Abstract
Background
Modern aggressive oncological treatment options for oral squamous cell carcinoma (OSCC) are inevitably associated with impaired general health-related quality of life (HRQoL) and oral HRQoL (OHRQoL). However, there is dire need for prospective and concomitant assessment of HRQoL and OHRQoL after different treatment regims. Hence, present study was designed to investigate HRQoL and OHRQoL in patients treated for OSCC using various modalities.
Methods
135 OSCC patients were grouped according to treatment rendered into Group A: surgery only; Group B: post-surgical radiotherapy (PRT); and Group C: post-surgical chemo-radiation (PCRT). The 12-item Short Form Health Survey (SF-12) and Oral Health Impact Profile-14 (OHIP-14) were intervened to assess HRQoL and OHRQoL respectively at 1-month and 6-months post-treatment.
Results
At 1-month post-treatment, patients who received PCRT showed significantly lower mean values for physical and mental domains of SF-12 and higher mean subscales and overall OHIP-14 (24.57 ± 2.62) score than those treated by surgery alone (10.55 ± 2.26) and PRT (20.20 ± 3.80), with largest differences between PCRT and surgery alone groups (p < 0.001). Social functioning, general health and bodily pain of SF-12 and functional limitations, physical pain and physical disability amongst OHIP-14 domains were greatly affected. Although few physical domains of SF-12 showed significant improvement, mental domains remained a greater problem after 6 months. However, OHRQoL was significantly poor in all the three study groups (p < 0.001).
Conclusion
Irrespective of the post-treatment duration, patients who received PCRT had worse HRQoL and OHRQoL. There is a need to identify factors associated with impaired HRQoL and OHRQoL to customize better therapeutic decisions.
Keywords: Oral cancer, Quality of life, Oral health-related quality of life, OHIP-14, SF-12
1. Introduction
In India, incidence rates for oral cavity cancers have increased in recent decade and over 1,000,000 new cases of oral squamous cell carcinoma (OSCC) are registered every year.1 OSCC patients are considered different than those with other head and neck (H&N) cancers because of the intricate tri-dimensional anatomy of the mouth and proximity to vital structures.2,3 The standardized treatment protocol for OSCC patients include surgery, radiotherapy, chemotherapy or combination of the three as per patient and tumor characteristics.4,5 The anatomical structures in the oral cavity carry out key functions including speech, taste, salivation, chewing and swallowing. Neoplasms in this region and necessary treatment may results in severe deficits in these functions leading to impaired oral health-related quality of life (ORHQoL). As oral health disparities are considered to affect overall health and well-being of an individual, these sequelaes could in turn negatively affect health-related QoL (HRQoL).6,7
Although constant remarkable advancements in the available treatment options have resulted in significant improvement in survival rates,8 many survivors experience treatment-associated consequences in daily life activities.9 As many of these after-effects can only be measured well by patients themselves, QoL evaluations has gained much attention as a valuable outcome measure in OSCC patients. Health-HRQOL is defined as a specific subset of quality of life, assessing symptoms, psychological aspects, and function10 and can be assessed using different validated instruments in oral cancer patients.3 OHRQoL instruments are more sensitive to evaluate impacts of oral conditions on routine activities as they reflect individual’s oral health, functional well-being, emotional well-being, expectations and satisfaction with care, and sense of self-esteem.11 Therefore, it is sensible to accompany generic HRQoL instrument with specific OHRQoL instrument for accurate and comprehensive QoL assessment in OSCC patients.
In recent era, clinician and patient driven interest in functional outcomes related to various treatment modalities have highlighted the need for this information as a pre-requisite for better therapeutic decisions to ensure optimized survival and functions.12 Moreover, despite substantial improvements in surgical and non-surgical treatment regimens, QoL of OSCC survivors has not adequately improved. Hence, it is of great importance that the focus on endpoints for clinical research is not only on survival but also on the patients’ experience and QoL outcomes. With this view in mind, present study was designed to evaluate general and oral HRQoL in OSCC patients who received oncological treatment.
2. Materials and methods
2.1. Study design and patients
The present prospective exploratory study was conducted on oral cancer patients attending Rashtrasant Tukdoji Maharaj Cancer Hospital, Nagpur, India. Ethics approval was obtained from the institutional ethics committee of Cancer Relief Society’s RST Regional Cancer Hospital, Nagpur India (approval no. RST/RCH: 444, June 2019). Clinically and histopathologically diagnosed cases of OSCC who underwent oncological treatment with surgery, post-surgical radiotherapy (RT) and/or chemotherapy (CT) were included. Post-treatment (PT) patients’ follow-up was recorded for next six months and the patients with disease free survival of six months after treatment were included in this study during a period of June 2019 to July 2020. Patients with history of previous H&N cancer, recurrent or distant disease and pre-treatment RT, CT, or surgery (other than a biopsy) were excluded. During the study period, out of 155 OSCC diagnosed cases, fifteen patients were non-eligible for the reasons including: eight patients denied for participation, five secondary to poor general health and two for unspecified reasons. Five patients died prior to follow-up at 6 months post-treatment. Therefore, a total of 135 OSCC patients who fulfilled the inclusion/exclusion criteria were enrolled in the study. All participants provided their informed consent and there were no financial implications for the patients. The recruited patients were grouped according to the oncological treatment they had underwent into three groups; Group A: patients who underwent surgery only (n = 45); Group B: patients who received post-surgical RT (PRT) (n = 45) and Group C: patients who received post-surgical chemo-radiotherapy (PCRT) (n = 45). Detailed case history including sociodemographic information and presence of any chronic disease was recorded. In the current study, the socio-economic status (SES) was determined through modified Kuppuswamy’s SES scale.13 Tumor data including oral cancer site, clinical staging,14 histopathological grading, given oncological treatment and data of radiation dosages and chemotherapy were collected.
2.2. Patient reported outcomes (PRO)
During the study project, for assessment of patient reported outcomes (PRO), all participants were interviewed by administering the instruments in two different sessions with a break of approximately 10 min. The PRO instruments were filled out twice: at 1-month and 6-months after complete oncological treatment.
2.3. Measurement of HRQoL
The 12-item short form health survey (SF-12) was used to assess the HRQoL. This self-reported validated instrument15 contains 12 items with 2- or 6-point Likert scales. These items result in 8 dimensions: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health. From these dimensions, a physical component summary (PCS) and a mental component summary (MCS) scores can be calculated following the scoring algorithm outlined in the manual, rendering scores with a mean of 50 and a standard deviation of 10. A higher summary score indicates better QoL.
2.4. Measurement of OHRQoL
The OHRQoL was assessed using the Oral Health Impact Profile (OHIP-14). The OHIP-14 comprises 14 items that explore seven dimensions of impact: functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability and handicap. While using OHIP-14, each participant was being asked to respond to each item according to the frequency of the impact on a 5-point Likert scale and coded as: never (score 0), hardly ever (score 1), occasionally (score 2), fairly often (score 3) and very often (score 4).16 Higher total scores indicate worse OHRQoL.
2.5. Statistical analyses
The data was analyzed statistically using Statistical Package for the Social Sciences, version 17.0. One-way ANOVA and Tukey HSD test were applied to find out the differences in mean scores of subscales and overall OHIP-14 as well as mean values of domains, PCS and MCS of SF-12 amongst the study groups. The independent student t-test was used to compare mean scores of subscales and overall OHIP-14 as well as mean values of domains, PCS and MCS of SF-12 between one-month PT and six-month PT follow-ups. The chi-square test was used to compare the sex, age groups, site, TNM staging, histopathological diagnosis, SES and comorbodity amongst the groups. The level of statistical significance was at p < 0.05.
3. Results
3.1. Demographic characteristics
135 potentially eligible patients were recruited and analyzed in the present study. Mean age of the patients was 46.83 ( ± 12.24) years and males comprised more than two third of the study participants. The majority of the patients were married (n = 128) and belonged to lower SES (67.40%). More than half of the patients had stage IV (57.77%) OSCC and gingivo-buccal sulcus (41.48%) followed by buccal mucosa (22.22%) were the prevalent sites. In regard to oncological treatment type, each study group included 45 patients (Table 1). The radiation therapy offered was 2D conventional RT, 3D conformal RT and intensity-modulated RT. The radiation dose was given in fractions of 2 Gy per day for 5 days a week for 6–7 weeks and ranged from 41.2 to 70 Gy with a mean total dose of 61.6 Gy. Patients assigned to RT with concurrent CT received intravenous cisplatin at a dose of 50 mg/m2 weekly along with standard fractionation RT.
Table 1.
Demographic and clinicopathological details of oral squamous cell carcinoma survivors.
| Variable | Surgery alone (Group A) (n = 45) | Post-surgical radiotherapy (GroupB) (n = 45) | Post-surgical chemo-radiotherapy (Group C) (n = 45) | Total (n = 135) | P value | |
|---|---|---|---|---|---|---|
| Sex | Male [n (%)] | 38 (84.44%) | 28 (62.22%) | 32 (71.11%) | 98 (72.59%) | P = 0.059 |
| Female [n (%)] | 7 (15.55%) | 17 (37.77%) | 13 (28.88%) | 37 (27.40%) | ||
| Age (years) | Mean (SD) | 48.44 (±12.36) | 43.20 (±10.38) | 48.86 (±13.23) | 46.83 (±12.24) | A > B (p = 0.101); C > B (p = 0.070); C > A (p = 0.985) |
| Age range | 26–72 | 20–65 | 32–80 | 20–80 | ||
| Site | Gingivo-buccal sulcus | 22 (48.88%) | 20 (44.44%) | 14 (31.11%) | 56 (41.48%) | P = 0.004 |
| Buccal Mucosa | 12 (26.66%) | 8 (17.77%) | 10 (22.22%) | 30 (22.22%) | ||
| Tongue | 1 (2.22%) | 10 (22.22%) | 12 (26.66%) | 23 (17.03%) | ||
| Retromolar region | 2 (4.44%) | 7 (15.55%) | 7 (15.55%) | 16 (11.85%) | ||
| Palate | 2 (4.44%) | 0 (00.00%) | 2 (4.44%) | 4 (2.96%) | ||
| Labial mucosa | 5 (11.11%) | 0 (00.00%) | 0 (00.00%) | 5 (3.70%) | ||
| Floor of mouth | 1 (2.22%) | 0 (00.00%) | 0 (00.00%) | 1 (0.74%) | ||
| TNM Staging | Stage I | 16 (35.55%) | 0 (00.00%) | 0 (00.00%) | 16 (11.85%) | P < 0.001 |
| Stage II | 17 (37.77%) | 0 (00.00%) | 0 (00.00%) | 17 (12.59%) | ||
| Stage III | 12 (26.66%) | 6 (13.33%) | 6 (13.33%) | 24 (17.77%) | ||
| Stage IV | 0 (00.00%) | 39 (86.66%) | 39 (86.66%) | 78 (57.77%) | ||
| HPD | WDSCC | 34 (75.55%) | 0 (00.00%) | 3 (6.66%) | 37 (27.40%) | P < 0.001 |
| MDSCC | 11 (24.44%) | 33 (73.33%) | 40 (88.88%) | 84 (62.22%) | ||
| PDSCC | 0 (00.00%) | 12 (26.66%) | 2 (4.44%) | 14 (10.37%) | ||
| Socio-economic status | Lower | 32 (71.11%) | 30 (66.66%) | 29 (64.44%) | 91 (67.40%) | P = 0.688 |
| Middle | 9 (20%) | 9 (20%) | 13 (28.88%) | 31 (27.40%) | ||
| Upper | 4 (8.88%) | 6 (13.33%) | 3 (6.66%) | 13 (9.62%) | ||
| Comorbidity | No | 35 (77.77%) | 33 (73.33%) | 21 (46.66%) | 89 (65.92%) | P = 0.013 |
| One | 4 (8.88%) | 7 (15.55%) | 15 (33.33%) | 26 (19.25%) | ||
| Two | 6 (13.33%) | 5 (11.11%) | 9 (20%) | 20 (14.81%) | ||
HPD: Histopathological diagnosis; WDSCC: Well differentiated squamous cell carcinoma; MDSCC: Moderately differentiated squamous cell carcinoma; PDSCC: Poorly differentiated squamous cell carcinoma.
3.2. Impact on HRQoL
After one month of treatment, the mean (SD) SF-12 scores for patients was 62.63 (24.30) for PCS-12 and 60.03 (14.83) for MCS. Whereas, the mean (SD) SF-12 scores were 76.34 (24.65) and 74.14 (13.33) for PCS and MCS respectively at 6 months of follow-up (Table 2).
Table 2.
Comparison of health-related quality of life of oral squamous cell carcinoma survivors among study groups at 1-month and 6-months of post-treatment.
| SF-12 | Study groups | N (135) | 1-month post-treatment |
6-months post-treatment |
Comparison between 1-month and 6-months post-treatment | ||||
|---|---|---|---|---|---|---|---|---|---|
| Mean | SD | p value | Mean | SD | p value | ||||
| PF | Surgery (A) | 45 | 74.44 | 34.74 | A < B, C < B (p = 0.464); C < B (p = 0.05) |
81.11 | 28.77 | A < B (p = 0.500); A > C (p = 0.134); B > C (p = 0.008) |
P = 0.324 |
| Post-surgical RT (B) | 45 | 83.33 | 28.20 | 88.88 | 23.57 | P = 0.313 | |||
| Post-surgical CRT (C) | 45 | 65.55 | 42.40 | 67.77 | 42.84 | P = 0.805 | |||
| Total | 135 | 74.44 | 36.06 | 79.25 | 33.67 | P = 0.258 | |||
| RP | Surgery (A) | 45 | 82.22 | 38.66 | A < B (p = 0.965) C < A (p < 0.566); C < B (p = 0.725) |
82.22 | 38.66 | A > B (p = 0.965); A > C (p = 0.566); B > C (p = 0.725) |
P = 1.00 |
| Post-surgical RT (B) | 45 | 80.00 | 40.45 | 80.00 | 40.45 | P = 1.00 | |||
| Post-surgical CRT (C) | 45 | 73.33 | 44.72 | 73.33 | 44.72 | P = 1.00 | |||
| Total | 135 | 78.51 | 41.22 | 78.51 | 41.22 | P = 1.00 | |||
| BP | Surgery (A) | 45 | 64.44 | 16.41 | A > B > C (p < 0.001) | 80.00 | 18.91 | A > B (p = 0.797); A > C, B > C (p < 0.001) |
P < 0.001 |
| Post-surgical RT (B) | 45 | 51.11 | 14.05 | 77.77 | 10.95 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 37.22 | 14.71 | 53.33 | 18.15 | P < 0.001 | |||
| Total | 135 | 50.92 | 18.68 | 70.37 | 20.30 | P < 0.001 | |||
| GH | Surgery (A) | 45 | 60.55 | 16.41 | A > B > C (p < 0.001) | 78.88 | 19.91 | A > B (p = 0.059); A > C (p = 0.001); B > C (p < 0.001) |
P < 0.001 |
| Post-surgical RT (B) | 45 | 47.22 | 14.32 | 87.20 | 13.73 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 32.22 | 13.71 | 65.55 | 17.09 | P < 0.001 | |||
| Total | 135 | 46.66 | 18.77 | 77.21 | 19.18 | P < 0.001 | |||
| V | Surgery (A) | 45 | 68.44 | 13.13 | A > B > C (p < 0.001) | 79.11 | 12.76 | A > B (p = 0.931); A > C, B > C (p < 0.001) |
P < 0.001 |
| Post-surgical RT (B) | 45 | 52.88 | 9.68 | 80.00 | 10.44 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 43.11 | 9.49 | 62.66 | 11.75 | P < 0.001 | |||
| Total | 135 | 54.81 | 15.05 | 73.92 | 14.09 | P < 0.001 | |||
| SF | Surgery (A) | 45 | 58.66 | 8.94 | A > B, A > C (p < 0.001); B > C (p = 0.022) |
71.55 | 13.13 | A > B (p = 0.001); A > C, B > C (p < 0.001) |
P < 0.001 |
| Post-surgical RT (B) | 45 | 43.11 | 7.33 | 63.55 | 7.73 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 37.77 | 11.45 | 54.66 | 9.90 | P < 0.001 | |||
| Total | 135 | 46.51 | 12.88 | 63.25 | 12.50 | P < 0.001 | |||
| RE | Surgery (A) | 45 | 95.55 | 20.84 | A > B (p = 0.279) A > C (p = 0.041) B > C (p = 0.629) |
95.55 | 20.84 | A > B (p = 0.767); A > C (p = 0.097); B > C (p = 0.349) |
P = 1.00 |
| Post-surgical RT (B) | 45 | 84.44 | 36.65 | 91.11 | 28.77 | P = 0.340 | |||
| Post-surgical CRT (C) | 45 | 77.77 | 42.04 | 82.22 | 38.66 | P = 0.603 | |||
| Total | 135 | 85.92 | 34.90 | 89.62 | 30.60 | P = 0.355 | |||
| MH | Surgery (A) | 45 | 68.88 | 10.91 | A > B > C (p < 0.001) | 77.77 | 9.74 | A > B (p = 0.481); A > C, B > C (p < 0.001) |
P < 0.001 |
| Post-surgical RT (B) | 45 | 53.77 | 11.13 | 75.55 | 8.40 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 36.00 | 10.09 | 56.00 | 9.14 | P < 0.001 | |||
| Total | 135 | 52.88 | 17.18 | 69.77 | 13.35 | P < 0.001 | |||
| PCS | Surgery (A) | 45 | 70.41 | 23.13 | A > B (p = 0.564); A > C (p = 0.001) B > C (p = 0.020) |
80.55 | 22.34 | B > A (p = 0.826); A > C (p = 0.006); B > C (p = 0.001) |
P = 0.037 |
| Post-surgical RT (B) | 45 | 65.41 | 21.05 | 83.46 | 19.32 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 52.08 | 25.24 | 65.00 | 27.86 | P = 0.024 | |||
| Total | 135 | 62.63 | 24.30 | 76.34 | 24.65 | P < 0.001 | |||
| MCS | Surgery (A) | 45 | 72.88 | 9.97 | A > B > C (p < 0.001) | 81.00 | 10.03 | A > B (p = 0.312); A > C, B > C (p < 0.001) |
P < 0.001 |
| Post-surgical RT (B) | 45 | 58.55 | 10.90 | 77.55 | 9.27 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 48.6667 | 12.17 | 63.88 | 13.68 | P < 0.001 | |||
| Total | 135 | 60.03 | 14.83 | 74.14 | 13.33 | P < 0.001 | |||
OSCC: Oral squamous cell carcinoma; RT: Radiotherapy, CRT: Chemo-radiotherapy; PF: Physical functioning; RP: Role physical; BP: Bodily pain; GH: General health; V: Vitality; SF: Social functioning; RE: Role Emotional; MH: Mental Health; PCS: Physical component summery; MCS: Mental component summery; SD: standard deviation.
At 1 month PT follow-up, groups A, B and C showed the mean SF-12 (SD) scores of 70.41 (23.13), 65.41 (21.05) and 52.08 (25.24) for PCS respectively. However, mean (SD) MCS values were 72.88 (9.97), 58.55 (10.90) and 48.66 (12.17) for study groups A, B and C respectively. These observations revealed that patients treated with PCRT had significantly lower mean values of PCS than those treated with surgery alone (p = 0.001) and PRT (p = 0.020). Similarly, for MCS, group C patients reported significantly lower mean values as compared to those in group A (p = 0.001) and B (p < 0.001). Among eight domains of SF-12, social functioning (58.66 ± 8.94) was reported to be highly affected aspect followed by general health (60.55 ± 16.41) and bodily pain (64.44 ± 16.41) in group A. Similar results were obtained for group B patients. However, general health (32.22 ± 13.71), mental health (36 ± 10.09) and bodily pain (37.22 ± 14.71) were greatly affected domains in group C patients (Table 2).
At 6 months PT follow-up, corresponding results were recorded for the mean SF-12 scores with lower mean values in group C (65 ± 27.86) patients than those in group A (80.55 ± 22.34) and B (83.46 ± 19.32) for PCS. Similarly, in regard to MCS, group C (63.88 ± 13.68) patients showed lower mean values as compared to groups A (81 ± 10.03) and B patients (77.55 ± 9.27). A significant improvement was observed in SF-12 scores for PCS (p < 0.001) and MCS (p < 0.001) when compared to scores at 1 month PT. A few of the domains found affected at 1 month PT remained a significant problem at 6 months after completed treatment namely social functioning, general health, bodily pain, vitality and mental health. Amongst these, social functioning and mental health showed lowest values in all the three study groups. No significant differences were observed for remaining domains of SF-12 (Table 2).
3.3. Impact on OHRQoL
The distribution of the mean subscale scores of OHIP-14 is presented in Table 3. The group C patients showed higher mean scores of all the seven subscales and overall OHIP-14 than group A & C patients both at one and six months after treatment. The mean (SD) overall OHIP-14 scores for group A, B and C were 10.55 (2.26), 20.20 (3.80) and 24.57 (2.62) respectively at 1 month of completed treatment. There was a significant decrease in mean (SD) overall OHIP-14 scores at 6 months PT follow-up with lower values of 2.80 (2.40), 13.62 (5.64) and 18.44 (4.73) for group A, B and C respectively. Statistically significant differences were reported for mean overall OHIP-14 scores among the three study groups at both 1 month (p˂ 0.001) and 6 months PT follow-up (p˂ 0.001). In particular, overall greatest clinically significant differences were noted between group A and group C. The functional limitations was found to be the most commonly affected domain, followed by physical pain and physical disability in all the three study groups after 1 month of treatment. Statistically significant differences were found between the three study groups in all the seven domains of OHIP-14 with largest differences amongst group A and group C. Corresponding results were observed at 6 months PT follow-up for individual subscales scores with higher scores in group C patients as compared to group A and B and largest differences between group A and group C.
Table 3.
Comparison of oral health-related quality of life of oral squamous cell carcinoma survivors among study groups at 1-month and 6-months of post-treatment.
| OHIP-14 | Study groups | N (135) | 1-month post-treatment |
6-months post-treatment |
Comparison between 1-month and 6-months post-treatment | ||||
|---|---|---|---|---|---|---|---|---|---|
| Mean | SD | p value | Mean | SD | p value | ||||
| FL | Surgery (A) | 45 | 2.64 | 0.60 | A < B < C (p < 0.001) | 0.60 | 0.61 | A < B < C (p < 0.001) | P < 0.001 |
| Post-surgical RT (B) | 45 | 3.51 | 0.50 | 1.68 | 0.70 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 4.00 | 0.00 | 2.82 | 0.44 | P < 0.001 | |||
| Total | 135 | 3.37 | 0.72 | 1.70 | 1.07 | P < 0.001 | |||
| PP | Surgery (A) | 45 | 2.48 | 0.75 | A < B, A < C (p < 0.001); B < C (p = 0.011) |
0.60 | 0.57 | A < B < C (p < 0.001) | P < 0.001 |
| Post-surgical RT (B) | 45 | 3.48 | 0.54 | 1.35 | 0.52 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 3.88 | 0.34 | 2.48 | 0.50 | P < 0.001 | |||
| Total | 135 | 3.28 | 0.81 | 1.48 | 0.95 | P < 0.001 | |||
| PD | Surgery (A) | 45 | 1.06 | 0.49 | A < B < C (p < 0.001) | 0.33 | 0.47 | A < B < C (p < 0.001) | P < 0.001 |
| Post-surgical RT (B) | 45 | 2.66 | 0.90 | 1.35 | 0.52 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 3.64 | 0.48 | 2.02 | 0.54 | P < 0.001 | |||
| Total | 135 | 2.45 | 1.25 | 1.23 | 0.86 | P < 0.001 | |||
| PhD | Surgery (A) | 45 | 1.37 | 0.49 | A < B < C (p < 0.001) | 0.44 | 0.54 | A < B < C (p < 0.001) | P < 0.001 |
| Post-surgical RT (B) | 45 | 2.93 | 0.61 | 1.40 | 0.49 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 3.86 | 0.31 | 2.40 | 0.61 | P < 0.001 | |||
| Total | 135 | 2.73 | 1.14 | 1.41 | 0.97 | P < 0.001 | |||
| MD | Surgery (A) | 45 | 0.91 | 0.51 | A < B < C (p < 0.001) | 0.33 | 0.47 | A < B, A < C (p < 0.001); B < C (p = 0.048) |
P < 0.001 |
| Post-surgical RT (B) | 45 | 2.02 | 0.83 | 1.40 | 1.55 | P = 0.021 | |||
| Post-surgical CRT (C) | 45 | 2.75 | 0.90 | 1.91 | 0.66 | P < 0.001 | |||
| Total | 135 | 1.89 | 1.08 | 1.21 | 1.20 | P < 0.001 | |||
| SD | Surgery (A) | 45 | 0.95 | 0.20 | A < B < C (p < 0.001) | 0.20 | 0.40 | A < B < C (p < 0.001) | P < 0.001 |
| Post-surgical RT (B) | 45 | 1.97 | 0.83 | 1.02 | 0.45 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 2.84 | 0.82 | 1.80 | 0.66 | P < 0.001 | |||
| Total | 135 | 1.92 | 1.03 | 1.00 | 0.83 | P < 0.001 | |||
| H | Surgery (A) | 45 | 1.11 | 0.85 | A < B < C (p < 0.001) | 0.28 | 0.45 | A < B < C (p < 0.001) | P < 0.001 |
| Post-surgical RT (B) | 45 | 2.84 | 0.70 | 1.17 | 0.53 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 3.53 | 0.62 | 2.35 | 0.64 | P < 0.001 | |||
| Total | 135 | 2.49 | 1.25 | 1.27 | 1.01 | P < 0.001 | |||
| overall | Surgery (A) | 45 | 10.55 | 2.26 | A < B < C (p < 0.001) | 2.80 | 2.40 | A < B < C (p < 0.001) | P < 0.001 |
| Post-surgical RT (B) | 45 | 20.20 | 3.80 | 13.62 | 5.64 | P < 0.001 | |||
| Post-surgical CRT (C) | 45 | 24.57 | 2.62 | 18.44 | 4.73 | P < 0.001 | |||
| Total | 135 | 18.44 | 6.57 | 11.62 | 7.92 | P < 0.001 | |||
OSCC: Oral squamous cell carcinoma; RT: Radiotherapy, CRT: Chemo-radiotherapy; FL: Functional limitation; PP: Physical pain; PD: Psychological discomfort; PhD; Physical disability; MD: Mental disability; SD: Social disability; H: Handicap; SD: standard deviation.
3.4. Correlation of clinical staging and histopathological grading with HRQoL & OHRQoL
The distribution of mean OHIP-14 scores and SF-12 scores for PCS and MCS are presented in Table 4. Patients with moderately differentiated squamous cell carcinoma (MDSCC) showed higher mean OHIP-14 scores than those with poorly differentiated and well differentiated SCC (WDSCC) at 1 month and 6 months PT follow-ups. Significantly lower mean values were noticed for PCS and MCS in patients who had MDSCC as compared to others at 1 month PT follow-up. Corresponding results were recorded at 6 months PT follow-up. Similarly, patients who had stage IV OSCC reported higher mean OHIP-14 scores and lower values for PCS and MCS at both the follow-ups.
Table 4.
Correlation of histopathological grading and clinical staging with post-treatment general and oral health related quality of life.
| Parameters | N | OHIP-14 |
SF-12 |
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PCS |
MCS |
|||||||||||||
| 1-month post-treatment |
6-months post-treatment |
1-month post-treatment |
6-months post-treatment |
1-month post-treatment |
6-months post-treatment |
|||||||||
| mean | SD | mean | SD | mean | SD | mean | SD | mean | SD | mean | SD | |||
| Histopatho-logical grading | WDSCC (A) | 37 | 11.27 | 3.54 | 3.64 | 4.47 | 68.24 | 24.31 | 79.22 | 22.87 | 71.35 | 11.22 | 79.59 | 11.07 |
| MDSCC (B) | 84 | 21.38 | 5.49 | 14.98 | 7.11 | 58.25 | 25.28 | 72.39 | 26.18 | 54.76 | 14.53 | 70.77 | 14.15 | |
| PDSCC (C) | 14 | 19.78 | 3.78 | 12.50 | 3.77 | 74.10 | 4.14 | 92.41 | 6.09 | 61.78 | 4.64 | 80.00 | 4.38 | |
| p-value | B > A (p<0.001), C>A (p<0.001), B>C (p = 0.496) |
B > A (p<0.001), C>A (p<0.001), B>C (p = 0.351) |
B > A (p = 0.088), C > A (p = 0.712), B < C (p = 0.058) |
B < A (p = 0.323), C > A (p = 0.191), B < C (p = 0.013) |
B < A (p < 0.001), C < A (p = 0.054), B < C (p = 0.152) |
B < A (p = 0.002), C > A (p = 0.994), B < C (p = 0.035) |
||||||||
| Clinical TNM Staging | Stage I (A) | 16 | 10.00 | 2.25 | 2.18 | 2.31 | 73.82 | 20.31 | 82.03 | 20.26 | 75.93 | 4.55 | 82.50 | 5.77 |
| Stage II (B) | 17 | 11.00 | 2.17 | 3.11 | 2.44 | 65.44 | 27.43 | 77.20 | 25.85 | 69.70 | 14.83 | 79.41 | 14.56 | |
| Stage III (C) | 24 | 15.75 | 6.25 | 9.41 | 7.84 | 66.92 | 20.06 | 81.51 | 17.62 | 64.16 | 13.40 | 77.29 | 8.59 | |
| Stage IV (D) | 78 | 22.62 | 3.81 | 16.08 | 5.70 | 58.41 | 24.89 | 73.39 | 26.86 | 53.39 | 12.49 | 70.32 | 14.08 | |
| p-value | A < B (p = 0.895), A < C (p < 0.001), A < D (p < 0.001), B < C (p = 0.002), B < D (p < 0.001), C < D (p < 0.001) |
A < B (p = 0.964), A < C (p = 0.001), A < D (p < 0.001), B < C (p = 0.003), B < D (p < 0.001), C < D (p<0.001). |
A>B (p = 0.747), A > C (p = 0.809), A > D (p = 0.093), B < C (p = 0.997), B > D (p = 0.693), C > D (p = 0.427 |
A > B (p = 0.943), A > C (p = 1.000), A > D (p = 0.579), B < C (p = 0.946), B > D (p = 0.939), C > D (p = 0.495) |
A > B (p = 0.472), A > C (p = 0.019), A > D (p<0.001), B>C (p = 0.493), B > D (p<0.001), C>D (p = 0.002) |
A > B (p = 0.896), A > C (p = 0.578), A > D (p = 0.003), B > C (p = 0.952), B > D (p = 0.040), C > D (p = 0.089) |
||||||||
WDSCC: Well differentiated squamous cell carcinoma; MDSCC: Moderately differentiated squamous cell carcinoma; PDSCC: Poorly differentiated squamous cell carcinoma; SD: standard deviation.
4. Discussion
The present study revealed that patients treated for OSCC experienced worse domains of HRQoL and OHRQoL; with greatest impairment in those who received post-surgical chemo-radiation. Although a remarkable improvement was reported in few physical domains of the HRQoL over the time, OHRQoL was remained significantly deteriorated at 6 months PT follow-up in all the three study groups.
In developing countries like India, in spite of higher prevalence, the QoL always remained a neglected part in oral cancer patients and till date, unfortunately only a few studies17 are documented in the literature on comparison of QoL after surgery, RT and CT. Hence, there was a dire need of exploring general and OHRQoL outcomes in OSCC survivors at frequent intervals to better understand and provide healthcare needs and support to them.
The patients in the present study had overall worse scores in majority of the SF-12 domains. Similar results were reported in the previous studies.2,18 The results of the present study demonstrated that patients who received PCRT (group C) had worse physical and mental health summary scores as compared to those treated by surgery alone (group A) (p = 0.001) and PRT (group B) (p = 0.020) at 1 month follow-up. This is in accordance with the past studies, which reported higher impacts of radiation/chemoradiation than surgery on HRQoL.19, 20, 21 Moreover, mean scores of all the eight functional domains of SF-12 were observed to be lower in patients who received PCRT than those treated by surgery alone and PRT, being statistically significant in the social functioning, general health, bodily pain, mental health and vitality. It was important to note that greatest differences were reported between patients treated with surgery alone and those who received PCRT (p = 0.001). Past studies also witnessed worse scores for general health and bodily pain.2,22 However, contradictory results were obtained by other studies in which better scores were reported for domains such as general health and vitality.23, 24, 25 These somewhat discordant observations could be due to HRQoL assessments performed at different time periods after the oncological treatment. Moreover, it is very difficult to understand exactly at what time, the QoL of such patients can improve.26
Observations at 6 months PT follow-up demonstrated corresponding results with significantly worse scores in patients who received PCRT than those treated by surgery alone and PRT for PCS and MCS. Although few domains of SF-12 showed significant improvement namely physical functioning, role physical and role emotional, other domains remained a greater problems for patients including social functioning, general health, bodily pain, vitality and mental health in all the study groups.
The present study did not observed significant differences in the domains of physical functioning and role physical at 1-month and 6-months PT follow-ups. These findings are in accordance with the reports of Barrios et al.2 where they found non-significant differences for physical functioning and role emotional domains between patients and controls. These results could be attributed to the fact that items of the physical functioning and role physical domains refer to regular daily activities and work that needs moderate efforts. The domains pertaining to MCS including social functioning and vitality were expected to be affected as OSCC patients always deal with psychological impacts even after treatment due to fear of recurrence.27 However, the MCS scores were reported to be increased at 6 months PT follow-up as compared to those at 1 month after oncological treatment in all the three study groups. Maybe this could be because of changes in individual expectations and adaptation to the situation over the time. The present study has explored the changes over time after 6 months of completed oncological treatment which allowed patients adequate time to adapt to the new situation. The gradual increase in social functioning and physical activities may further enhance physical and mental component summary scores and can help these patients to experience better life satisfaction and improve the survival rate.23,28,29
In the present study, at 1-month PT follow-up, patients who received PCRT had significantly worse OHRQoL as compared to those treated by post-operative radiotherapy PRT and surgery alone. The most important differences were noticed in domains namely functional limitations, physical pain and physical disability in patients treated with PCRT. Even after 6 months of time elapsed, OHRQoL was significantly worse in all the patients with greatest impairment in patients treated with PCRT. These findings in agreement with previous research,2,17,30 indicates that only surgical approaches had relatively less damage to oral structures and functions than combined treatment options. Majority of the patients reported difficulties in eating which could be related to previous reports of difficulty in chewing and swallowing in oral cancer treated patients.31,32 Past studies demonstrated that combination of available treatment options resulted in oral mucositis, pain, xerostomia, and difficulty in speaking, smiling and teeth cleaning.2,33 Furthermore, emotional disturbances, anxiety disorder and depression have been observed in oral cancer patients treated by combined therapy.33,34 We believe that the clinical judgment and early institution of preventive rehabilitation approaches would help in improving these PT complications and OHRQoL in oral cancer patients. It has been advocated that OHRQoL is an integral part of general health & well-being and can be useful in measuring the impact of oral health disparities on overall health and QoL. Therefore future studies are recommended to investigate the association between OHRQoL and general HRQoL in patients treated for OSCC.
Poor differentiation of tumor cells is the hallmark of aggressive behavior, invasion and migration. Similarly, advanced stage is associated with increased T size and node involvement, which indicates more local and distant tissues distruction respectively. Hence, we envisaged that poor differentiation of tumor cells and advanced clinical stage could be associated with poorer score of OHRQoL as well as general HRQoL. In this regard, we noticed that the patients who had MDSCC and stage IV OSCC had worse physical and mental health summary scores and poor OHRQoL at both 1 month and 6 months PT follow-ups.
The main strength of the present study is the prospective nature of the study which allowed us to perform a stable analysis of changes in general HRQoL and OHRQoL over the period of time. In addition, we have eliminated the important confounding factor related to heterogeneity in the type of H&N cancer by restricting inclusion of patients to only OSCC.
Due to generic nature of the OHRQoL instrument, the possibility of impact of other oral conditions that are present concomitantly with the OSCC (before and after treatment) cannot be ruled out. Therefore, OHRQoL could have assessed using oral cancer -specific OHRQoL measure and should be included in future studies. However, as generic measures are conceptually broader, it covers larger aspects of patients’ health. The follow-up period included in the present study is a bit shorter which did not allowed us to assess further long-term impacts of different oncological treatment regims on general HRQoL and OHRQoL. However, there is no consensus in the scientific literature about the specific follow-up period in regard to improvement in general HRQoL and OHRQoL. With the time frame of molecular remodeling in repair & regeneration in addition to psychological and functional adaptation to new situation in mind, we believe that 6-months period is ideal to judge for the future impact treatment modalities of OSCC. However, future prospective studies with longer duration with multiple time point analysis of parameters are warranted to have better insight.
5. Conclusions
OSCC patients who received PCRT had worse OHRQoL even after 6 months as compared to those treated with surgery alone. Although few of the physical domains of SF-12 showed improvement, others remained significantly affected. As oral health conditions considered having impact on overall health of an individual, early institution of rehabilitation programs could help enhance limited functional parameters and in turn, improve the overall QoL in OSCC survivors. To further authenticate the findings, multi-centric cohort studies on larger sample size with longer duration follow-ups are warranted. Furthermore, there is a dire need to identify factors associated with impaired general and oral HRQoL to customize better therapeutic decisions and minimize associated consequences.
Source of funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None declared.
Acknowledgement
We thank all the participants for their contribution and participation.
Contributor Information
Shailesh M. Gondivkar, Email: shailesh_gondivkar@yahoo.com.
Amol R. Gadbail, Email: gadbail@yahoo.co.in.
Sachin C. Sarode, Email: drsachinsarode@gmail.com.
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References
- 1.Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–316. doi: 10.1016/j.oraloncology.2008.06.002. [DOI] [PubMed] [Google Scholar]
- 2.Barrios R., Bravo M., Gil-Montoya J.A., Martinez-Lara I., Garcia-Medina B., Tsakos G. Oral and general health-related quality of life in patients treated for oral cancer compared to control group. Health Qual Life Outcome. 2015;13:9. doi: 10.1186/s12955-014-0201-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Chandu A., Smith A.C., Rogers S.N. Health-related quality of life in oral cancer: a review. J Oral Maxillofac Surg. 2006;64:495–502. doi: 10.1016/j.joms.2005.11.028. [DOI] [PubMed] [Google Scholar]
- 4.Zhang H., Dziegielewski P.T., Biron V.L. Survival outcomes of patients with advanced oral cavity squamous cell carcinoma treated with multimodal therapy: a multi-institutional analysis. J Otol Head Neck Surg. 2013;42:30–37. doi: 10.1186/1916-0216-42-30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Rogers S.N., Brown J.S., Woolgar J.A. Survival following primary surgery for oral cancer. Oral Oncol. 2009;45:201–211. doi: 10.1016/j.oraloncology.2008.05.008. [DOI] [PubMed] [Google Scholar]
- 6.Epstein J.B., Robertson M., Emerton S., Phillips N., Stevenson-Moore P. Quality of life and oral function in patients treated with radiation therapy for head and neck cancer. Head Neck. 2001;23:389–398. doi: 10.1002/hed.1049. [DOI] [PubMed] [Google Scholar]
- 7.Kreeft A., Molen L., Hilgers F., Balm A. Speech and swallowing after surgical treatment of advanced oral and oropharyngeal carcinoma: a systematic review of the literature. Eur Arch Oto-Rhino-Laryngol. 2009;266:1687–1698. doi: 10.1007/s00405-009-1089-2. [DOI] [PubMed] [Google Scholar]
- 8.Jemal A., Bray F., Center M.M., Ferlay J., Ward E., Forman D. Global cancer statistics. Ca - Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107. [DOI] [PubMed] [Google Scholar]
- 9.Rogers S.N. Quality of life perspectives in patients with oral cancer. Oral Oncol. 2010;46:445–447. doi: 10.1016/j.oraloncology.2010.02.021. [DOI] [PubMed] [Google Scholar]
- 10.Fayers M.P., Machin D., editors. Quality of Life-The Assessment, Analysis and Interpretation of Patient-Reported Outcomes. Wiley; Chichester: 2007. [Google Scholar]
- 11.Sischo L., Broder H.L. Oral health-related quality of life: what, why, how, and future implications. J Dent Res. 2011;90:1264–1270. doi: 10.1177/0022034511399918. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Dzioba A., Aalto D., Papadopoulos-Nydam G. Functional and quality of life outcomes after partial glossectomy: a multi-institutional longitudinal study of the head and neck research network. J Otolaryngol Head Neck Surg. 2017;46:56. doi: 10.1186/s40463-017-0234-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Singh T., Sharma S., Nagesh S. Socio-economic status scales updated for 2017. Int J Res Med Sci. 2017;5:3264–3267. [Google Scholar]
- 14.Greene F.L., Page D.L., Fleming I.D., editors. American Joint Committee on Cancer Staging Manual. Springer-Verlag; New York: 2002. [Google Scholar]
- 15.Gandek B., Ware J.E., Aaronson N.K. Cross-validation of item selection and scoring for the SF-12 health survey in nine countries: results from the IQOLA project. International quality of life assessment. J Clin Epidemiol. 1998;51:1171–1178. doi: 10.1016/s0895-4356(98)00109-7. [DOI] [PubMed] [Google Scholar]
- 16.Slade G.D., Nuttall N., Sanders A.E., Steele J.G., Allen P.F., Lahti S. Impacts of oral disorders in the United Kingdom and Australia. Br Dent J. 2005;198:489–493. doi: 10.1038/sj.bdj.4812252. [DOI] [PubMed] [Google Scholar]
- 17.Indrapriyadharshini K., Madankumar P.D., Karthikeyan G.R. Oral health-related quality of life in patients treated for oral malignancy at Kanchipuram district, India: a cross-sectional study. Indian J Canc. 2017;54:11–15. doi: 10.4103/ijc.IJC_116_17. [DOI] [PubMed] [Google Scholar]
- 18.Fang F.M., Tsai W.L., Chien C.Y., Chiu H.C., Wang C.J. Health-related quality of life outcome for oral cancer survivors after surgery and postoperative radiotherapy. Jpn J Clin. 2004;34:641–646. doi: 10.1093/jjco/hyh118. [DOI] [PubMed] [Google Scholar]
- 19.Bashir A., Kumar D., Dewan D., Sharma R. Quality of life of head and neck cancer patients before and after cancer-directed treatment- A longitudinal study. J Can Res ther. 2020;16:500–507. doi: 10.4103/jcrt.JCRT_311_18. [DOI] [PubMed] [Google Scholar]
- 20.Boscolo-Rizzo P., Stellin M., Fuson R. Long-term quality of life after treatment for locally advanced oropharungeal carcinoma: surgery and postoperative radiotherapy versus concurrent chemoradiation. Oral Oncol. 2009;45:953–957. doi: 10.1016/j.oraloncology.2009.06.005. [DOI] [PubMed] [Google Scholar]
- 21.Kim T.W., Youm H.Y., Byun H., Son Y.I., Baek C.H. Treatment outcomes and quality of life in oropharyngeal cancer after surgery-based versus radiation-based treatment. Clin Exp Otolaryngol. 2010;3:153–160. doi: 10.3342/ceo.2010.3.3.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Barrios R., Tsakos G., Gil-Montoya J.A., Montero J., Bravo M. Association between general and oral health-related quality of life in patients treated for oral cancer. Med Oral Patol Oral Cir Bucal. 2015;20:e678–684. doi: 10.4317/medoral.20714. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Llewellyn C.D., Weinman J., McGurk M. A cross-sectional comparison study of cognitive and emotional well-being in oral cancer patients. Oral Oncol. 2008;44:124–132. doi: 10.1016/j.oraloncology.2007.01.009. [DOI] [PubMed] [Google Scholar]
- 24.Herce-Lopez J., Rollon-Mayordomo A., Lozano-Rosado R., Infante-Cossio P., Salazar-Fernandez C.I. Assesment of quality of life of oral cancer survivors compared with Spanish population norms. Int J Oral Maxillofac Surg. 2013;42:446–452. doi: 10.1016/j.ijom.2012.11.014. [DOI] [PubMed] [Google Scholar]
- 25.Herce J., Rollón A., Lozano R., Salazar C., Gallana S. Quality of life in long-term oral cancer survivors: a comparison with Spanish general population norms. J Oral Maxillofac Surg. 2009;67:1607–1614. doi: 10.1016/j.joms.2008.12.039. [DOI] [PubMed] [Google Scholar]
- 26.Torres-Carranza E., Infante-Cossío P., Hernández-Guisado J.M., Hens-Aumente E., Gutierrez-Pérez J.L. Assessment of quality of life in oral cancer. Med Oral Patol Oral Cir Bucal. 2008;13:735–741. [PubMed] [Google Scholar]
- 27.Handschel J., Naujoks C., Kübler N.R., Krüskemper G. Fear of recurrence significantly influences quality of life in oral cancer patients. Oral Oncol. 2012;48:1276–1280. doi: 10.1016/j.oraloncology.2012.06.015. [DOI] [PubMed] [Google Scholar]
- 28.Grignon L.M., Jameson M.J., Karnell L.H., Christensen A.J., Funk G.F. General health measures and long-term survival in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg. 2007;133:471–476. doi: 10.1001/archotol.133.5.471. [DOI] [PubMed] [Google Scholar]
- 29.Sammut L., Ward M., Patel N. Physical activity and quality of life in head and neck cancer survivors: a literature review. Int J Sports Med. 2014;35:794–799. doi: 10.1055/s-0033-1363984. [DOI] [PubMed] [Google Scholar]
- 30.Bhalla A., Anup N., Bhalla A.P., Singh S.B., Gupta P., Bhalla S. Oral health related quality of life (OHRQoL) amongst head and neck cancer patients undergoing chemotherapy and radiotherapy at Sawai Mansingh hospital Jaipur, India. Scholars Acad J Biosci. 2015;3:3–12. [Google Scholar]
- 31.Biazevic M.G., Antunes J.L., Togni J., de Andrade F.P., de Carvalho M.B., Wünsch-Filho V. Survival and quality of life of patients with oral and oropharyngeal cancer at 1-year follow-up of tumor resection. J Appl Oral Sci. 2010;18:279–284. doi: 10.1590/S1678-77572010000300015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Dwivedi R.C., Chisholm E.J., Khan A.S. An exploratory study of the influence of clinical-demographic variables on swallowing and swallowing-related quality of life in a cohort of oral and oropharyngeal cancer patients treated with primary surgery. Eur Arch Oto-Rhino-Laryngol. 2012;269:1233–1239. doi: 10.1007/s00405-011-1756-y. [DOI] [PubMed] [Google Scholar]
- 33.Gallitis E., Droukas V., Tzakis M. Trismus and reduced quality of life in patients with oral squamous cell carcinoma, who received post-operative radiotherapy alone or combined with chemotherapy. HeSMO. 2017;8:29–36. [Google Scholar]
- 34.Pauli N., Johnson J., Finizia C., Andrell P. The incidence of trismus and long-term impact on health-related quality of life in patients with head and neck cancer. Acta Oncol. 2013;52:1137–1145. doi: 10.3109/0284186X.2012.744466. [DOI] [PubMed] [Google Scholar]