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Cervical cancer associated with detectable human papillomavirus (HPV+) RNA or DNA had significantly better outcomes, including survival, a large meta-analysis of published studies showed.

Patients who tested positive for HPV had a 62% improvement in disease-free survival (DFS), 44% improvement in cancer-specific survival (CSS), and 41% improvement in overall survival (OS), as compared with patients whose cancers had no detectable HPV. The presence of HPV was associated with a numerically lower risk of recurrence.

The findings challenge the view that HPV infection is necessary for development of cervical cancer, although alternative mechanisms remain undetermined, reported Eduardo L. Franco, DrPH, of McGill University in Montreal, and co-authors .

"The finding that testing positive for HPV compared with negative was associated with better overall survival has been reported in other systematic reviews and meta-analyses for anal and vulvar cancer," the authors noted in their discussion. "However, HPV is not considered a necessary cause of anal and vulvar carcinomas as it is for cervical cancer."

Multiple non-HPV mechanistic explanations have been put forth for the small minority of cervical cancers that are not HPV+, but the findings of this study "may be better explained by issues with HPV detectability," the authors added.

The findings are consistent with those of a showing that HPV positivity was associated with better DFS and OS. Franco and colleagues included additional studies published since then, included only studies that reported hazard ratios, and assessed the relationship between HPV status and cancer recurrence and CSS.

More than , a study that employed meticulous methodology to test for HPV DNA showed that 99.7% of cervical cancer specimens tested positive, leading to the concept that HPV is a "necessary cause" of the cancer. Since then, laboratories have had difficulty reaching that HPV-positivity threshold. Results have varied, but current evidence suggests about 10% of cases have no detectable HPV DNA, said Gregg Nelson, MD, of Tom Baker Cancer Center and the University of Calgary in Alberta.

Multiple explanations have been offered for the HPV- cervical cancers, including the intriguing possibility that the cancers started out HPV+ but became HPV- during cancer evolution.

"Maybe those cancers started off having HPV, but then as part of invasiveness, or in some cases the cancer has significant necrosis or dying off by other mechanisms, maybe the loss of HPV in that cancer is actually a surrogate for that particular cancer being more invasive," said Nelson, who is also a spokesperson for the Society of Gynecologic Oncology.

"This study [by Franco and colleagues] confirms the concept that HPV status is still and, regardless of what you think the mechanism is, appears to be a very strong signal of improved survival," he continued. "I don't think [the rate of HPV negativity] can all be blamed on suboptimal testing. I think it's possible that the HPV negativity is in some cases a surrogate for a more deadly cervical cancer."

Franco and co-authors revisited the relationship between HPV status and cervical cancer, adding studies published through Jan. 27, 2022 and extending the assessment beyond DFS and OS to include CSS and cervical cancer recurrence. Starting with 11,179 titles and abstracts, they culled the list to 77 studies. Not all studies were used for each outcome assessed.

Overall, the data showed an HPV prevalence of 81.7%. Analysis of 15 studies and 2,564 cases of cervical cancer produced a DFS hazard ratio of 0.38 for HPV positivity (95% CI 0.25-0.57). Examination of nine studies and 1,398 cases yielded a CSS hazard ratio of 0.56 (95% CI 0.44-0.71). For OS, analysis of 36 studies with 9,169 cases resulted in a hazard ratio of 0.59 (95% CI 0.47-0.74). The relationship between HPV status and risk of recurrence did not quite achieve statistical significance but trended in favor of positivity (HR 0.59, 95% CI 0.33-1.07) following an analysis of eight studies with 1,313 cases.

The authors did not address the study's potential implications for cervical cancer screening for HPV vaccination. Nelson said the strategy followed by his center's colposcopy program, and used by other centers as well, runs counter to the study's message that HPV negativity confers higher risk.

Patients with high-grade squamous intraepithelial lesions undergo a cone biopsy or loop electrosurgical excision procedure. At the 6-month follow-up visit patients have a Pap test and HPV assessment. Patients who test positive may have a directed biopsy or other types of tissue sampling. On the other hand, patients who are HPV negative and have no high-risk features are returned to their primary care physicians, who assume responsibility for routine follow-up, including Pap tests.

"It's sort of the opposite of the message that would be coming from this study," said Nelson. "We use the same approach for patients who are having screening Pap smears. If they have only low-grade changes and are HPV negative, they can stay in the community with their family doctors. If they are HPV positive with the oncogenic panel, they go right to colposcopy."

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