efficacy of newer drugs, such as celecoxib (Celebrex) and rofecoxib (Vioxx), that are specific inhibitors of COX-2 and whose long-term use may carry fewer deleterious side effects. These agents were approved by the FDA in 1999, after the cutoff for enrollment in the current study.

The extension of this work will also include the assessment of additional breast cancer risk factors, including estrogen-receptor status and overexpression of the HER-2/neu oncogene, in relation to the chemoprotective effects of both standard NSAIDs and the newer specific COX-2 blockers, Dr. Harris said.

WASHINGTON-Common over-the-counter pain relievers such as ibuprofen and aspirin, taken two or more times per week, may cause a significant reduction in the risk of breast cancer, according to a presentation at the 94th Annual Meeting of the American Association for Cancer Research (AACR abstract 4893).

NSAIDs Exert Chemoprotective Effects Against Breast Ca

CHICAGOGefitinib (Iressa) produced clinically meaningful improvement in disease-related symptoms in advanced non-small-cell lung cancer (NSCLC), David F. Cella, PhD, reported at the 39th Annual Meeting of the American Society of Clinical Oncology (abstract 2531). Dr. Cella is professor, Northwestern University, and director, Center on Outcomes, Research and Education (CORE), Evanston Northwestern Health-care, Evanston, Illinois. The study was supported by AstraZeneca.

The researchers studied symptom improvement in the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL 2) trial, which included 216 symptomatic patients with locally advanced or metastatic NSCLC who had more than two prior chemotherapy regimens containing platinum and docetaxel (Taxotere) (given separately or concurrently). Patients received 250 or 500 mg/d of oral gefitinib.

Disease-related symptoms were assessed weekly by the Lung Cancer Subscale (LCS) of the FACT-L questionnaire. The LCS includes seven items (cough, shortness of breath, tightness in chest, breathing difficulty, appetite loss, weight loss, and unclear thinking), and the maximum attainable (asymptomatic) score on the FACT-L is 28.

LCS response was defined as a 2 point or greater improvement in LCS score sustained for at least 4 weeks with no worsening at any interim weekly time point. "A group-average change in LCS score of 2 to 3 points was considered to be clinically meaningful and correlated with differences in weight loss, performance status, primary disease symptoms, best response to treatment, and time to disease progression," Dr. Cella said.

The median baseline LCS scores were 16.7 in the group receiving 250 mg/d gefitinib and 16 for patients receiving 500 mg/d.

"The overall symptom improvement rate across both doses was 39%. Symptom improvement was rapid: The median time to symptom improvement was 9 to 10 days, and the median duration was more than 7 months in the 250 mg/d group and 5.4 months in the 500 mg/d group," Dr. Cella reported.

Similar symptom improvement rates were seen when the 2-point criterion for symptom improvement was increased to 3 points. "Even applying a 7-point criterion gave symptom improvement rates of 16.7% and 11.4% for patients receiving 250 mg/m

A correlation between symptom improvement and tumor response was observed at both gefitinib dose levels, such that most patients who had an objective tumor response or stable disease showed symptom improvement (

Among the patients who survived for more than 8 weeks, median overall survival was greater for those who had symptom improvement than for those who did not (11.8 months vs 4.9 months, respectively). Patients who had symptom improvement but did not have a partial response had median overall survival of 9.7 months. Patients with stable disease also had longer median overall survival if they had symptom improvement than if they did not.

"Because it forecasts partial response and overall survival, the symptom improvement seen with gefitinib is unlikely to be due to a placebo effect. Symptom improvement information is clinically meaningful and complementary to a direct antitumor effect in these heavily pretreated patients with advanced NSCLC," Dr. Cella concluded.

CHICAGO&#151;Gefitinib (Iressa) produced clinically meaningful improvement in disease-related symptoms in advanced non-small-cell lung cancer (NSCLC), David F. Cella, PhD, reported at the 39th Annual Meeting of the American Society of Clinical Oncology (abstract 2531). Dr. Cella is professor, Northwestern University, and director, Center on Outcomes, Research and Education (CORE), Evanston Northwestern Health-care, Evanston, Illinois. The study was supported by AstraZeneca.

Gefitinib Improves Symptoms in Advanced NSCLC Patients

VANCOUVER, CanadaA tri-modal regimen integrating surgical resection with concurrent chemotherapy and radiation (CT/RT) in non-small-cell lung cancer (NSCLC) continued to show benefits in an updated analysis of Intergroup Trial 0139 presented at the 10th World Conference on Lung Cancer plenary session (abstract PL-4). Kathy Albain, MD, who gave the initial report at ASCO 2003 (abstract 2497), presented the updated results.

"With further follow-up, the significant difference in progression-free survival is still very solid. There is no weakening of the strength of the data at this point," said Dr. Albain, of Loyola University of Chicago’s Cardinal Bernardin Cancer Center.

Surgical resection has yielded encouraging results in patients with stage IIIA NSCLC and pathologically confirmed N2 nodes (pN2), but due to increased mortality and morbidity associated with surgery, CT/RT is the standard of care. Intergroup Trial 1039 was designed to test the value of resection after induction CT/RT vs full-course CT/RT therapy, in 429 patients with T1-3, pN2, M0 tumors.

All patients had induction chemoradiation with two cycles of cisplatin (Platinol) and etoposide and daily radiation to 45 Gy, then were randomized to either surgical resection (surgery arm) if disease progression had not occurred or uninterrupted radiotherapy to 61 Gy (CT/RT arm), each followed by two more courses of chemotherapy.

The median follow-up in this report was 71 months, which represented an additional 8 months beyond the 63-month data reported at ASCO. The analysis yielded updated disease-free and overall survival, a new Cox multivariate model, and revised patterns of failure in 392 evaluable patients (n = 201 surgery arm; n = 191 CT/RT arm).

Induction chemotherapy was delivered per protocol in 95% to 96% of patients in both arms. Significantly more patients in the surgery arm did not receive consolidation chemotherapy (42% vs 21%), but RT was delivered per protocol in significantly more patients in the surgery arm (97% vs 81%).

Toxicities were similar, although more patients died on the surgery arm. The only difference in grade 3-4 toxicity was more esophagitis in the CT/RT arm (20% vs 9%). Three deaths occurred on the CT/RT arm during or after consolidation. In the surgery arm, 14 patients died (10 of postoperative complications). Twelve deaths followed pneumonectomy, 8 of which were from acute respiratory distress syndrome.

Progression-free survival (PFS) was significantly better for patients in the surgical arm (P = .03). Median PFS was 13.4 vs 11.8 months, and 3-year PFS was estimated at 28% vs 19% for surgery vs CT/RT, respectively. Median overall survival was 22 months vs 22.3 months, and 3-year survival was 37% and 34%, respectively, Dr. Albain reported. "The hazard ratios crossed due to treatment-related deaths for both PFS and overall survival, and the log-rank P value was not significant," she said.

While early survival favors the CT/RT arm, the curves superimpose, then cross, and begin to separate at the median survival point of 22 months, she said. By year 3, there is an absolute survival benefit of 3% favoring the surgery arm, for a 10% proportional risk reduction. However, confidence intervals are wide and overlap at this point of follow-up. In the surgical arm, more patients are alive without progression (

 = .004), and more died without progression (

"Very little change has occurred in the outcome endpoints since the ASCO 2003 analysis," she noted. "Progression-free survival remains significant in favor of surgery, with no difference in overall survival. The absolute survival improvement with surgery at 3 years is still small. There is no change in the greater number of patients alive without progression with surgery, and in the fewer number who died without progression after CT/RT."

Overall patterns of failure were still similar between arms. There was a trend for greater local relapse with CT/RT in the primary site, nodes, and both (17% with surgery vs 26% with CT/RT; 

 = .08). The updated Cox multivariate model for overall survival found the significant independent predictors of poor outcome to be higher T stage, weight loss less than 5%, and older age. Performance status and tumor size did not prove predictive.

In the analysis of overall survival according to interim pathologic response data, N0 status continued to predict improved outcome whether or not there was residual primary tumor. Patients who were T0, N0 (pathological complete response) had a median survival of 36.7 months and a 3-year survival of 52%. Patients who were T0-1, N0 had a median survival of 36.7 months and a 53%
 3-year survival.

"Progression-free survival is superior for the trimodality arm with an apparent plateau, but overall survival does not appear to be statistically different. It is uncertain whether the plateau in median survival will translate into improved overall survival with longer follow-up," Dr. Albain concluded.

Discussant Harvey Pass, MD, professor of surgery and oncology, Karmanos Cancer Institute, Detroit, called Intergroup 0139 "the most anticipated randomized trial in lung cancer for a long time. It is a standard for randomized trials in induction therapy and serves as a springboard for trials we need to plan for the future."

He said that the study confirmed phase II trials showing that full doses of cisplatin/etoposide could be delivered with radiotherapy and that pathologic complete responses could be achieved in 18%. "The most intriguing part of the trial is that downstaging of N2 disease to N0 will occur in 46% to 48% of patients, and 3-year survival of this group is a phenomenal 53%, which is even better than the 44% we achieved in SWOG 8805," he said. [In SWOG 8805, 126 patients with pathologically staged IIIA/IIIB disease received cisplatin plus etoposide concurrent with radiation therapy followed by surgical resection.]

Dr. Pass said that results in the surgery arm "re-amplified the importance of nodal clearance on survival." The findings do not demonstrate that "everybody should get surgery after induction," but point to the need to determine which patients will have nodal downstaging by any induction method. To accomplish this, he said, pre- and postinduction PET scanning should be used in future trials.

The study still leaves unanswered several questions, such as whether the N2 downstaging is due to the radiotherapy, the chemotherapy, or the combination, and what contribution surgery really is making to the outcome. These questions are difficult because of the heterogeneity of the N2 population, and future studies should stratify these patients, he said.

VANCOUVER, Canada-A tri-modal regimen integrating surgical resection with concurrent chemotherapy and radiation (CT/RT) in non-small-cell lung cancer (NSCLC) continued to show benefits in an updated analysis of Intergroup Trial 0139 presented at the 10th World Conference on Lung Cancer plenary session (abstract PL-4). Kathy Albain, MD, who gave the initial report at ASCO 2003 (abstract 2497), presented the updated results.

Surgery After CT/RT Beneficial in NSCLC: Updated Data

CHICAGOMen with biochemical recurrence of prostate cancer after radical prostatectomy are more likely to develop distant disease if they present with a tumor that has a high Gleason grade or if they have a prostate specific antigen doubling time (PSADT) less than 12 months, Christopher Amling, MD, said at the 98th Annual Meeting of the American Urological Association (abstract 1489).

Since Gleason grade and PSADT were such strong predictors of the development of distant metastases in this study, these factors may identify which men are at high risk for disease progression and therefore would benefit from early clinical intervention, said Dr. Amling, a commander in the US Navy, a urologist at the Naval Medical Center, San Diego, and principal investigator of the study for the Center for Prostate Disease Research (CPDR). The data were gathered from the US Department of Defense’s CPDR Multicenter National Prostate Cancer Database, a nationwide registry of men treated for prostate disease in nine military hospitals.

The study included 3,739 men who had undergone radical prostatectomy between 1988 and 2002 and who were followed for a median of 4.52 years (range 2 to 15 years). The natural history of these men was reviewed to learn whether pretreatment PSA level, Gleason score, pathologic stage, or PSADT could predict eventual disease progression to metastasis.

Overall, about 47% of men had biochemical recurrence of prostate cancer, and 7.9% of these men went on to develop clinically detectable, systemic metastases, although only 16 men died of prostate cancer. The actuarial metastasis-free survival was about 80% at 10 years. The prostate cancer specific survival was more than 90%.

Analysis showed that the metastasis-free survival rate among men with biochemical recurrence declined with rising Gleason scores. After 10 years of follow-up, 80% of men with a Gleason score of 7 or less had no evidence of metastases. However, only about 70% of men with a Gleason score greater than 7 were alive after 10 years with no signs of metastatic disease.

Metastasis-free survival also dropped with shorter PSADTs. The 10-year metastasis-free survival rate was about 90% in men who had a PSADT of 12 months or more; however, it was only about 80% in men with a PSADT less than 12 months.

The men in this study reflect "patients we commonly encounter and institute treatment for," Dr. Amling said. "Gleason score and PSA doubling time are strong predictors of who will go on to develop distant disease even in a group of men who received treatment." 

CHICAGO-Men with biochemical recurrence of prostate cancer after radical prostatectomy are more likely to develop distant disease if they present with a tumor that has a high Gleason grade or if they have a prostate specific antigen doubling time (PSADT) less than 12 months, Christopher Amling, MD, said at the 98th Annual Meeting of the American Urological Association (abstract 1489).

Oncology NEWS International Vol 12 No 10

Mortality Rates for the Big Four Cancers Continue to Decline

NSAIDs Exert Chemoprotective Effects Against Breast Ca

Gefitinib Improves Symptoms in Advanced NSCLC Patients

Surgery After CT/RT Beneficial in NSCLC: Updated Data

PSA Doubling Time, Gleason Grade Predict Metastases