Research ArticleClinical Studies

Sex-specific Real-World 5-year Overall Survival Rates for (Radio)chemotherapy, Targeted Therapy, and Combinations in Patients With Head and Neck Cancer

JOSEFINE BAUDREXL, SEBASTIAN PIETZKA, MARIO SCHEURER, ALEXANDER SCHRAMM, FRANK WILDE, ANDREAS SAKKAS, SPYRIDOULA DERKA and MARCEL EBELING
Anticancer Research January 2024, 44 (1) 267-286; DOI: https://doi.org/10.21873/anticanres.16810

Abstract

Background/Aim: Sex-specific medicine, an emerging field in healthcare, has gained significant recognition and importance in recent years. To the best of our knowledge, there are currently no valid data on the influence of sex on 5-year overall survival of patients with head and neck cancer undergoing (radio)chemotherapy, targeted therapy, and combination treatments, using Real-World Data. We hypothesize that sex has a significant impact on 5-year overall survival across different therapy regimens for head and neck cancer. Patients and Methods: Data from head and neck cancer patients treated with different regimens from the TriNetX network were analyzed. Two groups were formed: Cohort I (female) and cohort II (male), which were matched 1:1 with respect to certain confounders. After defining the primary outcome as “death”, a Kaplan–Meier analysis was performed, and the risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were calculated. Results: A total of 16,529 patients with OSCC were analyzed. This retrospective case-matched analysis found a tendency for female patients to have a greater 5-year overall survival probability than male patients with respect to the various therapeutic regimens for OSCC. Conclusion: There is an urgent need for more personalized medicine in patients with head and neck cancer due to the limited data available. It is still questionable whether therapies are equally effective in men and women, although, according to the guidelines, the treatments are mostly the same for both sexes.

Key Words:

Sex-specific medicine, an emerging field in healthcare, has gained significant recognition and importance in recent years. It represents a paradigm shift in our approach to medical research and clinical practice, acknowledging that biological differences between men and women profoundly influence the way diseases manifest, progress, and respond to treatments. This evolution in medical thinking recognizes that a one-size-fits-all approach is often inadequate, and tailoring medical care to an individual’s sex can lead to more effective and personalized healthcare.

Clinical research is mainly performed on males, male mice, or cells from male hosts (1). Women of childbearing age are usually categorically excluded from pharmacological studies for safety reasons. This creates a more male-centered understanding of biology and pharmacology. It has been assumed that the cells of men and women are identical in structure and function. However, the first differences are already found at the chromosome level, XX versus XY (2). Men and women differ in their response to drugs. There are fundamental differences in hormones, total body water, the ratio of extracellular to intracellular water, and body surface area, as well as pharmacokinetics (3). There is a noticeable difference in plasma protein binding of several drugs comparing men to women, which often leads to more toxicity and side effects in women compared to men (4).

The second leading cause of death in both men and women is cancer, with men developing cancer at a higher percentage than women (5). In this regard, men have lower overall survival, which is primarily attributed to statistically more prevalent risk behaviors (smoking, alcohol consumption, unhealthy diets) and is associated with an increased risk of cancer (6). The more aggressive phenotype of hepatocellular carcinoma diagnosed more frequently in men can be used as an example. It was found that androgens had a more stimulatory effect and estrogen had a more protective effect concerning hepatocellular cancer (7).

“Medicine, as currently applied to women, is less evidence-based than that being applied to men” (8). There is increased interest in sex- and gender-sensitive medicine, both scientifically and culturally. Furthermore, although modern research is focused on the differences in pharmacokinetics and pharmacodynamics between men and women, there is still need for improvement. In summary, sex-specific research in medicine is essential to provide personalized and effective healthcare for both men and women. It helps in understanding the biological and hormonal differences between the sexes, tailoring treatments, preventing sex-specific diseases, and promoting equity in healthcare. This research contributes to the development of more effective, precise, and inclusive medical practices.

To the best of our knowledge, there are currently no valid data on the influence of sex on the 5-year overall survival of patients with head and neck cancer (HNC) undergoing (radio)chemotherapy, targeted therapy, and combination treatments, using Real-World Data.

We hypothesize that sex has a significant impact on 5-year overall survival with different therapy regimens for head and neck cancer. Data on discrepancies in patients are controversial and contributing factors have not been clarified.

The aim of this study was to analyze the overall survival of men and women with respect to different therapy regimens for head and neck carcinoma using Real-World Data from the TriNetX Global Health Research Network (TriNetX, Cambridge, MA, USA). Detailed data analyses were performed to improve understanding of how sex might change clinical prognoses in different therapy regimens.

Patients and Methods

Ethics statement. An exception was granted by the institutional ethics committee, due to the retrospective nature of the study and the de-identification of the data, exclusively used from the TriNetX Global Health Research Network. This is because all Healthcare Organizations (HCOs) that contributed data to TriNetX acquired written informed consent from either the patients themselves or their legal guardians.

Real-World Data. According to the definition provided by the U.S. Food and Drug Administration (FDA), Real-World Data (RWD) in the field of medical and healthcare encompass “data pertaining to the health status of patients and/or the delivery of healthcare, routinely collected from various sources”.

RWD originate from sources distinct from conventional clinical trials and is gathered independently of randomized clinical trials, which continue to serve as the benchmark for generating clinical knowledge. The inherent randomization of patients into distinct treatment groups and the stringent selection criteria applied in randomized clinical trials can pose challenges in translating their results into practical applications within Real-World clinical practice.

Real-World Evidence (RWE), derived from the utilization of RWD, offers a more accurate reflection of the actual clinical environment in which therapeutic interventions are administered. This includes considerations, such as patient demographics, comorbidities, adherence to treatment regimens, and concurrent treatments. RWD represents a valuable and comprehensive source of data that extends beyond the confines of traditional epidemiological studies, clinical trials, and laboratory-based experiments. Moreover, it offers a cost-effective alternative for data collection compared to the latter methods.

When appropriately employed and analyzed, RWD holds the potential to generate valid and unbiased RWE. This not only results in cost and time savings compared to controlled trials but also enhances the efficiency of research and decision-making processes in the fields of medicine and healthcare.

Data acquisition, allocation, and matching. The TriNetX Global Health Research Network provides access to medical records from more than 120 healthcare organizations (HCOs) in over 30 countries in North and South America, EMEA and Asia-Pacific including over 250,000,000 patients with more than 5 years of clinical history enabling the collection and exchange of longitudinal clinical data (9).

Target variables were sex and the outcome measure was 5-year overall survival.

We enrolled patients who fulfilled the following inclusion criteria: 1) head and neck cancer (International Classification of Diseases (ICD)-10 codes C00-C14), 2) radiotherapy (RT), 3) radiochemotherapy with platinum compound combination, 4) radiotherapy with cetuximab (RT + CTX), 5) chemotherapy with platinum compound combination and Cetuximab (CT + CTX), 6) chemotherapy with platinum compound combination and 5-fluorouracil and cetuximab (CT + 5-FU + CTX), 7) pembrolizumab (PB) mono, 8) pembrolizumab in combination with chemotherapy with platinum compound combination and 5-fluorouracil (PB + CT + CTX) from the TriNetX network were used (Figure 1).

Figure 1.
Figure 1.
Figure 1.

Consort flow diagram. ICD-10: International Classification of Diseases 10; C00- 14: malignant neoplasms of lip, oral cavity, and pharynx.

Exclusion criteria were 1) none (neo)adjuvant therapy, 2) follow-up data less than 5 years, 3) patients with medical records older than 20 years. There were no other specific selection criteria beyond the diagnosis and treatment type used for this study, to properly make use of real word data. To be included, patients’ medical records had to cover at least five years (1,825 days) of follow-up after visiting the HCO for an inpatient encounter. Medical records older than 20 years were excluded. This was done to enhance the efficiency of processing and delivering outcome analytics results.

Two groups were formed for the analyses: Cohort I with male patients, whereas patients in cohort II were female. As in previous published studies, to exclude confounders, cohorts I and II were matched 1:1 with respect to age, lymph node metastases, nicotine dependence and alcohol dependence. In addition, matching via lymph node metastases also allows comparison of patients with and without advanced and metastatic states. Other confounders were not considered in this study. This made it possible to get as close as possible to randomized study conditions (10, 11).

Data analysis. Descriptive statistics were used to describe baseline patient and surgery characteristics. All categorical variables are expressed as absolute values (n) and relative incidence (%). Patient age is presented with the mean value and standard deviation. A multivariable analysis was performed to find associations between sex and 5-year overall survival. The outcome was defined as “death” within a period of 5 years after the start of therapy. We focused on overall survival, since progression is not typically recorded in structured electronic health records (HERs), which is the source of most of the data provided by Healthcare Organizations to TriNetX. Kaplan–Meier analysis, Cox proportional hazards regression, and calculation of risk ratio (RR), odds ratio (OR), and hazard ratio (HR) were performed. Data analysis was limited to a period of 5 years after the first HNC diagnosis, as patients are regarded as healed in case of absence/no recurrence of HNC or metastases within the defined period. Statistical analysis was performed using the log-rank test with a p≤0.05 as statistically significant. For 1:1 matching, the propensity score-matching algorithm was used, where logistic regression is used to calculate a propensity score for each patient in the group. This can range from 0 to 1 and indicates the predicted probability that a patient is in cohort I or II given the patients covariates. The greedy nearest-neighbor matching algorithm with a caliper of 0.1 pooled standard deviation was used. The caliper setting within TriNetX has a fixed value of 0.1.

Results

Assessment, allocation, and matching. The database was queried on 09/23/2023, leading to the exclusion of 550 patient records that did not meet the inclusion criteria, particularly those acquired more than 20 years ago. Considering the inclusion and exclusion criteria a total of 16,529 patients from 73 HCOs were included in the study. A total of 1,564 female and 3,411 male patients received radiotherapy (RT; ratio: 1:2.18), 943 female and 2,872 male patients received radiochemotherapy (ratio: 1:3.05) with platinum compound combination, 256 female and 906 male patients received radiotherapy with cetuximab (RT + CTX; ratio: 1:3.54), 357 female and 879 male patients received chemotherapy with platinum compound combination and cetuximab (CT + CTX; ratio: 1:2.46), 149 female and 721 male patients received chemotherapy with platinum compound combination and 5-fluorouracil and cetuximab (CT + 5-FU + CTX; ratio: 1:4.84), as well as 1,030 female and 2,862 male patients received pembrolizumab (PB; ratio: 1:2.78) mono or 126 female and 453 male patients received pembrolizumab in combination with chemotherapy with platinum compound combination and 5-fluorouracil (PB + CT + CTX; ratio: 1:3.6). The respective number and percentages of deaths are shown in Table I.

View this table:
Table I.

Therapy regimens considered in this study, with their number and percentage of deaths.

All the aforementioned groups were compared with each other in terms of 5-year overall survival. After matching 1:1 for age, lymph node metastases, nicotine dependence, alcohol dependence and BMI, the two comparison groups no longer differed significantly with respect to potential confounders.

Radiotherapy. Before propensity score matching (PSM), the male cohort included 3,789 patients and the female cohort included 1,735 patients. Both cohorts differed significantly (p<0.05) for lymph node metastases, nicotine dependence, and alcohol abuse. After PSM, both groups consisted of 1,556 patients and did not differ significantly for any confounder (Figure 2, Table II).

Figure 2.
Figure 2.

Propensity score density function. Before PSM (right) and after PSM (left). (purple: male, green: female).

View this table:
Table II.

Patients’ characteristics of cohorts I (male) and II (female) before and after 1:1 matching for age, lymph node metastases, nicotine dependence, and alcohol dependence.

A total of 444 patients of cohort I (risk of death: 28.5%) and 401 patients of cohort II (risk of death: 25.8%) died within 5 years (Figure 3). The risk difference of 2.8% was not significant (p=0.083). The risk ratio (RR) was 1.107 [95% confidence interval (CI)=0.987-1.243], odds ratio (OR) was 1.150 (95%CI=0.982-1.347) and hazard ratio (HR) was 1.170 (95%CI=1.022-1.339) (Table III, Figure 4). In addition, a z-test for proportionality was performed. Median survival indicated the number of days when survival dropped below 50%, with “–” denoting that survival did not drop below 50% during the five years.

Figure 3.
Figure 3.

Patients with outcome “death” from cohort I and cohort II. (purple: male, green: female).

View this table:
Table III.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients.

Figure 4.
Figure 4.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients. (purple: male, green: female).

Radiochemotherapy (Platinum compounds). Before PSM, the male cohort included 2,952 patients and the female cohort included 965 patients. Both cohorts differed significantly (p<0.05) for alcohol abuse. After PSM, both groups consisted of 953 patients and did not differ significantly for any confounder (Figure 5, Table IV).

Figure 5.
Figure 5.

Propensity score density function. Before PSM (right) and after PSM (left). (purple: male, green: female).

View this table:
Table IV.

Patients’ characteristics of Cohort I (male) and II (female) before and after 1:1 matching for age, lymph node metastases, nicotine dependence, alcohol dependence, and body mass index (BMI).

A total of 456 patients of cohort I (risk of death: 47.8%) and 441 patients of cohort II (risk of death: 46.3%) died within 5 years (Figure 6). The risk difference of 1.6% was not significant (p=0.491). RR was 1.034 (95%CI=0.940-1.137), OR was 1.065 (95%CI=0.890-1.275) and HR was 1.117 (95%CI=0.980-1.273) (Table V, Figure 7). In addition, a z-test for proportionality was performed.

Figure 6.
Figure 6.

Patients with outcome “death” in cohort I and cohort II. (purple: male, green: female).

View this table:
Table V.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients.

Figure 7.
Figure 7.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients. (purple: male, green: female).

Radiotherapy and targeted-therapy (cetuximab). Before PSM, the male cohort included 911 patients and the female cohort included 258 patients. Both cohorts did not differ significantly (p<0.05) for any confounder before and after PSM. After PSM, both groups consisted of 258 patients (Figure 8, Table VI).

Figure 8.
Figure 8.

Propensity score density function. Before PSM (right) and after PSM (left). (purple: male, green: female).

View this table:
Table VI.

Patients’ characteristics of Cohort I (male) and II (female) before and after 1:1 matching for age, lymph node metastases, nicotine dependence, alcohol dependence, and body mass index (BMI).

A total of 152 patients of cohort I (risk of death: 58.9%) and 159 patients of cohort II (risk of death: 61.6%) died within 5 years (Figure 9). The risk difference of −2.7% was not significant (p=0.529). RR was 0.956 (95%CI=0.831-1.100), OR was 0.893 (95%CI=0.627-1.271) and HR was 1.065 (95%CI=0.852-1.330) (Table VII, Figure 10). A z-test for proportionality was also performed.

Figure 9.
Figure 9.

Patients with outcome “death” from cohort I and cohort II. (purple: male, green: female).

View this table:
Table VII.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients.

Figure 10.
Figure 10.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients. (purple: male, green: female).

Chemotherapy (platinum compounds) and targeted-therapy (cetuximab). Before PSM, the male cohort included 1,429 patients and the female cohort included 364 patients. Both cohorts did not differ significantly (p<0.05) for any confounder before or after PSM. After PSM, both groups consisted of 362 patients (Figure 11, Table VIII).

Figure 11.
Figure 11.

Propensity score density function. Before PSM (right) and after PSM (left). (purple: male, green: female).

View this table:
Table VIII.

Patients’ characteristics of Cohort I (male) and II (female) before and after 1:1 matching for age, lymph node metastases, nicotine dependence, alcohol dependence, and body mass index (BMI).

A total of 217 patients of cohort I (risk of death: 59.9%) and 211 patients of cohort II (risk of death: 58.3%) died within 5 years (Figure 12). The risk difference of 1.7% was not significant (p=0.650). RR was 1.028 (95%CI=0.911-1.161), OR was 1.071 (95%CI=0.796-1.440) and HR was 1.021 (95%CI=0.845-1.234) (Table IX, Figure 13). A z-test for proportionality was performed.

Figure 12.
Figure 12.

Patients with outcome “death” from cohort I and cohort II. (purple: male, green: female).

View this table:
Table IX.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients.

Figure 13.
Figure 13.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients. (purple: male, green: female).

Chemotherapy (platinum compounds with 5-fluorouracil) and targeted-therapy (cetuximab). Before PSM, the male cohort included 710 patients and the female cohort included 148 patients. Both cohorts did not differ significantly (p<0.05) for any confounder before and after PSM. After PSM, both groups consisted of 148 patients (Figure 14, Table X). A total of 85 patients of cohort I (risk of death: 57.4%) and 86 patients of cohort II (risk of death: 58.1%) died within 5 years (Figure 15). The risk difference of −0,7% was not significant (p=0.906). RR was 0.988 (95%CI=−0.119-0.106), OR was 0.973 (95%CI=0.613-1.543) and HR was 1.016 (95%CI=0.753-1.372) (Table XI, Figure 16). In addition a z-test for proportionality was performed.

Figure 14.
Figure 14.

Propensity score density function. Before PSM (right) and after PSM (left). (purple: male, green: female).

View this table:
Table X.

Patients’ characteristics of Cohort I (male) and II (female) before and after 1:1 matching for age, lymph node metastases, nicotine dependence, alcohol dependence, and body mass index (BMI).

Figure 15.
Figure 15.

Patients with outcome “death” from cohort I and cohort II. (purple: male, green: female).

View this table:
Table XI.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients. [Chi-squared (χ2): Log-rank statistic underlying distribution and hypothesis test; df: degree of freedom].

Figure 16.
Figure 16.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients. (purple: male, green: female).

Targeted-therapy (pembrolizumab). Before PSM, the male cohort included 2,904 patients and the female cohort included 1,035 patients. Both cohorts differed significantly (p<0.05) for lymph node metastases, nicotine dependence, and alcohol abuse. After PSM, both groups consisted of 1,035 patients and did not differ significantly for any confounder (Figure 17, Table XII).

Figure 17.
Figure 17.

Propensity score density function. Before PSM (right) and after PSM (left). (purple: male, green: female).

View this table:
Table XII.

Patients’ characteristics of Cohort I (male) and II (female) before and after 1:1 matching for age, lymph node metastases, nicotine dependence, alcohol dependence, and body mass index (BMI).

A total of 446 patients in cohort I (risk of death: 43.1%) and 405 patients in cohort II (risk of death: 39.1%) died within the timeframe of 5 years (Figure 18). The risk difference of 4% was not significant (p=0.067). RR was 1.101 (95%CI=0.993-1.221), OR was 1.178 (95%CI=0.989-1.404) and HR was 1.100 (95%CI=0.961-1.258) (Table XIII, Figure 19). In addition, a z-test for proportionality was performed.

Figure 18.
Figure 18.

Patients with outcome “death” from cohort I and cohort II. (purple: male, green: female).

View this table:
Table XIII.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients. [Chi-squared (χ2): Log-rank statistic underlying distribution and hypothesis test; df: degree of freedom].

Figure 19.
Figure 19.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients. (purple: male, green: female).

Targeted-therapy (pembrolizumab) and chemotherapy (platinum compounds with 5-fluorouracil). Before PSM, the male cohort included 442 patients and the female cohort included 127 patients. Both cohorts differed significantly (p<0.05) for lymph node metastases and nicotine dependence. After PSM, both groups consisted of 127 patients and did not differ significantly for any confounder (Figure 20, Table XIV).

Figure 20.
Figure 20.

Propensity score density function. Before PSM (right) and after PSM (left). (purple: male, green: female).

View this table:
Table XIV.

Patients’ characteristics of Cohort I (male) and II (female) before and after 1:1 matching for age, lymph node metastases, nicotine dependence, alcohol dependence, and body mass index (BMI).

A total of 66 patients in cohort I (risk of death: 50.2%) and 63 patients in cohort II (risk of death: 49.6%) died within 5 years (Figure 21). The risk difference of 2.4% was not significant (p=0.707). RR was 1.048 (95%CI=0.822-1.335), OR was 1.099 (95%CI=0.672-1.798) and HR was 0.913 (95%CI=0.646-1.291) (Table XV and Figure 22). A z-test for proportionality was also performed.

Figure 21.
Figure 21.

Patients with outcome “death” from cohort I and cohort II. (purple: male, green: female).

View this table:
Table XV.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients. [Chi-squared (χ2): Log-rank statistic underlying distribution and hypothesis test; df: degree of freedom].

Figure 22.
Figure 22.

Kaplan–Meier survival analysis for a 5-year interval of male and female patients.

Discussion

The intent of this study was to evaluate the influence of sex on overall survival in patients with head and neck cancer undergoing different therapy regimens according to international guidelines. It was assumed that male and female patients differ significantly in overall survival in the first 5 years after the start of therapy. The hypothesis was confirmed. A tendency was shown for female patients to have a greater 5-year survival probability than male patients.

Primary radical radiotherapy can be used either for curative intention, to improve local tumor control after or before surgical therapy (adjuvant or neoadjuvant radiotherapy), or to reduce tumor-related symptoms (palliative radiotherapy). By comparing the outcome between male and female patients undergoing exclusively radiotherapy we found that female patients appear to have a higher 5-year overall survival probability than male patients. In a systematic review of De Courcy et al. (12) it was reported that there are more side effects concerning radiotherapy in male mice than in female mice. However, the risk of developing a solid tumor was found to be higher in women after prolonged exposure to radiation compared to men (13).

There was a similar finding concerning primary radiochemotherapy regarding male and female patients. Primary radiochemotherapy consisted of platinum based compounds (14, 15). In patients with advanced, inoperable, and nonmetastatic oral cavity carcinoma, primary radiochemotherapy should be preferred to radiotherapy alone, especially in the age groups up to 70 years. Chemotherapy is often given concomitantly with radiotherapy, and after surgical treatment has been completed (adjuvant radiochemotherapy). Postoperative radiation or radiochemotherapy should be given in cases of advanced T-category (T3/T4), scarce or positive resection margins, perineural invasion, vascular invasion, and/or lymph node involvement. In this analysis a higher 5-years overall survival probability was found in female patients compared to male patients. Unger et al., found that “among non-sex-specific cancers, the risk of cardiotoxicity may be higher for women than men, especially among those treated with chemotherapy” (16). This is in contrast to our findings. As previously suggested, we suppose that overall health seeking behavior is greater in women than in men, which leads to a higher survival probability. Women tend to seek more health information and care than men (17). Men tend to neglect disease and pain and therefore use less health services as well as routine checks in comparison to women (18). This might contribute to a lower 5-year survival probability compared to women.

Radiochemotherapy in combination with cetuximab is an alternative to radiochemotherapy alone. In a randomized multicenter trial, the benefit of the EGF receptor-targeted monoclonal antibody cetuximab in combination with radical radiotherapy in advanced head and neck cancer was investigated. An improvement in local tumor control and overall survival of 11 and 10%, respectively, was shown, compared to radiotherapy alone, with no increase in radiation toxicity (19). Concerning the combination of chemotherapy with cetuximab, patients with incurable tumor disease but a good general and performance status should be assigned to palliative platinum-based chemotherapy in combination with cetuximab according to the guidelines. In our analysis, we showed a higher 5-year survival probability in female patients compared to male patients when focusing on the treatment of either radiochemotherapy or chemotherapy in combination with cetuximab. Only the combination of chemotherapy with platinum compounds and cetuximab showed a similar 5-year survival probability in male and female patients. Interestingly, previous research has shown that women tend to develop more severe adverse events than men receiving targeted therapy (16).

The PD-1 receptor-targeted antibody pembrolizumab should be used as first-line monotherapy or in combination with platinum and 5-fluorouracil in patients with PD-L1-expressing tumors and immune cells (CPS ≥1) (20). In patients pathologically lacking PD-L1 expression in tumor or immune cells (CPS <1), the EGF receptor-targeting antibody cetuximab should be used in the palliative setting as first-line therapy in combination with platinum (preferably cisplatin) and 5-fluorouracil (EXTREME regimen) in patients in good general health who no longer qualify for local therapy (21). A large phase III trial of 882 patients evaluated the administration of pembrolizumab alone or in combination with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (20). Here, the subgroup of patients with oral cavity carcinoma was approximately 30%. Pembrolizumab alone showed improved overall survival of 14.9 versus 10.7 months compared with cetuximab in combination with chemotherapy in a population with a CPS score of 20. With a CPS of 1, the survival benefit was 2 months. In combination with chemotherapy, pembrolizumab improved survival by 2.3 months (13.0 versus 10.7 months) over cetuximab with chemotherapy in the overall population, with an improved survival of 3.7 months in patients with a CPS score of 20 and an improved survival of 3.2 months in those with a CPS score of 1. Immunotherapy with pembrolizumab alone or in combination with chemotherapy showed a tendency of a higher 5-year survival for female patients compared to male patients. This also stands in contrast to previous findings where female patients tended to show more adverse effects and less tolerability concerning immunotherapy (16). Grassadonia et al. showed in a meta-analysis of phase III randomized clinical trials, that the positive effects of checkpoint inhibitors on progression free survival and overall survival are greater for male patients than female patients (22).

The strengths of this Real-World Data analysis lie in its substantial patient cohort and the application of PSM to mitigate the influence of confounding factors. We conducted matching based on age and common risk factors like smoking and alcohol consumption. This retrospective study relied on data sourced from the TriNetX database. Notably, this study did not delve into HPV status or other histopathological aspects, such as UICC stage, lymph node metastasis, or extracapsular spread (ECS), due to the inherent limitations of the database. TNM data is limited to the patients whose data comes from the cancer registry. Outside cancer registries TNM data is recorded in free-text, thus a Natural-Language-Processing (NLP) extraction is necessary. NLP is still challenging because it needs financial resources, and it is necessary to implement data quality control measures to make this data trustworthy. The utilization of ICD-10 codes also precluded the retrieval of information pertaining to differences in tumor stage and pathohistological features. Subsequent studies should encompass a more granular examination of histopathological details, including tumor stage, grading, HPV status, and surgical resection status.

Furthermore, it is important to acknowledge the study’s constraints, such as the unavailability of data on the cause of death to determine whether it was cancer-related; this information could not be gleaned from the TriNetX database. Additionally, the employed Real-World Data was collected globally and encompassed information furnished by various healthcare organizations (HCOs) in Europe, the Middle East, Africa, Asia, North America, and South America. Regrettably, this multi-center analysis did not account for national and international disparities in the management of oral cancer patients and epidemiological discrepancies.

The findings need to be interpreted cautiously considering the limitations discussed above. At a minimum, the harvested data support the hypotheses that female patients have a greater 5-year survival probability than male patients with respect to the various therapeutic regimens for head and neck cancer. In previous studies rather opposite results have been obtained. Female patients showed more adverse effects, poorer tolerability of the treatment and shorter overall survival. A possible explanation is that in our analysis exclusive Real-World Data were used. The data collected are clinical data from real patients and were not obtained from studies. This might encourage further research.

Conclusion

A tendency was shown for female patients to have a greater 5-year overall survival probability than male patients with respect to the various therapeutic regimens. However, it is not clear why women are more likely to have more adverse effects in therapy but still have a higher survival probability. It is still questionable whether therapies are equally effective in men and women, although the guidelines for therapies are mostly the same for both sexes. The aim should be to move towards personalized medicine, to adjust dosages and to reduce toxicity for different sexes.

Footnotes

  • Authors’ Contributions

    All Authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Marcel Ebeling and Josefine Baudrexl. The first draft of the manuscript was written by Marcel Ebeling and Josefine Baudrexl and all Authors commented on previous versions of the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors have no relevant financial or non-financial interests to disclose in relation to this study.

  • Received November 19, 2023.
  • Revision received December 7, 2023.
  • Accepted December 12, 2023.

References

  1. ↵
    1. Clayton JA
    : Studying both sexes: a guiding principle for biomedicine. FASEB J 30(2): 519-524, 2016. DOI: 10.1096/fj.15-279554
    OpenUrlCrossRefPubMed
  2. ↵
    1. Mauvais-Jarvis F,
    2. Bairey Merz N,
    3. Barnes PJ,
    4. Brinton RD,
    5. Carrero JJ,
    6. DeMeo DL,
    7. De Vries GJ,
    8. Epperson CN,
    9. Govindan R,
    10. Klein SL,
    11. Lonardo A,
    12. Maki PM,
    13. McCullough LD,
    14. Regitz-Zagrosek V,
    15. Regensteiner JG,
    16. Rubin JB,
    17. Sandberg K,
    18. Suzuki A
    : Sex and gender: modifiers of health, disease, and medicine. Lancet 396(10250): 565-582, 2020. DOI: 10.1016/S0140-6736(20)31561-0
    OpenUrlCrossRefPubMed
  3. ↵
    1. Reale C,
    2. Invernizzi F,
    3. Panteghini C,
    4. Garavaglia B
    : Genetics, sex, and gender. J Neurosci Res 101(5): 553-562, 2023. DOI: 10.1002/jnr.24945
    OpenUrlCrossRefPubMed
  4. ↵
    1. Soldin OP,
    2. Mattison DR
    : Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 48(3): 143-157, 2009. DOI: 10.2165/00003088-200948030-00001
    OpenUrlCrossRefPubMed
  5. ↵
    1. Siegel RL,
    2. Miller KD,
    3. Jemal A
    : Cancer statistics, 2017. CA Cancer J Clin 67(1): 7-30, 2017. DOI: 10.3322/caac.21387
    OpenUrlCrossRefPubMed
  6. ↵
    1. McCartney G,
    2. Mahmood L,
    3. Leyland AH,
    4. Batty GD,
    5. Hunt K
    : Contribution of smoking-related and alcohol-related deaths to the gender gap in mortality: evidence from 30 European countries. Tob Control 20(2): 166-168, 2011. DOI: 10.1136/tc.2010.037929
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Li Y,
    2. Xu A,
    3. Jia S,
    4. Huang J
    : Recent advances in the molecular mechanism of sex disparity in hepatocellular carcinoma. Oncol Lett 17(5): 4222-4228, 2019. DOI: 10.3892/ol.2019.10127
    OpenUrlCrossRefPubMed
  8. ↵
    Putting gender on the agenda. Nature 465(7299): 665-665, 2010. doi: 10.1038/465665a
    OpenUrlCrossRefPubMed
  9. ↵
    1. Palchuk MB,
    2. London JW,
    3. Perez-Rey D,
    4. Drebert ZJ,
    5. Winer-Jones JP,
    6. Thompson CN,
    7. Esposito J,
    8. Claerhout B
    : A global federated real-world data and analytics platform for research. JAMIA Open 6(2): ooad035, 2023. DOI: 10.1093/jamiaopen/ooad035
    OpenUrlCrossRef
  10. ↵
    1. Hertel M,
    2. Hagedorn L,
    3. Schmidt-Westhausen AM,
    4. Dommisch H,
    5. Heiland M,
    6. Preissner R,
    7. Preissner S
    : Comparison of five-year survival rates among patients with oral squamous cell carcinoma with and without association with syphilis: a retrospective case-control study. BMC Cancer 22(1): 454, 2022. DOI: 10.1186/s12885-022-09583-4
    OpenUrlCrossRefPubMed
  11. ↵
    1. Heym M,
    2. Heiland M,
    3. Preissner R,
    4. Huebel C,
    5. Nahles S,
    6. Schmidt-Westhausen AM,
    7. Preissner S,
    8. Hertel M
    : The risk of oral squamous cell carcinoma in patients with and without somatoform disorders including bruxism: A retrospective evaluation of 309,278 individuals. Front Oncol 12: 1080492, 2023. DOI: 10.3389/fonc.2022.1080492
    OpenUrlCrossRefPubMed
  12. ↵
    1. De Courcy L,
    2. Bezak E,
    3. Marcu LG
    : Gender-dependent radiotherapy: The next step in personalised medicine? Crit Rev Oncol Hematol 147: 102881, 2020. DOI: 10.1016/j.critrevonc.2020.102881
    OpenUrlCrossRefPubMed
  13. ↵
    1. Preston DL,
    2. Ron E,
    3. Tokuoka S,
    4. Funamoto S,
    5. Nishi N,
    6. Soda M,
    7. Mabuchi K,
    8. Kodama K
    : Solid cancer incidence in atomic bomb survivors: 1958-1998. Radiat Res 168(1): 1-64, 2007. DOI: 10.1667/RR0763.1
    OpenUrlCrossRefPubMed
  14. ↵
    1. Gonzalez-Angulo AM,
    2. Litton JK,
    3. Broglio KR,
    4. Meric-Bernstam F,
    5. Rakkhit R,
    6. Cardoso F,
    7. Peintinger F,
    8. Hanrahan EO,
    9. Sahin A,
    10. Guray M,
    11. Larsimont D,
    12. Feoli F,
    13. Stranzl H,
    14. Buchholz TA,
    15. Valero V,
    16. Theriault R,
    17. Piccart-Gebhart M,
    18. Ravdin PM,
    19. Berry DA,
    20. Hortobagyi GN
    : High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27(34): 5700-5706, 2009. DOI: 10.1200/JCO.2009.23.2025
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Pignon JP,
    2. Bourhis J,
    3. Domenge C,
    4. Designé L
    : Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet Lond Engl 355: 949-955, 2000.
    OpenUrl
  16. ↵
    1. Unger JM,
    2. Vaidya R,
    3. Albain KS,
    4. LeBlanc M,
    5. Minasian LM,
    6. Gotay CC,
    7. Henry NL,
    8. Fisch MJ,
    9. Lee SM,
    10. Blanke CD,
    11. Hershman DL
    : Sex differences in risk of severe adverse events in patients receiving immunotherapy, targeted therapy, or chemotherapy in cancer clinical trials. J Clin Oncol 40(13): 1474-1486, 2022. DOI: 10.1200/JCO.21.02377
    OpenUrlCrossRefPubMed
  17. ↵
    1. de Vries ST,
    2. Denig P,
    3. Ekhart C,
    4. Burgers JS,
    5. Kleefstra N,
    6. Mol PGM,
    7. van Puijenbroek EP
    : Sex differences in adverse drug reactions reported to the National Pharmacovigilance Centre in the Netherlands: An explorative observational study. Br J Clin Pharmacol 85(7): 1507-1515, 2019. DOI: 10.1111/bcp.13923
    OpenUrlCrossRefPubMed
  18. ↵
    1. European Commission, Directorate-General for Health and Consumers
    : The state of men health in Europe. LU, Publications Office, 2011. DOI: 10.2772/60721
    OpenUrlCrossRef
  19. ↵
    1. Bonner JA,
    2. Harari PM,
    3. Giralt J,
    4. Azarnia N,
    5. Shin DM,
    6. Cohen RB,
    7. Jones CU,
    8. Sur R,
    9. Raben D,
    10. Jassem J,
    11. Ove R,
    12. Kies MS,
    13. Baselga J,
    14. Youssoufian H,
    15. Amellal N,
    16. Rowinsky EK,
    17. Ang KK
    : Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6): 567-578, 2006. DOI: 10.1056/NEJMoa053422
    OpenUrlCrossRefPubMed
  20. ↵
    1. Burtness B,
    2. Harrington KJ,
    3. Greil R,
    4. Soulières D,
    5. Tahara M,
    6. de Castro G Jr.,
    7. Psyrri A,
    8. Basté N,
    9. Neupane P,
    10. Bratland Å,
    11. Fuereder T,
    12. Hughes BGM,
    13. Mesía R,
    14. Ngamphaiboon N,
    15. Rordorf T,
    16. Wan Ishak WZ,
    17. Hong RL,
    18. González Mendoza R,
    19. Roy A,
    20. Zhang Y,
    21. Gumuscu B,
    22. Cheng JD,
    23. Jin F,
    24. Rischin D, KEYNOTE-048 Investigators
    : Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394: 1915-1928, 2019. DOI: 10.1016/S0140-6736(19)32591-7
    OpenUrlCrossRefPubMed
  21. ↵
    1. Vermorken JB,
    2. Mesia R,
    3. Rivera F,
    4. Remenar E,
    5. Kawecki A,
    6. Rottey S,
    7. Erfan J,
    8. Zabolotnyy D,
    9. Kienzer HR,
    10. Cupissol D,
    11. Peyrade F,
    12. Benasso M,
    13. Vynnychenko I,
    14. De Raucourt D,
    15. Bokemeyer C,
    16. Schueler A,
    17. Amellal N,
    18. Hitt R
    : Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359(11): 1116-1127, 2008. DOI: 10.1056/NEJMoa0802656
    OpenUrlCrossRefPubMed
  22. ↵
    1. Grassadonia A,
    2. Sperduti I,
    3. Vici P,
    4. Iezzi L,
    5. Brocco D,
    6. Gamucci T,
    7. Pizzuti L,
    8. Maugeri-Saccà M,
    9. Marchetti P,
    10. Cognetti G,
    11. De Tursi M,
    12. Natoli C,
    13. Barba M,
    14. Tinari N
    : Effect of gender on the outcome of patients receiving immune checkpoint inhibitors for advanced cancer: a systematic review and meta-analysis of phase III randomized clinical trials. J Clin Med 7(12): 542, 2018. DOI: 10.3390/jcm7120542
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Sex-specific Real-World 5-year Overall Survival Rates for (Radio)chemotherapy, Targeted Therapy, and Combinations in Patients With Head and Neck Cancer
JOSEFINE BAUDREXL, SEBASTIAN PIETZKA, MARIO SCHEURER, ALEXANDER SCHRAMM, FRANK WILDE, ANDREAS SAKKAS, SPYRIDOULA DERKA, MARCEL EBELING
Anticancer Research Jan 2024, 44 (1) 267-286; DOI: 10.21873/anticanres.16810
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords