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    -  Peerawong T
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    -  Tangthongkum M
    -  Kongkamol C
    -  Hirunpat S

 
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ORIGINAL ARTICLE
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Tumor volume as a prognostic factor on the median survival in locally advanced oral cancer treated with definitive chemoradiotherapy


1 Department of Radiology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
2 Department of Otolaryngology Head and Neck Surgery, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
3 Research Unit of Holistic Health and Safety Management in the Community, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand

Date of Submission01-Feb-2020
Date of Decision13-Feb-2020
Date of Acceptance29-Oct-2020
Date of Web Publication19-Sep-2021

Correspondence Address:
Narumon Janmunee,
Department of Radiology, Faculty of Medicine, Prince of Songkla University, Songkhla
Thailand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_86_20

PMID: 33753617

  Abstract 


Background: Surgery has been the mainstay treatment for oral cancer. Patients who do not receive surgery are generally treated with concurrent chemoradiotherapy (CCRT). Many factors play a role in patients' survival; tumor volume might be one of those factors. This study aims to determine the effect of the pre-treatment tumor volume on the survival of oral cancer.
Methods: Retrospective study of patients with histological confirmed squamous cell carcinoma, stage III–IV oral cancer, who received definitive CCRT. Tumor volume from pre-treatment computed tomography (CT) scans were reviewed and analyzed. The optimal cut-off tumor volume was evaluated by receiver operating characteristic (ROC) curve analysis.
Results: Among 67 patients, half of the primary tumor sites were oral tongue. The median total tumor volume (TTV) was 73.25 cm3, while the median survival was 12.5 months (95% confidence interval: 10.9-20.3). The optimal cut-off TTV ≥52.9 cm3 (P < 0.0001). The median survival of the patients, who had tumor volume <52.9 cm3 were 34.4 months, and for tumor volume ≥52.9 cm3 were 8.6 months (P < 0.0001). Multivariate analysis showed that TTV ≥52.9 cm3, and intensity-modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT) technique had significantly influenced the overall survival.
Conclusion: TTV had an influence on the overall survival of locally advanced oral cancer. In addition, TTV may be considered as a factor in selecting the appropriate treatment option for these patients.


Keywords: Chemoradiotherapy, mouth neoplasms, survival, tumor burden Total tumor volume influenced the overall survival of locally advanced oral cavity squamous cell carcinoma. It may be considered as a factor in selecting the appropriate treatment for these patients.



How to cite this URL:
Janmunee N, Peerawong T, Rordlamool P, Bridthikitti J, Tangthongkum M, Kongkamol C, Hirunpat S. Tumor volume as a prognostic factor on the median survival in locally advanced oral cancer treated with definitive chemoradiotherapy. Indian J Cancer [Epub ahead of print] [cited 2021 Oct 27]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=308060





  Introduction Top


The global age-standardized incidence rate of lip and oral cancer was relatively large at 5.8 per 100,000 in men and 2.3 per 100,000 in women in 2018.[1] High incidence rate of oral cancer are found in South Asia and Southeast Asia.[2],[3] Approximately 90% are squamous cell carcinoma.[4],[5] Tobacco and alcohol consumption are strong risk factors.[6] Oral cancer has a significant cause of morbidity and mortality, especially in locally advanced stage.

In general, treatment selection depends on many factors, such as tumor staging, comorbidity, and performance status. The primary treatment for locally advanced oral cancer is surgery followed by adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT).[7],[8],[9],[10] For patients who are not surgical candidates, either due to medical comorbidity, unresectable disease or patient preference, primary radiation therapy or CCRT will be considered.[11],[12] Radiotherapy with curative intent is usually performed with 70 Gy in 35 fractions, for an overall treatment time of 7-8 weeks. In the meta-analysis of locally advanced head and neck cancer, the 5-year overall survivals are 36.4% and 31.3%, with and without chemotherapy for loco-regional treatment of oral cancer, respectively. However, approximately 30% and 50% of patients died in the first and second years, respectively, after diagnosis.[13] Additionally, 49% of patients will suffer from severe mucositis, causing pain, suffering, and weight loss.[12] Long-term side effects, such as xerostomia, can be reduced by treatment with intensity-modulated radiotherapy (IMRT) technique; however, there is no benefit in improving the clinical outcome.[14],[15] Hence, the balance between survival and toxicity is the essential point in treating head and neck cancer.

Tumor volume is a controversial pre-treatment factor, which generally refers to tumor hypoxia in a large tumor volume; however, the influence of tumor volume in head and neck cancer for radiotherapy is still a controversy. There seems to be some effect on survival with chemoradiotherapy, but not in primary radiotherapy.[16],[17],[18],[20] However, from a retrospective study, tumor volume did not show to have a significant influence on survival in the surgical aspect, with postoperative radiotherapy, radical radiotherapy, or chemoradiotherapy in advanced larynx cancer patients.[21] Focusing on the oral cavity, tumor volume affects survival in surgical patients.[22] However, there is no data on patients who received chemoradiotherapy.

This study will determine the effect of the pre-treatment tumor volume in locally advanced oral cavity squamous cell carcinoma on the median overall survival in patients treated with definite chemoradiotherapy.


  Materials and Methods Top


Patient selection

In this retrospective study, data of any patient with oral cancer, who received radiation therapy at Songklanagarind hospital, Songkhla, Thailand from January 2009 to March 2016 was retrieved from the hospital database. The inclusion criteria were: patients with histologically confirmed stage III-IV according to American Joint Committee on Cancer (AJCC) 8th edition 2017, squamous cell carcinoma of oral cavity, treated with concurrent chemoradiotherapy with age above 18 years. Patients were excluded if they had primary lip cancer, metastatic disease, or second primary cancer.

Data collection

Data on age, gender, comorbidities, Eastern Cooperative Oncology Group (ECOG) score, weight before and after treatment, body mass index (BMI), smoking and drinking status, percutaneous endoscopic gastrostomy (PEG) insertion, tumor subsites, TNM staging, the modality of treatment, date of starting treatment along with date and status of the last contact was recorded.

Treatment regimens

The decision on treatment regimens was based on the multidisciplinary tumor board recommendation, which considered the patients' preference, performance status, medical conditions as well as risks of general anesthesia. The previous study from our hospital showed that prophylactic PEG insertion decreased severe weight loss during treatment in nasopharyngeal cancer patients.[23] Thus, we intended to perform prophylactic PEG insertion to every patient who will receive CCRT unless they denied the procedure. Patients who denied prophylactic PEG insertion and lost weight >10% or had swallowing problems during radiation therapy would be considered to perform nasogastric (NG) tube insertion. Patients were treated with conventional radiation, three-dimensional radiotherapy (3D-CRT), IMRT or volumetric-modulated arc therapy (VMAT) technique. The total radiation dose of 70 Gy in 35 fractions was given to primary cancer and pathologic lymph nodes. Treatment was delivered by 6 megavoltage (MV) linear accelerators. For the patients who received CCRT, most patients received single-agent cisplatin during RT, with planned two to three cycles (100 mg/m2) on days 1, 22, and 43. Alternative chemotherapy based on potential toxicities and pre-existing medical conditions like carboplatin (AUC2 or AUC5-6) or cisplatin weekly (40 mg/m2) was given.

Tumor volume assessment

Pre-treatment computed tomography (CT) scans of the patients were reviewed by an experienced neurological diagnostic radiologist for restaging (TNM staging, AJCC 8th edition, 2017). For the tumor volume delineation process, the pre-treatment CT scan was delineated by a consensus of three radiation oncologists, using the Eclipse treatment planning system, version 10.0 (Varian Medical System, Palo Alto, CA). Tumor volumes calculated by the treatment planning system and measured in cubic centimeters (cm3), were classified as primary tumor volume, nodal tumor volume, and primary plus nodal volume or total tumor volume (TTV).

Outcome measurements

The primary outcome was median overall survival. Overall survival was defined as time from treatment start date to last seen date or death. The last seen date and survival status were updated on 01 April 2018.

Ethical approval

Ethical approval was obtained from the Human Research Ethics Committee of Faculty Medicine, Prince of Songkla University (Research Ethics Committee (REC) number: 60-110-07-4).

Statistical analysis

Descriptive statistics were used to describe clinical data. The survival analysis was determined by a Kaplan–Meier estimator. Receiver operating characteristic (ROC) curve analysis was used with the Youden's Index to determine an optimal tumor volume cut-off point. In the associations of predictor variables, univariate and multivariate analysis was performed with Cox proportional hazards regression models. A P value of less than 0.05 was considered statistically significant. The data were analyzed with R software version 3.3.3.


  Results Top


Patients characteristics

Of 1020 patients with stage III and IV oral cancer, 180 patients received definitive radiotherapy; among them, 113 patients did not meet inclusion criteria. Finally, 67 patients were analyzed. Most of the patients were men (55, 82.1%), with a mean age of 57.9 (range 26-81) years, and ECOG performance status was 1 in 57 (85.1%) patients. Almost all of them had T stage 3–4 and N stage 2-3, with half of the primary tumor sites being the oral tongue. As for the radiation techniques, 41 (61.2%) patients were treated with 3D-CRT techniques. Salvage treatment was performed in only 25 patients (4/5 with chemotherapy and the rest with surgery). The details are shown in [Table 1].
Table 1: Patient characteristics

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Tumor volume and overall survival

The median primary tumor volume was 58.1 cm3 (interquartile range [IQR]: 28.9-97.5), the median nodal volume was 5.9 cm3 (IQR: 2.5 - 23.4), and the median TTV was 73.3 cm3 (IQR: 41.5-159.2). The median follow-up was 12.5 months; 52 (77.6%) had died. The median survival was 12.5 months (95% confidence interval [CI]: 10.9-20.3). There were 20 (29.8%) patients who achieved a complete response after CCRT, and 9 of 20 (45%) patients had locoregional recurrent after CCRT.

The ROC curve and Youden's index analysis revealed the optimal cut-off TTV ≥52.9 cm3 was associated with significantly decreased overall survival (P < 0.001) [Figure 1]. The median survival of the patients who had a TTV <52.9 cm3 was 34.4 months and for a TTV ≥52.9 cm3 was 8.6 months (P < 0.0001)
Figure 1: Kaplan-Meier of overall survival, according to Total Tumor Volume (TTV)

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Univariate and multivariate analysis

Variables found to be strongly associated with survival in the univariate analysis included: Primary tumor volume, TTV, and radiation technique [Table 2], while gender, age, ECOG score, weight change at three months, PEG insertion, smoking, drinking, tumor site, T stage, N stage, nodal volume, salvage treatment, and Charlson comorbidity index were not significantly associated with survival.
Table 2: Univariate analysis for the factors influencing overall survival (n=67)

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Strongly associated factors, including TTV ≥52.9 cm3 and radiation technique, were analyzed in multivariate analysis. However, we considered the factors that had a P value <0.2 also to be analyzed were BMI before treatment and PEG insertion. T stage, N stage, primary tumor volume and nodal volume were not included in the analysis because of their collinearity to TTV.

Multivariate analysis showed that TTV ≥52.9 cm3 and treatment with an IMRT/VMAT radiation technique were the factors that were significantly related to more inferior overall survival [Table 3].
Table 3: Multivariate analysis for the factors influencing overall survival, for primary plus pathological nodal volume (n=67)

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  Discussion Top


Our study result showed that greater TTV has negative impact on overall survival in locally advanced squamous cell carcinoma oral cancer. Our findings may have considered that the TTV may be a factor in selecting the appropriate treatment modality for these patients.

In the literature review for head and neck cancer, some studies showed similar results with ours. For example, in CCRT setting, Knegjens et al. studied squamous cell carcinoma of head and neck cancer (oral cavity, oropharynx, and hypopharynx) stage III and IV (M0), and reported that the hazard ratio (HR) for local recurrence and overall survival increased per 10 cm3 volume increase.[19] Kurek et al. studied 107 patients with squamous cell carcinoma of the head and neck (hypopharynx, oropharynx, oral cavity, larynx, and nasopharynx), which showed that patients with greater pre-therapeutic tumor volume had worse survival.[16] While, Timmermans et al. studied patients with T3–T4 larynx cancer treated with radiotherapy, CCRT, or total laryngectomy with postoperative radiotherapy, who reported that in CCRT group the tumor volume had a significant impact on local control, but not overall survival.[21] Focused on advanced oral cancer, surgery followed by either adjuvant radiation therapy alone or adjuvant CCRT has been the treatment of choice. Mücke et al. conducted a prospective study in patients with stage T1-4, N1-3, M0 invasive squamous cell carcinoma of the tongue. They were treated with surgery and post-operative radiation therapy. Their result showed that large tumor volume was associated with a significantly lower overall survival.[22] These studies showed heterogeneous results of tumor volume having an association with overall survival; however, most of them demonstrated that increased tumor volume had an association with worse overall survival. The result from our study showed concordant outcome and increased tumor volume associated with worse overall survival.

Primary tumor volume is also a function of the T stage; however, the T stage was not significantly associated with survival in the univariate analysis in our study. Generally, the T stage of the oral cavity use pathological staging from surgery for operable tumors, but our study used clinical staging obtained from CT scan combined with the physical examination. Kreppel et al. reported that there were some discordance between the clinical T stage and pathological T stage (38%); only pathological T-classification was predictive of survival in multivariate analysis.[24] Therefore, clinical T staging in our study might be over or understaged, and it possibly lead to non-significant difference in survival between the T stage. Furthermore, the number of patients in the T2 stage was too small when compared with T3 and T4. If the number increased, we might detect more differences.

Surprisingly, regarding the radiation technique, we found that patients treated with IMRT/VMAT had lower overall survival than those treated with conventional radiotherapy. This conflicts with a previous report on the study of concurrent chemotherapy treatment in locally advanced oropharyngeal cancer, which showed no difference in survival outcome between IMRT and conventional radiotherapy. But IMRT had significant lower grade ≥2 xerostomia.[14] Another study in the postoperative radiation therapy for oral cancer showed that there was no difference in overall survival between conventional, 3D-CRT and IMRT techniques.[15] However, in our study we had a very low number of subjects in the IMRT/VMAT group, so there is not enough power to find an association.

In our study, median survival was only 12.5 months, which seem to be low when compared with other concurrent chemoradiotherapy in oral cancer studies.[11],[25],[26] The reason may be from the definition of overall survival in our study. We used the first day of RT to the date of death or the date of the last follow-up, instead of the day of entry into the study or the day of diagnosis.

For clinical applications, the tumor volume may be the prognostic factor to predict who are unlikely to benefit from CCRT in locally advanced unresected oral cancer. For example, in a large tumor volume, if the patient has good performance status, the intensification of treatment may be considered. To date, randomized studies from the locally advanced head and neck cancer found no other treatment modality option, for either unresected or organ sparing approaches, that had better overall survival than CCRT, whether it is for induction chemotherapy followed by CCRT,[27],[28] a combination of CCRT with other drugs like antibodies against the epidermal growth factor receptor,[29] or induction chemotherapy followed by concurrent RT with cetuximab.[30] If patients have a poor performance status and are elderly in age, the palliative radiation treatment may be the preferred treatment option.[31]

To the best of our knowledge, this was the only study that reported on the association of tumor volume and overall survival in patients with oral cancer treated with definite CCRT. For delineating tumor volume in our study, a contouring process was performed using CT scan imaging and consensus of three radiation oncologists were reached. It may be more accurate if an automated computer system is developed and a magnetic resonance imaging (MRI) scan is coupled with CT fusion for tumor volume delineation. However, there are some limitations in our study. Due of its retrospective design, selection bias could not be avoided. Further prospective studies and a larger sample of subjects are needed to investigate the association between tumor volume and survival outcome in radiotherapy for oral cancer.

Chemotherapy doses and regimens in our study were varied. The cumulative doses of cisplatin might affect the survival outcome, but the cut-off point has remained unclear. In MACH-NC meta-analysis, only the Intergroup 2382 trial's patients received the lowest cumulative doses, cisplatin 20 mg/m2 weekly (a cumulative dose of 140 mg/m2), who did not have a survival benefit concurrent with radiation therapy compared with radiation alone.[32] A systematic review from six prospective randomized trials in definitive CCRT setting founded that higher cumulative cisplatin doses (range 140 mg/m2 to 270 mg/m2) were significantly correlated with overall survival.[33] Whereas Ang et al. mentioned that a substantial fraction of patients could not receive the planned third cycle of 100 mg/m2 cisplatin due to significant toxicity. They suggested that a cumulative cisplatin dose of approximately 200 mg/m2 might be sufficient.[34] For chemotherapy regimens, weekly cisplatin and 3-weekly cisplatin did not seem to have a difference in overall survival.[35],[36] In our study, there was a limitation because we did not plan to evaluate the effect of cumulative doses of chemotherapy and regimens. However, most of patients in our study received a cumulative cisplatin dose of 300 mg/m2 during radiation therapy.

In conclusion, TTV influenced the overall survival of locally advanced oral cavity squamous cell carcinoma. Our study showed TTV ≥52.9 cm3 associated with poor survival outcomes. In addition, TTV may be considered as a factor in selecting the appropriate treatment option for these patients.

Financial support and sponsorship

The research was supported by grant from Faculty of Medicine, Prince of Songkla University.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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