|Ahead of print publication
Comparison of treatment response in cervical carcinoma patients infected with human papillomavirus 16 and human papillomavirus 18 who are treated with chemoradiation
Geeta S Narayanan, MS Ganesh, Rishabh Kumar
Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, Karnataka, India
|Date of Submission||15-Mar-2019|
|Date of Acceptance||06-Dec-2019|
|Date of Web Publication||11-Jun-2020|
B 58, South City 1, Gurgaon - 122 007, Haryana
Source of Support: None, Conflict of Interest: None
Objectives: The primary objective of this study was to compare the treatment response of cervical carcinoma patients infected with human papillomavirus (HPV) 16 and HPV 18 who are treated with chemoradiation.
Materials and Methods: Ninety-six biopsy-proven cervical cancer patients, suitable for curative treatment with definitive radio-chemotherapy with International Federation of Gynecology and Obstetrics Stage IB2–IIIB, were included in this prospective study. HPV testing was done using TRUPCR® HPV 16 and 18 real-time polymerase chain reaction kit. All the patients received a dose of 83–90 Gy total equieffective dose to the high risk clinical target volume(HRCTV) using tele- and brachytherapy.
Results: Of the 96 patients, 79 (82.3%) patients were positive for HPV DNA. Seventy-three patients showed HPV genotype 16 positivity and six patients were positive for genotype 18. The response was correlated with HPV genotype. There was a statistically significant increase in complete radiological response in HPV 16 compared to HPV 18 and negative groups at 3 months, 80.8%, 50%, and 52.9%, respectively (χ2 = 36.5, P < 0.001). There was also a statistically significant increase in clinical response at 3 months in HPV 16 group compared to HPV 18 and negative groups, 87.5%, 50%, and 50%, respectively (χ2 = 29.9, P < 0.001). The age, volume of the disease, overall treatment time, average hemoglobin level, and the number of blood transfusions did not have any correlation.
Conclusion: HPV genotype 16 positivity shows higher complete response in cervical carcinoma patients treated with definitive chemoradiation compared to HPV 18 genotype. Further HPV genotyping could potentially help stratify cervical cancer patients for more effective therapeutic regimens.
Keywords: Cervical cancer, human papillomavirus genotype, response
|How to cite this URL:|
Narayanan GS, Ganesh M S, Kumar R. Comparison of treatment response in cervical carcinoma patients infected with human papillomavirus 16 and human papillomavirus 18 who are treated with chemoradiation. J Can Res Ther [Epub ahead of print] [cited 2020 Jul 12]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=286538
| > Introduction|| |
Cervical cancer is the second most common cancer in women worldwide, and persistent infection with human papillomavirus (HPV) is a major etiological factor. Each genotype of HPV has its association with various risk factors. There are more than 170 HPV genotypes that have been identified and classified according to their L1 open reading frame. Two HPV species, alpha-7 that consists of HPV 18, 39, 45, 59, 68, and 70 and alpha-9 comprising HPV 16, 31, 33, 35, 52, 58, and 67, have been identified and might be responsible for over 80% of all cervical cancer cases. Many studies in the past have investigated the prognostic value of HPV infection in cervical cancer patients, but they have resulted in conflicting results.
Not much is known about the effect of HPV on the response to chemoradiation and the patient's clinical outcome. In-vitro studies have suggested that the presence of E6 and E7 proteins derived from the virus correlates with reduced radiosensitivity. As recurrent cervical cancer might develop in approximately 10%–15% of Stage I–IIA patients and 30%–50% of Stage IIB–III patients due to variable responses to radiotherapy (RT) and computed tomography (CT) as well as surgery, it is crucial to look for predictors for failure. Further stratification based on the types of HPV strains for cervical cancer might be vital in improving the survival rate in this heterogeneous HPV-infected patients. This type of classification may help clinicians across the globe in tailoring appropriate therapeutic and follow-up strategies for patients at a high risk of disease recurrence.
Our study was designed to assess the relationship between high-risk HPV genotype and response to treatment in cervical cancer patients treated with definitive chemo-RT.
Aims and objectives
The primary objective was to compare the treatment response of cervical carcinoma patients infected with HPV 16 and HPV 18 who are treated with chemoradiation.
The secondary objectives were to find out the HPV positivity rate in diagnosed cervical cancer cases, to estimate the number of HPV high-risk genotypes, and to compare response between positive and negative HPV patients in the same study group.
| > Materials and Methods|| |
The sample size for this study was 96 patients (with the prevalence of HPV 16 as 48.4%, a precision of 10%, and an alpha error of 5% [based on the study done by Schwartz et al.]).
Patients presenting to Vydehi Cancer Centre were included for the study prospectively. Inclusion criteria were patients with biopsy-proven carcinoma of the uterine cervix considered suitable for curative treatment with definitive concurrent chemoradiation with Performance Status 0–2 (Eastern Cooperative Oncology Group) and International Federation of Gynecology and Obstetrics (FIGO) Stages IB2–IIIB. Patients with metastatic disease, with previous total or partial hysterectomy with recurrence, and patients with prior radiation therapy to pelvis were excluded from the study. Pretreatment evaluation included complete blood count, renal function tests, HIV and HBsAg serology testing, chest X-ray, CT/magnetic resonance imaging (MRI) scan abdomen and pelvis with contrast, biopsy, and HPV typing.
Patients' age, FIGO stage, tumor size on imaging, average hemoglobin (Hb) level during treatment, and status of lymph node enlargement were recorded. Written informed consent was obtained from all patients, and the institutional ethics committee approved the study.
Human papillomavirus genotyping
HPV testing was done using TRUPCR® HPV 16 and 18 real-time polymerase chain reaction (RT-PCR) kit. The TRUPCR® HPV 16 and 18 RT-PCR kit is a qualitative in-vitro test that amplifies and detects HPV 16 and 18 DNA in cervical cells collected in liquid media. DNA is extracted from samples and is then amplified using real-time amplification and detected using fluorescent reporter dye probes specific for HPV 16 and 18. In RT-PCR, the fluorescent signal is generated from the presence of an oligonucleotide probe specific for target DNA sequence. The probe contains a fluorescent dye molecule on its 5' end and a quencher molecule on its 3' end. The probe hybridizes with one of the chains of the amplified fragment. During synthesis of a complementary chain, Taq DNA polymerase which possesses 5'-3' exonuclease activity cleaves the probe. As a result, the fluorescent dye and quencher dye are separated, and the total fluorescence of reaction volume increases in direct proportion to the number of amplicon copies synthesized during PCR. The fluorescent signal is measured in each cycle of reaction, and the threshold cycle value is determined from the obtained curve. The threshold cycle is proportional to the initial number of DNA copies in a sample, and its value allows qualitative comparisons of analyzed and control samples. In this kit, three independent reactions are running in parallel in two tubes: the first detects HPV 16 (FAM channel), and internal control DNA (Texas Red) which allows excluding unreliable results, and the second detects HPV 18 (HEX channel). The DNA was extracted using QIAamp DNeasy Blood and Tissue Kit (Qiagen, Valencia, CA, USA).
Radiotherapy and chemotherapy
All the patients received external beam radiation therapy (EBRT) on the linear accelerator with three-dimensional conformal technique to a dose of 4600–5000 cGy in 23–35 fractions, 5 fractions/week. High-dose rate intracavitary RT was delivered once a week with a fraction dose of 7 Gy prescribed to the HRCTV, for 3–4 times to a total effective dose of at least 85–90 Gy to the HRCTV (EBRT Plus Brachy). Injection cisplatin 40 mg/m2 was administered concurrently, weekly during EBRT.
Treatment response assessment was done using the RECIST criteria version 1.2. Clinical examination was performed after EBRT and 3rd-month follow-up. The radiological response was assessed using MRI at the 3rd-month follow-up.
Data were analyzed using SPSS software for Windows IBM SPSS statistics for windows version 23 (IBM corp Armonk, N.Y, USA). Frequency distribution of category and response variables was determined. A Chi-square test of proportions was done to compare HPV status with the response after RT.
| > Results|| |
A total of 96 patients with diagnosed carcinoma cervix, planned for definitive chemoradiation therapy, were included in the study. The patient characteristics are summarized in [Table 1].
The most common histology was squamous cell carcinoma (SCC) in eighty patients (92.7%), adenocarcinoma was seen in six patients, and papillary squamotransitional in one case. All the patients received planned radiation therapy. Eighty-five patients received chemotherapy with cisplatin, and the remaining patients received carboplatin. Four patients did not receive chemotherapy as they were unfit. Majority cases in our study were Stage II (76%), with majority finishing the entire course of chemoradiation along with brachytherapy within 49 days. The mean treatment time was 47 days, and majority of the patients had an average Hb of >10 throughout the treatment [Table 1]. HPV detection rate with our RT-PCR detection kit was 82%, among which 76% were positive for HPV 16, 6.3% were positive for HPV 18, and 17% were HPV negative [Table 2]. None of the patients had both HPV 16 and 18 positivity. A total of 92 patients received the planned treatment (chemoradiation followed by brachytherapy). Four patients were not fit for chemotherapy due to old age and were treated with radiation. All the patients received EBRT as well as brachytherapy [Table 3].
At 3 months, 77% of the patients achieved complete clinical response, 19% had partial response, and 1% (only one patient) had progressive disease who turned out to be HPV 18 positive. The responses are documented in [Table 4].
We correlated the response of chemoradiation with the HPV genotype. There was no significant difference in response immediately following EBRT, as shown in [Table 5]. However, there was a significant increase in complete radiological response in HPV 16 compared to HPV 18 and negative groups at 3 months. The complete response rates were 80.8%, 50%, and 52.9% for HPV 16 genotype, HPV 18 genotype, and HPV 16/18 negative, respectively (χ2 = 36.5, P < 0.001). The similar significant increase in clinical response was seen at 3 months in HPV 16 group (87.5%) compared to HPV 18 (50%) and negative groups (50%) (χ2 = 29.9, P < 0.001), as shown in [Table 5].
The age, volume of the disease, overall treatment time, presence of lymph nodes, average Hb level, and the number of blood transfusions did not have any correlation with the HPV genotype on analysis of variance testing, as shown in [Table 6].
| > Discussion|| |
Significant variability in survival rates is often observed between different sets of cervical cancer patients with the same FIGO stage. Looking for new biomarkers as predictors of response is important. Although HPV infection has proven to be an important preliminary event in the tumorigenesis and pathophysiology of cervical cancer, reports on the clinical impact of tumors that develop from different HPV types are conflicting. For example, early data from Germany showed that HPV 16 positivity predicted poor prognosis and was associated with high-risk histological features and metastasis, with factors such as pelvic node metastasis, lymphatic space invasion, and poorly differentiated SCCs. They also concluded that HPV DNA and HPV 16 were associated with a poor prognosis on univariate analysis, but on multivariate analysis, the only HPV 16 infection was found to be significantly associated with prognosis. Other studies from Asia and North America reported that cervical cancer patients infected with HPV 18, rather than HPV16, were associated with a poor outcome,, with pelvic lymph node metastasis and deeper stromal invasion being more common in HPV 18-associated cervical cancer. Whereas, HPV 31- and HPV 58-infected cervical cancers were found to be associated with better survival outcome., However, HPV type did not have any prognostic value in the other studies., As there is a lack of data from the South Asian countries with regard to the prognostic value of HPV genotypes in cervical cancer, our study based from the Indian subcontinent compared the response to chemoradiation between HPV 16 and HPV 18 genotypes. We found that there was a statistically significantly increased rate of complete response by both clinical and radiological examination in patients with HPV genotype 16 than with HPV genotype 18 at 3 months, 80.8% vs. 50% respectively (χ2 = 36.5, P < 0.001). Similar results were reported by Hang et al. In their study on univariate analysis, it was found that HPV 16-infected cancers were associated with better overall survival (OS) (P = 0.037). After adjusting for age, FIGO stage, and therapy, HPV 16 showed a hazard ratio (HR) of 0.36 (95% confidence interval [CI]: 0.18–0.74; P = 0.005) for OS. Wang et al. compared the prognostic value of various HPV genotypes in patients with advanced cervical cancer treated with concurrent chemoradiation or radiation alone. There was a statistically significant improvement in disease-specific survival in the chemoradiation (concurrent chemoradiotherapy [CCRT]) group for HPV 18-positive (60.9% vs. 30.4%, P = 0.019) and HPV 58-positive (69.3% vs. 48.9%, P = 0.026) patients compared with the RT-alone group. In contrast, the differences in survival with CCRT compared with RT alone in the HPV 16-positive and HPV 33-positive subgroups were not statistically significant (P = 0.86 and P = 0.53, respectively). The authors felt that HPV genotype might be a predictive factor for the better effect of CCRT in patients with advanced SCC of the cervix.
In a meta-analysis by Li et al. as a whole, the results clearly determined that positive HPV DNA was a better prognostic factor in cervical cancer, with better disease-free survival (pooled HR = 0.362, 95% CI = 0.252–0.519, P < 0.000) and better OS (pooled HR = 0.610, 95% CI = 0.457–0.814, P = 0.001). In our study, the complete responders were higher in HPV 16-positive patients than in HPV-negative patients (80.8 vs. 52.9%, respectively), and the difference was statistically significant (χ2 = 29.9, P < 0.001). It is pretty clear that due to its significant prognostic effects, HPV status of cervical cancer is now an important prognostic marker, and its assessment should be done before treatment. Similar meta-analysis results have also been reported in HPV-positive head-and-neck SCC., HPV-negative primary cancers, which showed a great potential to metastasize, were found to have more aggressive p53 mutations than HPV-positive cancers in the normal development process, resulting in more severe deregulation of normal growth control and a worse prognosis.,
The HPV DNA detection rate in our study (82%) was comparable to that of the study by Ferdousi et al. However, in another Indian study, the detection rate was almost 99%. In our study, the HPV genotyping kit used did not cover other high-risk genotypes; hence, the prevalence of true HPV-positive cases might have been underestimated. In another Indian study, the prevalence of HPV infection was 93.80% in cervical carcinomas, 54.32% in inflammatory smear, and 19.11% in case of the normal cervix. The most prevalent genotype was HPV 16 (87.28%) followed by HPV 18 (24.56%) and HPV 51 (3.46%).
In our study, eight patients were HPV genotype 18 positive. Given the much lower prevalence of HPV 18 in cervical cancer than HPV 16 in our geography and study population, independent studies with large sample size are required to assess the impact of HPV 18 on patients' prognosis.
Studies have also looked into the role of multiple HPV genotype infection and persistence of HPV infection after treatment as prognostic factors. Infection with various HPV genotypes has been associated with poor survival; in a study by Nogueira Dias Genta et al., comparison between multiple and single genotype infections was made. Age, clinical staging, histological type, and multiple HPV genotype infection detected in the same tumor specimen were associated with poor OS on multivariate analysis (P < 0.05), although there was no specific HPV genotype among the alpha-7 and alpha-9 species that had affected the survival. In a Swedish cohort study, patients with cervical cancer who had multiple HPV strains had a higher overall recurrence rate (44%) when compared to single strain-infected tumors (24%) (P = 0.027). In addition, the overall rate of recurrence for patients with tumors containing HPV from both alpha species 7 and 9 was statistically significantly higher (80%) when compared to alpha species 7 or 9 alone (25%) (Pearson's Chi-square test; P = 0.0002). Even distant recurrences were statistically significantly higher in patients with multiple HPV infections (Pearson's Chi-square test; P = 0.0022). The distant recurrence rate for tumors developing from a single strain of HPV infection was 15%, whereas 40% for multiple strain-infected tumors. This study provides compelling evidence that cervical cancer co-infected with multiple HPV genotypes results in poor outcome in the form of recurrence, both distant and local survival. The reasons behind why multiple HPV infections affect survival are not fully understood. However, it has been postulated that the presence of multiple HPV genotypes might increase the length of persistent HPV infection and possibly the risk of carcinogenesis and may also reduce response to chemo-RT. Few more studies have described the association of multiple HPV infections and cervical cancer, but the results have been inconsistent. Some studies have suggested a possible role for multiple HPV infections in the development or progression to neoplasia. In contrast, other studies have shown that the development of cervical preinvasive lesions or invasive cancer in women with multiple HPV infection genotypes of HPV was similar to those infected by a single HPV genotype.,
Multiple past studies showed that there are a high local recurrence and poor survival in patients with cervical cancer who have persistence of HPV infection. Nagai et al. reported the first study in which HPV infection status was examined before, during, and after RT. Their data demonstrated that cervical carcinomas that are HPV DNA positive and persisted with its DNA till the end of RT were highly predictive of local recurrence. Moreover, multivariate statistical analysis showed that the persistence of HPV DNA represented an independent and the most powerful prognostic factor. Our study to the best of our knowledge is one of the first studies that provides information regarding treatment response in patients who are infected with HPV 16, 18, both, or none. In another Indian study by Mahantshetty et al., locally advanced cervical cancers treated with radical radio (chemo) therapy, persistent of HPV 16/18 infection resulted in poor outcomes. The results of our study are comparable to the ones found in the literature, as shown in [Table 7]. With multiple studies now finding a correlation with HPV genotype and prognosis, there is a need for creating personalized therapies based on HPV for cervical cancer.
| > Conclusion|| |
HPV genotype 16 positivity shows the higher complete response in cervical carcinoma patients treated with definitive chemoradiation compared to HPV 18 genotype. Further HPV genotyping can potentially stratify cervical cancer patients for more effective therapeutic regimens, response assessment, and follow-up. Patients with alpha-9-type HPV virus (e.g., HPV 16) associated with cervical cancer might require less aggressive therapy to reduce side effects, whereas those associated with alpha-7 (e.g., HPV 18) species may need more aggressive treatment and closer monitoring.
Financial support and sponsorship
This research was supported and funded by Rajiv Gandhi University of Health Sciences.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]