© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 4, 251,
February 21, 2001
© 2001 Oxford University Press
IN THIS ISSUE |
Human papillomavirus (HPV) infection is now considered the main cause of cervical cancer. Three papers in this issue of the Journal focus on extending knowledge of this causal relationship and its implications for prevention efforts.
Harro et al. (p. 284) conducted a double-blind, placebo-controlled, dose-escalation trial in healthy adults to evaluate the safety and immunogenicity of an HPV type 16 (HPV16) vaccine composed of virus-like particles containing the major structural viral protein L1. Volunteers received 10-µg or 50-µg doses of the vaccine given without or with alum or MF59 as adjuvants at 0, 1, and 4 months. All vaccine formulations were well tolerated and induced high serum antibody responses. At high dose, the presence of adjuvant was not associated with the increase in the antibody titer. The authors conclude that this HPV vaccine is highly immunogenic even without adjuvant and can induce antibody response at a level roughly 40-fold higher than what has been observed after natural infection.
One of the most common abnormal cervical diagnoses found by the Pap smear is an equivocal one: atypical squamous cells of undetermined significance (ASCUS). Because no consensus exists as to the appropriate clinical management of women who receive such a diagnosis, the National Cancer Institute began a randomized, multicenter clinical trial of women diagnosed with ASCUS and compared the sensitivity and specificity of three management arms: immediate colposcopy, colposcopy only if repeat cytology (Pap smear) show a higher grade lesion (conservative management), and colposcopy only if an initial test for HPV is positive. Using colposcopy as the gold standard, Solomon et al. (p. 293) found that HPV testing had higher sensitivity than and comparable specificity to that of a single repeat Pap test for detecting high-grade cervical lesions. The authors conclude that this combination of sensitivity and specificity makes HPV testing an excellent option for the management of ASCUS.
Some evidence suggests that some variants of HPV16 are more strongly associated with cervical cancer risk than others. Hildesheim et al. (p. 315) designed a rigorous population-based, case–control study of stronger design than previous studies to investigate the association between HPV16 variants and cervical cancer. Examining women with a range of severity of cervical lesions, they were able to distinguish, by polymerase chain reaction and sequencing, different variant forms of HPV16, including the European prototype and non-European variants. The authors report that the non-European variants were associated substantially more strongly with high-grade lesions and cervical cancer risk than the European-like variants, and the results did not change when adjusted for other risk factors, including host genetic factors.
In an editorial on all three studies, zur Hausen (p. 252) speculates on their impact and puts the current research on HPV and cervical cancer into a historical context.
"A vaccine composed of the four HPV types seen most frequently in cervical cancer . . . would theoretically be able to protect against approximately 80% of cervical cancers."
—Harro et al.
Better Treatment for Small-Cell Lung Cancer
The combination of etoposide plus cisplatin (EP) is considered a standard therapy for small-cell lung cancer (SCLC). In a phase III randomized clinical trial, Pujol et al. (p. 300) compared this treatment with a four-drug regimen, PCDE, containing EP plus cyclophosphamide (C) and 4'-epidoxorubicin (D) to determine whether drug intensification improves survival of patients with extensive SCLC. Patients in the four-drug PCDE arm had a statistically significant higher frequency of combined complete plus partial responses compared with those in the EP arm. The patients receiving PCDE also survived longer than those in the EP arm with 30% less risk of death and slow progression of disease. Hematologic toxicity was higher in the PCDE arm, but the toxicity-related death rate was not statistically different. The authors conclude that, compared with EP, the PCDE regimen yielded a higher response rate and a better survival rate in patients with extensive SCLC without affecting the quality of life during chemotherapy.
In an editorial, Johnson (p. 254) commends the authors for using an appropriate study design. However, he expresses some concerns regarding the longer treatment cycle used and questions whether the improvement in long-term survival is worth the increase in treatment-related toxicity.
Trends in U.S. Lung Cancer Mortality
Nationwide patterns of mortality from lung cancer appear to be related to population trends in cigarette smoking, the dominant cause of the disease. Earlier studies of U.S. lung cancer mortality have focused on cohorts of people born in or before 1950. To examine lung cancer mortality trends in more recent birth cohorts, Jemal et al. (p. 277) analyzed death certificate data—including race, sex, age, year of death, and cause of death—using statistical models. They found that, compared with older birth cohorts, the rate of decrease in lung cancer deaths slowed among people born after 1950, consistent with evidence that smoking initiation rates for children who were 12–17 years old increased in 1965 through 1977. The authors conclude that their results lend additional support to the need for promotion of smoking-cessation programs for teenagers.
Hypoxia-Inducible Factor-1
and Breast Carcinogenesis
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor composed of HIF-1 and HIF-1
that regulates gene expression in critical pathways involved in tumor growth and metastases. The amount of active HIF-1 is controlled by the amount of HIF-1 because HIF-1 is abundantly present in cells. Using the amount of HIF-1 as a reflection of HIF-1 activity, Bos et al. (p. 309) found that the frequency of HIF-1-positive cells in breast tissue specimens increased with pathologic stage. HIF-1 levels were higher in poorly differentiated invasive lesions than in the corresponding type of well-differentiated lesions. They found that increased levels of HIF-1 are associated with increased proliferation and increased expression of vascular endothelial growth factor and estrogen receptor. They conclude that increased levels of HIF-1, and therefore increased HIF-1 activity, are potentially associated with more aggressive tumors.
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