HPV and （ Neutrophil-to-lymphocyte ratio ） NLR are Prognostic Indicators of Laryngeal Cancer Patients Receiving Concurrent Chemoradiotherapy

doi:10.21203/rs.3.rs-815919/v1

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Research Article

HPV and （ Neutrophil-to-lymphocyte ratio ） NLR are Prognostic Indicators of Laryngeal Cancer Patients Receiving Concurrent Chemoradiotherapy

https://doi.org/10.21203/rs.3.rs-815919/v1

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Background and objectives: After receiving radical concurrent radiotherapy and chemotherapy, some patients with laryngeal cancer still have recurrence, and the recurrence time of different patients is different, which will pose a threat to the quality of life and survival of patients. The purpose of our study is to find out the factors that can predict the recurrence of laryngeal cancer, provide more accurate and individualized treatment for patients with laryngeal cancer, and improve the quality of life of patients.

Methods：We collected follow-up data from 123 patients with laryngeal cancer who were admitted to the First Affiliated Hospital of Wenzhou Medical University between 2010 and 2015. These patients received only radical concurrent chemoradiotherapy after diagnosis. Univariate Cox analysis was used to find the factors related to Progression-free survival（PFS）in patients with laryngeal cancer. Multivariate Cox regression analysis was used to determine the factors and indicators that could predict patients' PFS. The Receiver Operating Characteristic curve（ROC curve） was used to determine the optimal truncation value of the forecast index.

Results：Univariate Cox regression analysis showed that HPV, lymph node metastasis, NLR, （lymphocyte-to-monocyte Ratio）LMR and white blood cell count were related to PFS in patients with laryngeal cancer. Multivariate Cox regression analysis showed that positive HPV and NLR were effective predictors of PFS in laryngeal cancer. According to the ROC curve, the area under the curve of NLR is 0.743, and the optimal truncation value is 2.26.

Conclusions：HPV and NLR are reliable predictors of PFS in patients with laryngeal cancer receiving concurrent chemoradiotherapy, which can provide help and suggestions for follow-up and individualized treatment of laryngeal cancer after treatment.

Cancer Biology

HPV

laryngeal carcinoma

NLR

concurrent chemoradiotherapy

PFS

Laryngeal cancer is one of the most common head and neck malignancies, and its incidence is about the second among all head and neck tumors[1]. Approximately 180,000 new cases of throat cancer are diagnosed worldwide each year[2]. Laryngeal cancer often occurs in middle-aged and elderly people over 40 years old, among which male is more common than female[3]. According to histological classification, laryngeal carcinoma can be divided into squamous cell carcinoma, adenocarcinoma, undifferentiated carcinoma and some rare other types. According to the location of tumor, laryngeal cancer can be divided into supraglottic, glottic and subglottic. Among them, glottic laryngeal carcinoma is the most common type, accounting for 60–70% of all laryngeal cancers[4]. At the same time, because the tumor is located on the vocal cords and surrounding tissues, the symptoms of glottic laryngeal cancer such as hoarseness appear earlier than those of the other two types of laryngeal cancer, so as to be detected earlier.

For laryngeal cancer, there are many treatments, including surgery, neoadjuvant chemoradiotherapy, adjuvant chemoradiotherapy, radical concurrent chemoradiotherapy, immunotherapy and biological therapy[1]. Most patients with throat cancer undergo surgery as part of their treatment for the disease. Surgical treatment includes total laryngectomy and partial laryngectomy, but either surgical method can cause great damage to the laryngeal function, affect the patient's pronunciation, and thus affect the patient's quality of life. At present, more and more clinical studies have shown that induction chemotherapy combined with radiotherapy or concurrent radiotherapy for patients with advanced laryngeal cancer can achieve the same curative effect as radical surgery, and more than half of the patients can retain their vocal function. Therefore, in the process of clinical treatment, a considerable proportion of patients will choose concurrent radiotherapy and chemotherapy to treat laryngeal cancer[5, 6]. With the development of medical physics and the update of radiotherapy equipment, radiotherapy has not only been limited to the initial two field pair penetration or field block irradiation, but three dimensional appropriate radiotherapy and inverse intense-modulated radiotherapy have become the main radiotherapy methods. These radiotherapy methods can kill tumor cells more accurately and protect the surrounding normal tissues to the maximum extent, thus reducing the adverse effects of radiotherapy[7–9]. For laryngeal cancer, chemotherapy drugs have not been greatly updated in recent decades, and are still combined with platinum, 5-Fu, docetaxel and other drugs[10–12]. In clinical work, we have observed that some patients with laryngeal cancer who receive radical concurrent radiotherapy and chemotherapy can have a longer survival period, while others can progress quickly. If we can predict the time of disease progression after treatment and estimate the possible changes in the patient's condition, then we can adjust the treatment plan in a more timely manner, make more accurate and individualized treatment for patients, prolong the survival period of patients and improve the quality of life of patients.

At present, TMN staging is mainly used to predict the overall survival time and progression-free survival time of tumor patients. However, we observed significant differences in PFS even among patients with the same TNM staging. Therefore, there is an urgent need for other predictors to help predict patients' progression-free survival time, predict the possible changes in patients' condition in advance, and provide reliable evidence for patients' next treatment plan. At present, there are a number of clinical tools that can help predict the patient's disease changes. For example, ctDNA, proteins, genes, and so on[13–16]. However, these methods are expensive, and the testing procedures are complicated, which greatly consumes the time and money of patients. There is an urgent need for inexpensive, readily available molecular markers that can predict the course of a patient's disease.

Recently, there have been many findings about the predictive role of inflammatory factors in solid tumors[17–19]. However, no studies have yet revealed the value of NLR in laryngeal cancer patients receiving concurrent chemoradiotherapy. At the same time, our study showed that HPV infection and NLR were predictors of progression-free survival in patients receiving concurrent chemoradiotherapy for laryngeal cancer. It can help us predict the changes of the patient's condition and make timely adjustments to the treatment plan, so as to better extend the survival period of patients and improve the quality of life of patients.

Patient selection

In our study, a total of 123 patients with laryngeal cancer who received concurrent chemoradiotherapy in the First Affiliated Hospital of Wenzhou Medical University from 2010 to 2014 were enrolled. These patients received only radical concurrent chemoradiotherapy for various reasons after being diagnosed with laryngeal cancer. The inclusion conditions were as follows:（1）The patients ranged in age from 30 to 80 years old；（2）Pathologically diagnosed as laryngeal malignancy；（3）Only radical concurrent chemoradiotherapy was received after diagnosis；（4）The whole treatment process was carried out in the First Affiliated Hospital of Wenzhou Medical University with complete follow-up data；（5）The patient did not have other hematologic diseases that could affect blood inflammatory markers, such as systemic lupus erythematosus, thrombocytopenia purpura, etc. Blood markers such as red blood cells, white blood cells, platelets, CEA, SCC, LMR, NLR and so on were collected from these patients. We also collected personal characteristics of the patients, such as age, sex, smoking history, alcohol consumption history, BMI, whether they had HPV infection, and so on. At the same time, we also collected the characteristics of the patient's tumor, such as location, whether there is lymph node metastasis, etc.

Treatment protocol

All enrolled patients received a full course of concurrent chemoradiotherapy. The target area was delineated as follows: GTV was the primary tumor and metastatic lymph nodes as seen by imaging；CTV1 includes GTV, whole laryngeal structure, piriform fossa, lingual epiglottic stream, paraspinal space, preepiglottic space, whole thyroid cartilage, and lymph drainage area. CTV2 includes the supraclavicular prophylactic area of the lower neck. The distributed dose and total dose were given according to PTV. The distributed dose of PGTV was 2.12Gy, the total dose was 70Gy/33 times, the distributed dose of PTV1 was 1.82Gy, the total dose was 60Gy/33 times, and the distributed dose of PTV2 was 1.8Gy, the total dose was 50-54Gy/28-30Gy times. The supraglottic lymph node drainage area included bilateral neck region II-IV lymph node drainage area, the T3-4 glottic cancer target area delineated the ipsilateral supraglottic area, and the lesions in the subglottic area included bilateral VI lymph nodes on the basis of the delineation of the supraglottic area. The chemotherapy regimen is a platinum-based regimen for 3-4 weeks, and the specific dosage varies according to the side effects of patients and changes in body surface area. This study has been approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University. At the same time, we also obtained the informed consent of the patient and his family, and signed the informed consent.

Evaluation strategy

PFS was selected as the end point of this study. PFS is defined as the time between the onset of treatment for a cancer disease and the observation of disease progression or death from any cause. We used CT, MRI, ultrasound, endoscopy and other imaging methods to reevaluate the situation after tumor treatment. Within 1 year after the end of treatment, we performed reexaminations at 1, 3, 6, and 12 months respectively. One year after the end of treatment, patients were re-evaluated every 3-6 months. Tumor progression was assessed according to RECIST1.1 criteria. The minimum sum of the diameters of all target lesions measured throughout the course of the disease was used as a reference, and a relative increase of at least 20% in the sum of diameters was used as a reference for tumor progression (if the baseline measurement was the minimum, the baseline value was used as a reference). In addition, an increase of at least 5mm in the absolute value of the tumor diameter and sum is also considered as disease progression (one or more new lesions are also considered as disease progression). All imaging evaluations were completed by 2-3 senior chief physicians in our hospital.

Data statistics

All statistical analyses were performed using a social science statistical software package, version 22.0 (SPSS Inc.Chicago, IL, USA). All the included data not only included blood indicators such as red blood cells, white blood cells and platelets, but also included patient characteristics such as age, BMI and smoking history. Univariate Cox regression analysis was used to look for factors associated with post-treatment PFS in patients with laryngeal cancer. Multivariate Cox regression analysis was used to determine the predictors of PFS. Receiver operating characteristic curves were used to determine the optimal truncation value of the predictors. The K-M curve is used to plot the survival curve. Chi-square test was used to analyze the relationship between the predictive indexes and the basic parameters of patients. P < 0.05 was considered statistically significant.

In total, we collected data on 123 patients undergoing concurrent chemoradiotherapy for laryngeal cancer. All ages ranged from 44 to 85 years, with an average age of 66 years; Follow-up ranged from 2 to 72 months, with an average of 18.9 months. We grouped supraglottic and subglottic laryngeal cancers into one group (52 patients). There was a separate group of 71 patients with glottic laryngeal cancer. At the same time, we divided the BMI into normal group and abnormal group according to the normal value, with 64 and 59 people respectively. The presence or absence of lymph node metastasis was observed in 61 and 62 patients respectively. The other parameters are shown in Table 1 below.

We analyzed the data using univariate Cox regression, and we found that HPV infection (OR 1.545 (95% CI 1.079-2.214), p <0.05), lymph node metastasis, white blood cells, NLR (OR 1.629 (95% CI 1.132-2.344), p <0.05) and LMR (OR 0.670 (95% CI 0.464-0.968), p <0.05) were associated with PFS of laryngeal cancer after concurrent chemoradiotherapy (Table 2). Subsequently, we used multivariate Cox regression to analyze the above five significant indicators, and the results showed that HPV(OR 1.605 (95% CI 1.106-2.329), p <0.05), lymph node metastasis and NLR(OR 1.721 (95% CI 1.186-2.499), p <0.05) were predictive indicators of PFS in patients with laryngeal cancer（Table 3）. Patients with laryngeal cancer infected with HPV had significantly longer PFS than those without HPV infection. Among patients with HPV infection, the average PFS was 22.6 months; In patients without HPV infection, the average PFS was 15.9 months（Figure 1）. Patients with a lower NLR had significantly longer PFS than those with a higher NLR（Figure 2）. We then use the receiver operating curve to find the best truncation value for NLR. According to the ROC curve（Figure 3）, the best truncation value is 2.26, and the basis below the curve is 0.743, which has good diagnostic significance. At the same time, we used chi-square analysis to test the relationship between HPV, NLR and patients' basic characteristics. Chi-square test showed that HPV was only associated with lymph node metastasis（Table 4）, while NLR was not associated with other indicators（Table 5）.

Laryngeal carcinoma is one of the most common malignant tumors in the head and neck, and most of its pathological types are squamous cell carcinoma[20]. The occurrence of laryngeal cancer is related to genetic factors, living environment and living habits. Some occupational exposure to carcinogens, such as long-term exposure to asbestos, mustard gas and other staff; People living in areas with high air pollution for a long time; People infected with HVP virus and the elderly who smoke and drink for a long time are at high risk of laryngeal cancer[21, 22]. At present, the standard treatment for laryngeal cancer is surgery or concurrent chemoradiotherapy. Surgery is mainly divided into total laryngeal surgery and half laryngeal surgery, but no matter which type of surgery, it has a greater impact on the patient's pronunciation function. Therefore, a large proportion of patients will choose concurrent chemoradiotherapy for the treatment of laryngeal cancer. Studies have shown that concurrent chemoradiotherapy can be as effective as surgery[23, 24]. However, similar to surgical treatment, some patients still have recurrence or metastasis at some point after radical radiotherapy or chemotherapy. This will give the patient's physical and psychological will cause another blow, aggravating the patient's economic burden. Therefore, if the recurrence and metastasis time of patients after treatment can be effectively predicted, it is undoubtedly good news for patients with laryngeal cancer. Previous studies have looked at predictors of survival in patients with laryngeal cancer after surgery. In patients undergoing concurrent chemoradiotherapy, few studies have looked for predictors. For this purpose, our study confirmed that HPV-negative patients and patients with higher NLR were poor predictors of patients with laryngeal cancer after concurrent chemoradiotherapy.

HPV is A papillomatous vacuolavirus genus A belonging to the family Papillomavirus, which is A spherical DNA virus, which can cause the squamous epithelium proliferation and even canceration of human skin mucosa[25, 26]. Previous studies have shown that people with HPV infection have a higher risk of throat cancer than people without HPV infection[27]. But interestingly, our study found that HPV-positive laryngeal cancer patients who received concurrent chemoradiotherapy had a lower risk of recurrence and metastasis than HPV-negative laryngeal cancer patients, which is somewhat inconsistent with what we have traditionally thought. Some studies have analyzed that the reason may be that HPV-infected laryngeal cancer patients are more sensitive to radiotherapy and chemotherapy. After receiving concurrent radiotherapy and chemotherapy, HPV-positive laryngeal cancer patients have a higher control rate[28, 29]. Other studies speculated that the better prognosis of HPV-positive tumors might be related to the immunity of the body, because they found in animal experiments that the proliferation rate of HPV-positive tumor cells in normal immunized mice was significantly slower than that of HPV-negative mice, but the same experimental results were not found in immunodeficient nude mice[30]. So when we look at a patient with HPV-positive laryngeal cancer, we can make a bold assumption that the patient will respond well to radiotherapy and chemotherapy and may have a longer PFS.

In previous studies, the predictive role of NLR and some inflammatory markers in solid tumors has been reported. Jia Fu Ji et al showed that inflammatory and nutritional markers were predictors of survival in gastric cancer patients receiving neoadjuvant chemotherapy and D2 lymphadenectomy[31]. Z Lin and J Xu et al suggested that systemic inflammatory markers could predict postoperative prognosis of renal cancer[32]. Garcia-ortiz MV and his team suggested that the combination of NLR and other indicators could improve the predictive value of prognosis in metastatic pancreatic cancer[33]. However, there is no association between NLR and laryngeal cancer patients receiving concurrent chemoradiotherapy, and our study is filling this gap. A total of 123 laryngeal cancer patients undergoing concurrent chemoradiotherapy were enrolled in our study. We used the ROC curve to determine the optimal cutoff value for the patient's NLR. Fifty-eight patients had a value greater than or equal to 2.26, and 65 patients had a value less than 2.26. The mean PFS of laryngeal cancer patients with NLR greater than or equal to 2.26 was 15.2 months, which was much smaller than that of patients with NLR less than 2.26. The mean PFS of laryngeal cancer patients with NLR less than 2.26 was 22.3 months. P < 0.05, with statistical significance. As for why NLR can predict the survival time of laryngeal cancer patients, we conclude that there may be several reasons according to the analysis of some previous studies. The value of NLR is obtained by dividing the count of neutrophils by the count of lymphocytes. Neutrophils and lymphocytes are important immune cells in human body, and their number is related to the immune function of human body. If their numbers are reduced, the body's immune function may be impaired. They may not be able to kill tumor cells directly, but they may somehow be able to inhibit their proliferation and distant metastasis [34, 35]. It has also been suggested that tumor-induced neutrophils can promote tumor metastasis through blood circulation [36]. As a basic component of the immune system, lymphocytes can inhibit the proliferation of tumor cells, inhibit migration and destroy metastasis[37]. In addition, some studies have suggested that the reduction of lymphocytes before treatment may be related to the reduced therapeutic effect of solid tumors. This evidence supports the role of hemoinflammatory factors such as NLR in solid tumor prediction.

However, our research also has some shortcomings. First of all, this is a single center retrospective study, and the number of participants is small, so the results may be unstable. We need to expand the study number and use data from multiple centers in the future. Secondly, our study only independently proved the relationship between HPV and NLR and laryngeal cancer patients receiving concurrent chemoradiotherapy, which could not be immediately applied to clinical practice. We should give a more reasonable prediction model by integrating various factors. Finally, the endpoint selected in this study is PFS. In tumor patients, OS is actually a more convincing indicator. We need to continue to follow up patients to achieve OS-related factors.

HPV and NLR were predictors of laryngeal cancer in patients receiving concurrent chemoradiotherapy. We can use these two indicators to assist in the selection of treatment strategies for laryngeal cancer patients.

HPV：Human Papilloma Virus NLR：Neutrophil-to-Lymphocyte Ratio PFS：Progression-Free Survival ROC curve：Receiver Operating Characteristic curve LMR：Lymphocyte-to-Monocyte Ratio CEA： Carcinoembryonic Antigen BMI: Body Mass Index CTV: Clinical Target Volume GTV: Gross Target Volume PTV: Planning Target Volume PFS: Progression-Free Survival OS: Overall Survival

Acknowledgements

We appreciate the efforts of all members of our radiotherapy department and the support of all the patients’ families

Authors’ contributions

KJL was involved in data analysis, interpretation and manuscript writing. QYL, YYX and ZYS were involved in collection and assembly of data. CLZ and RYX was involved in conception and design. All authors read and approved the final manuscript

Funding

This article is not funded by any fund.

Availability of data and materials

The dataset in this study is available by request from the corresponding author. For more information, please contact the corresponding author

Ethics approval and consent to participate

All the procedures followed were in accordance with the ethical guidelines of the Helsinki Declaration. The study protocol was approved by the Medical Ethical Committee of the First Affiliated Hospital of Wenzhou Medical University.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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HPV and （ Neutrophil-to-lymphocyte ratio ） NLR are Prognostic Indicators of Laryngeal Cancer Patients Receiving Concurrent Chemoradiotherapy

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Patient selection

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Data statistics

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Conclusion

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Authors’ contributions

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Availability of data and materials

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