HPV 16/18 Linked to Increased Relapse Risk in Cervical Cancer

Jason Harris

cervical cancerPersistent HPV 16/18 infection correlated with higher locoregional relapse, overall relapse, and was also associated with early relapses in women with locally advanced cervical cancers treated with radical radiochemotherapy.

Investigators included results from 135 women in a prospective, observational study at Tata Memorial Hospital, Mumbai, India, to quantify HPV viral load prior to treatment, during treatment, and up to 2 years after completion of treatment. Pretreatment HPV16/18 DNA was detected in 126 (93%) patients, with HPV-16 present in 91%. The mean log (±SD) HPV-16 and HPV-18 viral load at pretreatment was 4.76 (±2.5) and 0.14 (±2.1) copies/10 ng of DNA, respectively.

At 9 months, 66% of patients had persistent HPV infection. Those with persistent HPV16/18 infection (n = 89) had a significantly higher incidence of overall relapses (49% vs 28%; P = .024) and locoregional relapses (32% vs 11%; P = .02) compared with patients who had HPV clearance by 9 months.

From May 2010 to April 2012, investigators recruited 150 women into the study. Fifteen were excluded for lack of adequate samples for HPV detection.

All patients (N = 135) underwent radical radiation therapy and brachytherapy as per standard institutional guidelines. External beam radiation therapy (EBRT) was delivered to whole pelvis with box field arrangement either on tele cobalt machine or linear accelerator (6 MV/15 MV) using conventional or 3D conformal radiotherapy technique to a dose of 40 Gy to 50.4 Gy delivered at 1.8 Gy to 2.0 Gy per fraction over 4 to 5 weeks.

Patients deemed fit enough also received chemotherapy with weekly 40 mg/m2 of cisplatin concurrent with EBRT. Patients subsequently received 2 to 5 fractions of high-dose rate intracavitary brachytherapy once weekly to a dose of 7 Gy to point A.

Following treatment completion, investigators contacted patients every 3 months for 2 years, followed by check-ups every 6 months for the next 3 years and annually thereafter.

Persistent disease was defined as any clinically detectable disease after 3 months of treatment completion. Locoregional recurrence was defined as biopsy proven, clinically or radiologically detected relapse within the pelvis after achieving complete response.

Median age was 50 years (range, 24-65) years. Sixty-nine patients (51.1%) were staged as FIGO IB2-IIB and 66 patients (48.9%) as FIGO IIIA-IIIB.

Investigators observed clinical complete response in 117 women (86.6%), partial response in 12 (9%), and stable/progressive disease in 6 (4.4%) by 9-month posttreatment follow-up.

At a median follow-up of 60 months, 56 patients (41.5%) had relapsed. Relapses were local in 16 patients (12%), locoregional in 4 (3%), distant alone in 22 (16%), and local plus distant in 14 (10%). Thirty-four patients (25%) had relapses with a locoregional component.

At baseline, 89 (66%) patients were positive for HPV16 alone, 34 (25.1%) had both HPV 16 and 18, 3 (2.2%) were positive for HPV18 alone, and 9 patients (6.7%) were negative for both HPV types. The mean log (±SD) and viral load before radiation was 4.76 (±2.5) copies/10 ng of HPV16 DNA and 0.14 (±2.1) copies/10 ng of HPV18 DNA.

Investigators observed a significant decline in HPV viral load in subsequent follow-ups (P <.0001). HPV16-positive patients were more likely to respond to radiochemotherapy than HPV18-positive patients (P <.0001). However, investigators did not see a significant correlation between pretreatment HPV viral load and clinical response (P = .896).

Quantitative HPV viral load at 9 months’ posttreatment also showed a correlation between incidence of overall relapse (P = .07) and especially locoregional relapse (P = .01). At 24 months’ posttreatment, 62% of patients in in the clearance group showed no evidence of disease compared with 30% in the persistent infection group. However, investigators found no correlation between incidence of reinfection and relapse rates.

On univariate analyses, FIGO stage, nodal status, pretreatment hemoglobin level, radiation dose, clinical response, and HPV infection status at 9 months and 24 months’ posttreatment had a significant impact on relapse-free survival (RFS), locoregional control (LRC), and overall survival (OS). However multivariate analysis showed that only nodal status and pretreatment hemoglobin had a significant impact on RFS and OS, while persistent HPV infection by 24 months affected LRC and RFS.
Mahantshetty U, Tanuja T, Pushpa N, et al. Impact of HPV 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy - A prospective observational study [published online December 1, 2017]. Gynecol Oncol doi: 10.1016/j.ygyno.2017.11.034.
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