Journal of Cancer Research and Therapeutics Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 6, Num. 3, 2010, pp. 282-289

Journal of Cancer Research and Therapeutics, Vol. 6, No. 3, July-September, 2010, pp. 282-289

Original Article

Analysis of prognostic factors in 1180 patients with oral cavity primary cancer treated with definitive or adjuvant radiotherapy

V Murthy¹, JP Agarwal¹, S Ghosh Laskar¹, T Gupta¹, A Budrukkar¹, P Pai², P Chaturvedi², D Chaukar², A D«SQ»Cruz²

¹ Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India
² Head and Neck Surgery, Tata Memorial Hospital, Mumbai, India

Correspondence Address:V Murthy, Assistance Professor & Consultant Radiation Oncologist, Tata Memorial Hospital and Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Mumbai, India, vmurthy@actrec.gov.in

Code Number: cr10064

PMID: 21119254

DOI: 10.4103/0973-1482.73360

Abstract

Keywords: Oral cavity, adjuvant radiotherapy, prognostic factors

Introduction

Oral cavity squamous cell carcinoma (OCSCC) is one of the leading causes of cancer related death in developing countries particularly India. ^[1] Of the 274300 new cases recorded worldwide in 2002, almost two thirds were in developing countries. ^[2] Apart from Indian subcontinent, high rates of oral cancer have also been observed in Central, Eastern and Southern Europe, parts of France, South America and Oceania. ^[3],[4] The high risk in Indian population is related to the popularity of pan-tobacco (combination of betel leaf, lime, areca nut and sun cured tobacco) chewing in the region. The present study was undertaken to identify various prognostic factors following radical or adjuvant radiation of oral cavity primary tumors.

Materials and Methods

The present study is an audit of outcome of 1180 patients with oral cavity primary tumor treated from 1990-2004 with either definitive or adjuvant radiotherapy within a single head or neck radiotherapy department. All patients were evaluated clinically and underwent staging with appropriate clinical and radiological investigations. The intent and modality of treatment was decided in the joint clinic depending on the stage and performance status of the patient. Patients with early stage disease were treated with either surgery alone or radical radiotherapy. Patients who underwent surgery and had high risk features on histopathology (defined as tumor thickness >5mm, soft tissue or bone infiltration, perineural invasion, close or positive cut margins, poorly differentiated tumors, positive nodes with or without perinodal spread) were considered for postoperative radiotherapy (PORT). Patients with advanced disease were planned for a combined approach of surgery followed by radiotherapy. Patients who were inoperable due to medical reasons were offered radical radiotherapy with or without chemotherapy. None of the patients received postoperative adjuvant chemotherapy. Although this was an audit of patients treated in the service mode, data was collected prospectively and updated at each follow up.

Treatment details

Surgery

The type and extent of surgery for the primary was decided by the site, extent of the primary, need for reconstruction and nodal status. Neck dissection was carried out for all patients with a clinically positive neck. Those with a clinically negative neck and deemed to be at high risk of nodal metastasis underwent an elective neck dissection.

Radiotherapy details

External beam radiotherapy (EBRT) was used either in definitive or adjuvant setting. The target volume encompassed regions of gross disease/postoperative tumor bed and potential sites of microscopic spread. Megavoltage beams were used for all the patients. The choice of beam arrangement (anterolateral wedge pair or bilateral opposing) was based on the site of primary tumor. Wedges and tissue compensators were used routinely to ensure homogenous dose distribution. Patients treated with definitive radiotherapy received 66-70 Gy in 33-35 fractions over 7-7.5 weeks. In the adjuvant setting, patients received 56- 60 Gy (2 Gy per fraction, once a day) over six weeks. Higher total dose upto 66-70 Gy was considered in patients with positive surgical margins. A small proportion of patients were treated with either radical brachytherapy alone or with boost brachytherapy in combination with EBRT. The dose of brachytherapy was decided by the intent of treatment and quality of implant.

Follow up and patient evaluation

All patients were required to follow up six weeks after completion of treatment for response and toxicity assessment. Subsequently, patients were followed up in the clinic every three months for the first two years and every six months thereafter. Clinical examination was done at every visit. Endoscopic and radiological evaluation was done as clinically indicated. On clinical suspicion of recurrence, biopsy was obtained. Patients who did not attend the clinic on scheduled follow up days were contacted through reply paid postcards or telephonically to update the disease and patient status. Patients not responding to the above measures were considered as lost to follow up and were censored for statistical analysis. Persistence of primary or nodal disease six weeks after the conclusion of definitive treatment was considered as persistent disease. Reappearance of either primary or/and nodal disease was considered as local, regional or locoregional relapse. For disease free survival (DFS) estimates, distant metastasis and second primary tumors were also taken into consideration.

Statistical Analysis

SPSS^® version 14.0 was used for statistical analysis. For the purpose of statistical analysis, all the patients were divided into patients treated with surgery and postoperative radiotherapy and those treated with definitive radiotherapy. As location within the oral cavity could also affect the outcome, we divided patients into Group 1 which included those with gingivoalveolobuccal primary and Group 2 which included patients with oral tongue and floor of mouth primary. Local control (LC), Locoregional control (LRC, defined as) and DFS for the entire group and both the subgroups was calculated using the Kaplan Meier method. Local failure was defined as persistence of disease or reappearance of disease at or in close vicinity to the primary site. Locoregional failure was defined as persistence of disease or reappearance of disease either at the primary site, draining regional lymph nodes, or both. For the purpose of analysis of DFS recurrence of disease at either the primary, regional or distant site or the appearance of a second primary in the upper aero-digestive tract were considered as events. All estimates were calculated from the date of starting treatment until the defined event if any or until last contact or death. The effect of various known prognostic factors on LC, LRC and DFS was evaluated with log rank test for univariate analysis. Cox regression analysis with backward conditional method was used for multivariate analysis. P value of less than 0.05 was considered as statistically significant.

Results

Patient characteristics are detailed in [Table - 1] and [Table - 2]. From 1990-2004, the head and neck unit treated 1180 patients with either definitive (223 patients, 19%) or post operative adjuvant radiotherapy (957 patients, 81%). The median age of all patients was 50 years (range 16-86 years).While most of the patients in the present study were in their fifth decade, 268 patients (22.7%) were below the age of 40 years. There were 870 (74%) males and 310 (26%) females. The male to female ratio (3:1) was maintained above and below the age of 40 years. Tobacco was used in some form by 75% of all the patients and 53% of the women. The rate of tobacco use was similar in males and females both above and below the age of 40 years.

Of the entire patient population, 810 patients (68.7%) had tumors of the Gingivo-alveolo-buccal complex, lip and hard palate (Group 1) and 370 patients (31.3%) had primary lesions in tongue and floor of mouth (Group 2). At diagnosis, 21% patients had stage I/II disease and 75% had stage III/IV disease. At presentation, 45% patients were clinically node. Although incidence of nodal metastasis was similar in both groups, stratification by T stage revealed a higher propensity of nodal metastasis with increasing T stage in patients with oral tongue carcinoma as compared to patients with gingivo-alveolo-buccal complex carcinoma (T3: 59.4% vs 50%, P= 0.76 and T4: 60.9% vs 57.9%, P= 0.52). The incidence of contralateral neck node metastasis was also higher in patients with tongue and floor of mouth lesions as compared to gingivo alveolobuccal lesions (5.4% vs 2.6%, P=0.77).

Surgical Details

Surgery for the primary lesion involved either wide excision of tumor (35%), segmental or marginal mandibulectomy (40%) or bite excision (14%). Neck dissection was done in 85% of the patients while 5% were kept under observation. Information regarding the detailed surgical procedure was unavailable in 10% of the patients. Pathologically, 8% of the patients had a positive cut margin. Correlation between clinical and pathological nodal and overall stage [Table - 3] revealed that following surgery, 32.7% of the patients underwent nodal upstaging while 17.9% underwent nodal down staging. With regard to overall stage, 15.6% of the patients underwent pathological upstaging and 7.6% were downstaged [Table - 4]

Radiotherapy Details

In patients receiving postoperative adjuvant radiotherapy, the median time to initiation of radiotherapy was 45 days (range 9-150 days). The median radiotherapy dose was 60 Gy (range 46-66 Gy) and the median overall treatment time was 45 days.

In the definitive radiotherapy group, the median radiotherapy dose was 64 Gy (range 60-70 Gy) and the median overall treatment time was 47 days (range 27-152 days). Within the definitive radiotherapy group while 122 (54.7%) patients received radical radiotherapy alone, 37 patients (16.6%) underwent either radical or boost brachytherapy. Of these 92% were treated with low dose rate (LDR) brachytherapy and 8% were treated with high dose rate (HDR) brachytherapy. In the LDR group, the mean brachytherapy dose was 23.5 Gy (15-45 Gy) with a median dose rate of 45cGy/hour (25-150cGy/hour). Three patients received HDR brachytherapy boost of 14-20 Gy in 3-5 fractions. 64 patients within the EBRT group (28.7%) received either sequential (n=39) or concurrent chemotherapy (n=25).

In the entire cohort of 1180 patients, 1066 (90.2%) patients completed the planned treatment without any unscheduled gap. In 60 patients (5.1%), the planned total dose could not be delivered due to acute toxicity. Another 37 patients (3.1%) did not complete treatment due to either social or personal reasons. Detailed information was missing in another 1.7% of the patients.

Treatment Outcomes

The median follow up for the entire cohort was 24 months (range 1-166 months). The three year LRC was 58% for the entire cohort with 65% in those undergoing PORT and 32% in those undergoing definitive radiotherapy (P<0.001). In a preliminary analysis that included all the patients, choice of treatment was identified as a significant factor that determined overall outcome [Figure - 1]. Additionally, as prognostic factors varied between those receiving adjuvant and definitive radiotherapy two different analyses were carried out. [Table - 5].[Table - 6],[Table - 7] show the effect of various factors on LC, LRC and DFS for the entire cohort and two subgroups separately.

Postoperative Adjuvant Radiotherapy

The three year LC, LRC and DFS in this group were 74%, 65% and 60%, respectively. In univariate analysis, primary site, pathological nodal status, perinodal extension and cut margin status were statistically significant for LC, LRC and DFS [Table - 6]. Additionally, pathological stage (P=0.07) and tobacco use (P=0.07) were borderline significant for DFS on univariate analysis. On multivariate analysis, while pathological nodal status, perinodal extension and cut margin retained statistical significance, the site of primary was of borderline statistical significant (P=0.07).

Definitive Radiotherapy

The three year LC, LRC and DFS were 34%, 31% and 30%, respectively. In the definitive radiotherapy group while age less than 40, primary site, T stage, nodal status and overall stage were statistically significant for LC, LRC and DFS [Table - 7]; on multivariate analysis all these factors except primary site retained their statistical significance.

Patterns of Failure

The patterns of local, regional and locoregional recurrence in patients receiving definitive and adjuvant radiotherapy in Groups 1 and 2 are enumerated in [Table - 8] and [Table - 9], respectively. While local recurrence was the most common type of failure in both definitive and adjuvant setting in both the groups, a higher percentage of nodal failures were observed in Group 2 in patients receiving adjuvant radiotherapy (P=0.003).

Salvage Treatment

Of the 423 patients who had recurrent disease limited to primary and/or nodal sites, only 16.3% of the patients (n=73) were amenable to surgical salvage. Another 5% (n=34) were treated with radiotherapy while others received either palliative chemotherapy (10%) or symptomatic care only. Of those who underwent salvage 33% had complete response, another 10% had partial response, 20% had no response or progressive disease and the response was not assessable or recorded in 35% of the patients.

Discussion

The present series analyzes the outcomes of 1180 patients treated with either adjuvant or definitive radiotherapy and for the purpose of analysis we categorized the patients into two different sets (adjuvant and definitive radiotherapy). Additionally, as location within the oral cavity could affect the outcome, patients were further sub grouped into Group 1 and 2 depending upon the anatomical location as specified earlier. The statistical analyses in this present study analyzes the effect of various prognostic factors in the entire cohort and within the specified subgroups, the details of which are discussed.

Patient Demographics

In the present cohort, the median age at diagnosis was 50 years. This is concordant with the median age reported from the Asian countries ^[5],[6] but a decade less than that reported in the United States of America and Europe. ^[7] In recent years, increasing number of patients throughout the world are being diagnosed with oral cavity squamous carcinoma at a young age (less than 40 years). In the historical series, young patients have not accounted for more than 6% of patients. ^[8],[9] However, in published data from hospital based registries from USA, up to 14% increase has been observed over the last 25 years in those below the age of 40 years. ^[10] Similarly, an increase has also been observed in the proportion of young patients in the Indian subcontinent where 16-28% of patients with oral cavity cancer are below the age of 40 years. Consistent with the reports from Indian subcontinent, in our database 22% (n=268) of the patients were below the age of 40.

It has been postulated that OCSCC below the age of 40 may have higher representation of females and those who have never used tobacco and this subgroup of patients may represent a biologically distinct entity. ^[11] However this has often been based on results from small group of patients and conclusions have often been equivocal. In the present series, which is also the largest reported series in patients less than 40 years of age, we did not observe variation in sex distribution and tobacco use above and below the age of 40 years. We did not observe any differences in LC, LRC or DFS between tobacco users and nonusers below the age of 40 years. It has also been suggested that young patients may present with a higher stage at the time of diagnosis. ^[12] In the present series no difference was observed between stage distribution in those above and below the age of 40 years (21% vs 19% stage I/II). With regard to difference in outcome and inherent biological aggressiveness even within early stages in those with a younger age, we failed to demonstrate any difference in LC, LRC and DFS for the entire cohort and those treated with adjuvant radiotherapy. However, for the subgroup receiving definitive radiotherapy inferior LC, LRC and DFS was observed in those below the age of 40 years [Table - 6]. Age below 40 years turned out to be significant both on univariate and multivariate analysis in subgroup of patients treated with definitive radiotherapy suggesting a need for aggressive combined modality treatment in this young population. Lack of difference in LC, LRC and DFS in the entire cohort and those being treated with PORT prevents us from making any conclusive statements regarding the biological aggressiveness in those less than 40 years of age. However, a definite difference in outcome in spite of similar baseline characteristics in those above and below the age of 40 in the definitive radiotherapy group gives a strong reason to suspect that OCSCC in patients below the age of 40 years may represent a distinct biological entity and aggressive combined modality locoregional treatment may be required in younger population to match the outcomes in those above the age of 40 years. Other than age, none of the patients related factors either in the entire cohort or in the two subgroups affected LC, LRC and DFS.

Anatomic Subsite

Anatomic subsite has been proposed to be an independent prognostic factor in oral cavity tumors. Though single institution series have reported inferior outcomes in patients with tongue and floor of mouth primary lesion, ^[13] others have failed to demonstrate difference between proposed subsites. ^[14] In the present series for the overall cohort, anatomic subsite was a significant factor on univariate analysis [Table - 5]. On multivariate analysis although subsite retained its significance for LRC and DFS for the group of patients treated with adjuvant radiotherapy, no difference was observed in those treated with definitive radiotherapy. This pattern could partly be explained by examining the patterns of failure between Group 1 and Group 2 patients as patients with tongue and floor of mouth primary had a higher nodal failure than those with alveolobuccal primaries (11.5% vs 6.8%). In definitive radiotherapy, subsite was not a significant factor suggesting that in the presence of medical comorbidity, inoperability and advanced locoregional disease, anatomical subsite may not be a significant prognostic factor.

T stage

For the purpose of analysis, T1/2 were grouped as early T stage and T3/4 were grouped together as advanced T stage. However, no difference was identified in LC, LRC and DFS either in the entire cohort or the subgroups. Lack of discrimination in outcomes with regard to T stage could be due to the limitation in the pathological staging system in the present series and other series ^[15] points out the fallacy of T staging on OCSCC and need to re-examine the T grouping in OCSCC.

Nodal Status

In the present series, nodal status was identified as the single most important factor impacting LRC and DFS in the entire cohort and in the treatment subgroups. Patients with N2/3 disease fared significantly worse than those with a lower nodal stage. Similar results have been observed by other authors wherein nodal status has been identified as the single most important factor not only for LRC but also for development distant metastasis. ^[16],[17]

In the PORT group, we evaluated the correlation between clinical and pathological nodal stage. Of the 957 patients undergoing PORT, 38% of the clinically N0 patients turned out to be N+ (upstaged) on pathological examination. Amongst those with clinically N1 disease, 33% turned out to be pathologically N0 (downstaged) and another 35% had a higher nodal pathological stage (upstaged). This indicates the shortcomings of clinicoradiological examination in truly predicting difference between reactive and metastatic nodal involvement and in detecting multiplicity. Of those with clinically N2a disease while one third of the patients were down staged another 47% were upstaged. This could have been possibly due to misinterpretation of true nodal size clinically, which is probably due to associated nodal inflammation in patients who were downstaged and inability to detect multiplicity in those who were upstaged. Similar observations were also observed in other nodal stages. This suggests that clinical examination is not enough to appropriately stage patients. Overall while 18% of the patients were down staged on pathological examination almost 37% of the patients were upstaged [Table - 3]. This discordance in nodal staging is also reflected in the differences in outcome of those with clinical N0/1 disease as compared to pathological N0/1/ staging. Nearly 8% difference in LRC and DFS was observed by using pathological rather than clinical staging, with patients staged pathologically having a better outcome than those staged clinically [Table - 6]. It would be reasonable to keep the magnitude of this difference in mind while comparing clinicopathological outcome data in literature.

Overall Stage

Like nodal staging, interesting observations were made regarding overall staging following surgery. In patients undergoing surgery, access to clinical and pathological staging allowed us to evaluate the correlation between clinical and pathological stage. Following pathological staging while 32% patients underwent a nodal upstaging and 18% were down staged, only 15% patients were upstaged and 8% were downstaged as far as overall stage was concerned. This is due to the fact that all changes in nodal status may not reflect as changes in overall stage. Though change in nodal status from N0 to N1/2 or vice versa is reflected in change of overall stage, any upstaging of N2 disease may not reflect in the overall stage. If one were to estimate the percentage nodal and overall stage change from clinical to pathological evaluation, we observed that nodal to stage change follows a rule of halves i.e for every two patients undergoing a change in nodal staging, one patient would have a change in overall stage. As is evident in the lack of difference in LC, LRC and DFS with regard to clinical and pathological stage this phenomenon may lead to blurring of the impact of nodal change on LRC and DFS. With regard to stage as a prognostic factor in those undergoing definitive radiotherapy; though significant difference was observed between early and advanced stage on univariate analysis, overall stage lost its significance on multivariate analysis.

Though stage was not a prognostic factor, certain observations regarding clinical and pathological staging are worth discussing. In the PORT group while there was only 1-4% difference in LC, LRC and DFS amongst those with early and advanced disease when clinical staging was used, this difference increased to 8-13% when pathological staging was used [Table - 6]. This difference was essentially due to improvement in outcomes in those with early stage disease. This can be explained by the fact that pathological stages include patients who are truly early as compared to clinical staging where a few patients with advanced stages may get included inadvertently amongst those classified as early stages. This data though does not give enough information regarding stage as a prognostic factor, it allows us to predict correction for the effects of inaccuracy of clinical staging amongst those with early stage disease. While interpreting results from series employing clinical staging alone 3-12% improvement in LC, LRC and DFS can be presumed to account for the errors in clinical staging.

Choice of Treatment Modality

Across all stages, PORT had superior outcomes than radical radiotherapy with regard to LC, LRC and DFS [Table - 5]. Though in patients with stage I disease both radical radiotherapy and PORT had equivalent LC and LRC, for all other stages PORT had significantly better LC,LRC and DFS than radical radiotherapy. Though we cannot disregard the difference in outcome between two modalities in potentially resectable tumors (stage II/III), the difference in outcomes in stage IV disease could have been exaggerated due to selection bias for surgical and nonsurgical treatment.

Cut Margin and Perinodal Extension (PNE)

In the present series, about 8% (78/957) of the patients undergoing surgery had a positive cut margin which has been reported as a poor prognostic factor in literature. The presence of a positive cut margin led to 9-20% reduction in DFS, LRC and LC. Apart from nodal involvement, presence of PNE has been postulated as an independent adverse prognostic factor. ^[15] Patients with PNE had inferior LRC and DFS as compared to those without PNE. Aggressive treatment with addition of chemotherapy and escalation of dose improves outcomes in these patients ^[18],[19]

Radiotherapy Dose

We also evaluated the effect of total radiotherapy dose in patients undergoing definitive and adjuvant radiotherapy. Although there is a suggestion of a dose response relationship in HNSCC, we could not establish any dose response relationship in those undergoing either definitive or adjuvant radiotherapy. Higher doses of radiotherapy in those with a positive cut margin did not result in any gain in LC, LRC or DFS. The lack of difference could be due to the large difference in the number of patients with and without positive margins and limited number of patients receiving <50 Gy and >60 Gy.

Conclusion

In a large cohort of patients with cancer of the oral cavity treated at a single center, postoperative radiotherapy showed superior outcomes as compared to definitive radiotherapy especially in advanced stages. The results of the present series of patients treated with PORT alone leave a significant scope for improving outcomes further by adopting treatment intensification.

References

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