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ORIGINAL ARTICLE
Year : 2013  |  Volume : 50  |  Issue : 4  |  Page : 349-355
 

Is there a role of induction chemotherapy followed by resection in T4b oral cavity cancers?


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiodaignosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Head and Neck Surgery, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication24-Dec-2013

Correspondence Address:
K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.123627

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 » Abstract 

Objective: The objective of the following study is to investigate the efficacy and impact of induction chemotherapy in T4b oral cavity cancers. Materials and Methods: It's a retrospective analysis of prospectively collected data of T4b oral cavity cancer patients who were offered induction chemotherapy and then assessed for resectability at the end of 2 cycles of chemotherapy. Post-induction these patients either underwent surgical or non-surgical local intervention depending upon their response. These patients were then followed-up until either recurrence progression or death whichever was later. Statistical analysis was performed by SPSS version 16. Descriptive analysis was performed. Factors affecting achievement of resectability were sought by univariate and multivariate analysis. The impact of surgery on overall survival (OS) was studied using Kaplan Meier survival analysis with the use of log rank test. Results: A total of 110 patients received chemotherapy. Median age been 41.5 years (range 25-66 years). 21 (20%) of our patient received 3 drug regimen while the rest of our patients received 2 drug regimen. Partial response was achieved in 28 patients, stable disease in 49 patients and progression was noted in 23 patients. Resectability was achieved in 34 (30.9%) of 110 patients. The estimated median OS in patients who underwent surgery was 18.0 months (95% confidence interval [CI]: 13.6-22.46 months) and for those treated with non-surgical treatment was 6.5 months (95% CI: 5.6-7.4 months) (P = 0.0001). Conclusion: Use of induction chemotherapy is safe and can achieve resectability in 30.9% of our T4b patients. In those patients undergoing resection have much better OS then those who underwent non-surgical local treatment.


Keywords: Induction chemotherapy, oral cavity cancers, unresectable


How to cite this article:
Joshi A, Patil V M, Noronha V, Juvekar S, Deshmukh A, Chatturvedi P, Chaukar D A, Agarwal J P, Ghosh S, Murthy V, D'cruz A, Prabhash K. Is there a role of induction chemotherapy followed by resection in T4b oral cavity cancers?. Indian J Cancer 2013;50:349-55

How to cite this URL:
Joshi A, Patil V M, Noronha V, Juvekar S, Deshmukh A, Chatturvedi P, Chaukar D A, Agarwal J P, Ghosh S, Murthy V, D'cruz A, Prabhash K. Is there a role of induction chemotherapy followed by resection in T4b oral cavity cancers?. Indian J Cancer [serial online] 2013 [cited 2019 Nov 21];50:349-55. Available from: http://www.indianjcancer.com/text.asp?2013/50/4/349/123627



 » Introduction Top


Surgery remains the main stay of treatment for advanced oral cavity cancers. [1],[2],[3] However, the oral cavity is anatomically close to the infra-temporal fossa and masticator space (MS), explaining the frequent involvement of these spaces in the oral cavity primaries. [4],[5] Despite advances in surgical and reconstructive techniques, surgery involving complete clearance of these sites is extensive and extremely morbid. [6],[7] Consequently, these tumors are conventionally considered as unresectable. The American Joint Committee on Cancer (AJCC) staging system recognizes the advanced nature of such lesions and classifies the T stage as 4b. [8]

The current standard of management of T4b cancers is radical chemo-radiation alone. The results of chemo radiation or radical radiation alone in T4b cancers are not satisfying with 1-year disease-free survival in various studies ranging from 10% to 40% respectively. [9],[10],[11],[12],[13],[14],[15],[16] Surgery is an option in exceptional cases. In a recent article Liao et al. reported results from their center on upfront surgery in T4b oral cavity cancers below the infrahyoid notch. The 5 year loco-regional control rate was 47%. [17],[18] However, these are individual institutional reports and are not generally reproducible in conventional practice.

With such disappointing outcomes, alternative treatment paradigms are required. The TA Χ 323 and TA Χ 324 trials incorporating upfront induction chemotherapy in unresectable and locally advanced head and neck cancers provided encouraging results. [19],[20] Considering our own unpublished experience with nonsurgical modalities in T4b oral cavity cancers, we started administering neoadjuvant chemotherapy (NACT) in unresectable T4b oral cavity cancers with the intention of making them amenable for surgery.

The present report presents the analysis of our data of unresectable T4b oral cavity tumors. We have focused on achievement of resectability post induction chemotherapy, factors affecting achievement of resectability, tried to identify any specific subgroup which could undergo surgery consistently and the impact of such surgery on overall survival (OS).


 » Materials and Methods Top


This is an analysis of prospectively collected data of consecutive patients with T4b oral cavity cancer treated in a tertiary cancer center in an economically disadvantaged country from June 2009 to December 2010. All the patients were offered NACT with curative intent. These patients were considered inoperable upfront at a multidisciplinary clinic which included surgical oncologists, medical oncologists, radiation oncologists and radiologist. The findings on axial imaging, which staged the tumors to AJCC stage IVB, are shown in [Table 1].
Table 1: Baseline details of patients


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Patients offered NACT had adequate hematological and normal biochemical parameters and did not have any uncontrolled co-morbidities. Patients received either a 3 drug combination of Docetaxel, cisplatin and 5-fluorouridine (DCF regimen) or a 2 drug combination of a platinum agent and a taxane. The choice of regimen was determined by patient choice and logistics.

The platinum agent preferred was cisplatin in all patients except those in whom the serum creatinine clearance as calculated by the modified Cockcroft-Gault formula was below 60 ml/min. Carboplatin was used as the alternative in patients with impaired renal clearance.

Standard premedication was used before chemotherapy. The DCF regimen consisted of Docetaxel (at a dose of 75 mg/m 2 of the body-surface area) administered as a 1-h intravenous infusion, followed by intravenous cisplatin (75 mg/m 2 ) over a period of 60 min and 5 fluorouracil (750 mg/m 2 /day, total 3750 mg/m 2 ) administered as a continuous 24-h infusion for 5 days. All patients received primary granulocyte colony-stimulating factor (G-CSF) prophylaxis and oral antibiotic prophylaxis from day 6 to day 10. In the 2-drug regimens, Paclitaxel at a dose of 175 mg/m 2 was administered over 3 h and the platinum agent was either cisplatin at a dose 75 mg/m 2 over 1 h or Carboplatin at a dose of AUC 5 over 1 h. G-CSF was used as secondary prophylaxis in patients who had febrile neutropenia requiring inpatient admission.

All patients were assessed on day 8 and day 20 of all cycles for toxicity and clinical response. Cycles were repeated every 21 days. In patients developing any grade 4 or life-threatening toxicity, there was a dose reduction of 25% in subsequent cycles. Only the maximum grades of toxicity encountered by the patients in accordance with common terminology criteria for adverse events (CTCAE version 4.02) are reported.

All patients after the completion of 2 cycles of chemotherapy were evaluated for clinical and radiological response in the multidisciplinary joint clinic. In patients who had adequate shrinkage of the tumor had led to clearing of the MS or of the infratemporal fossa where given the option of surgery. Following surgery all patients were planned for adjuvant radiation with or without chemotherapy on the basis of the surgical pathological report. In those patients where the disease was considered unresectable even after induction chemotherapy, the treatment offered was radical radiation with or without concurrent chemotherapy, palliative radiation, palliative chemotherapy or supportive care alone. The treatment decision was made based on the performance status, extent of disease and patients choice. All the patients, irrespective of treatment were followed-up until progression, recurrence, relapse or death, whichever occurred earliest. The data was censored on 30 th April 2013 at the time of analysis. The status of all the patients was updated after checking the electronic medical records, case files and personal communication.

Statistical analysis

Statistical analysis was performed using SPSS software version 16. Descriptive analysis has been performed. Correlation analysis was done to study the relationship between achievement of partial response and resectability. In view of dichotomous nature of the variable spearman correlation coefficient was use. The strength of relation between the 2 factors was tested with linear regression analysis. The effect size is reported in accordance with Cohen 1988. [21] The Chi-square, Fischer exact test and Logistic regression analysis were performed to identify whether resectability achievement would be predicted by space which are involved, type of regimen used and use of Docetaxel containing regimen. The Chi-square and Fischer exact test were done to identify whether 3 drug regimen or Docetaxel containing regimen lead to a higher amount of toxicity. Progression free survival (PFS) was calculated from the date of first chemotherapy till date of recurrence or progression or until date of death if it occurred prior to failure. OS was calculated from date of first chemotherapy till date of death. Kaplan Meier survival analysis used for estimation of median survival in the whole population. Impact of prognostic factors on survival was explored using the log rank test. Those factors having a statistically significant impact were then used for Cox proportional hazard model for multivariate analysis.


 » Results Top


Over the mentioned time period in our database, 110 T4b patients were offered NACT. The baseline characteristics and reason for chemotherapy are shown in [Table 1].

The majority of our patients had buccal mucosa as the primary site. Patients with MS involvement could be divided into 2 subgroups based on the extension of tumor above (29 patients) and below (73 patients) an axial plane at the level of mandibular notch [Figure 1]. Details of the chemotherapy regimens are provided in [Table 2].
Table 2: Details of chemotherapy schedule received


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Figure 1: A 3 dimensional contour of mandible, masticator space (MS) and high infratemporal fossa. Panel A demonstrates the MS in light yellow color. In Panel B the part of MS above the sigmoid notch is been depicted in light red color. It's been termed as hich infratemporal fossa

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100 (90.9%) patients received at least 2 cycles of chemotherapy. The median number of cycles delivered were 2 (range 1-3). 10 patients took only one cycle. Six had disease progression, 1 had severe toxicity and 3 withdrew consent for chemotherapy. Only 4 patients received dose reduction (20% in 3 patients and 25% in 1 patient). Of these 4 patients 2 had received 3 drug regimens while the other 2 had received 2 drug regimens.

Efficacy

The response assessment was done and resectability achieved is shown in [Table 3].
Table 3: RECIST response and achievement of resectability


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The overall response rate was 28%. To investigate if there was a significant association between partial response and resectability achievement, a non-parametric correlation was computed. The spearman rho statistic was calculated, rs (110) =0.39, P = 0.0001. It was a positive correlation which would mean that patients who achieved a partial response tend to have a higher likelihood of achieving resectability. Using Cohen's (1988) guideline the effect size is medium. Simple regression was conducted to investigate how well a partial response predicts for achievement of resectability. These results were statistically significant F (1,110) =19.80, P < 0.01. The adjusted R squared value was 0.15. This indicates that 15% of the variance of achieving resectability was explained by the partial response. In accordance with Cohen this is a small effect size. The partial response achieved with 3 drug regimen as opposed to 2 drug regimen was not statistically significant using a Fischer exact test. Further the achievement of partial response with a Docetaxel containing regimen as opposed to regimen without Docetaxel was also not statistically significant using the Pearson Chi-square test.

On univariate analysis for achievement of resectability, the involvement of MS without tumor extension above jugular notch (P = 0.02), use of 3 drug regimen (P = 0.023), use of Docetaxel containing regimen (P = 0.01) were significant factors for achievement of resectability [Table 4]. However on conduction of logistic regression analysis to assess whether when considered together, the 3 factors significantly predicted achievement of resectability, only involvement of MS below jugular notch (P = 0.02) was an independent variable predicting achievement of resectability.
Table 4: Crosstab showing relation between achievement of resectability and various factors


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Toxicity of NACT (n = 110)

The details of grade 3-4 toxicity can be seen in [Table 5]. The rate of febrile neutropenia was 12.72%. One patient had severe febrile neutropenia with necrotizing enterocolitis and succumbed to the infection. Grade 3-4 hematological toxicity was more common with 3 drug regimen (36.36%) than with 2 drug regimen (4.5%) (P = 0.0001), it was more in Docetaxel containing combinations (25% vs. 2.85%) (P = 0.001) and there was no effect of age (below 40 years or above 40 years) on grade 3-4 hematological toxicity.
Table 5: Highest grade of toxicity associated with induction chemotherapy


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Post neoadjuvant treatment

The treatment offered post induction chemotherapy was radical treatment in 61 patients (55.45%) and palliative treatment in rest. 100 patients completed NACT. Post-NACT surgery was done in 29 patients, chemo radiation in 30 patients, radical radiation in 2 patients, palliative radiation in 19 patients, palliative chemotherapy in 13 patients and 7 patients did not undergo any further treatment. Four of these 7 patients who did not undergo local treatment had achieved respectability; however due to personal reasons and logistics they never underwent surgery. The other 3 had progressed after 2 cycles and were found eligible only for supportive care.

Post NACT surgery details

The median duration between completion of chemotherapy and date of surgery was 1.58 months. Though 34 patient had achieved resectability, 29 patients underwent surgery, 4 of these 5 patients defaulted and one patient opted for chemo radiation. All patients underwent a R0 resection. The margin statuses in these patients were wide in 18 patients and close in 9 patients. No patient had achieved pathological complete response. Pathological downgrading in staging was achieved in 7 patients, with 1 tumor being pT1, 3 being pT2 and pT3 respectively. 27 patients received adjuvant post-operative chemo radiation. One patient received only post-operative radiation and one patient had local recurrence while awaiting the start of chemo radiation. The median biologically equivalent dose received was 72 Gy 10 ( 52.8-79.2 Gy 10 ). All patients were planned with conventional fraction schedule 200 cGy per fraction for 5 days a week with conventional, two, parallel, lateral opposing portals, source to axis distance technique with dose prescription been done along the central axis on the mid separation point.

Post NACT radiation details

The radiation delivered radical chemo radiation in 30 patients, radical radiation in 2 patients and palliative radiation in 19 patients. The median biologically equivalent doses of radiation administered were 84 Gy 10 , 73.20 Gy 10 and 47.80 Gy 10 respectively in radical chemo radiation setting, radical radiation and in palliative setting. All patients were planned with conventional fraction schedule of 2 Gy per fraction for 5 days a week with conventional, two, parallel, lateral opposing portals, source to axis distance technique with dose prescription been done along the central axis on the mid separation point in radical setting. The dose per fraction in palliative setting varied between 200 and 400 cGy.

Failure pattern

64 patients have had failure defined as local recurrence or progression in 53 patients and distant in failed. The pattern of failure is shown in [Table 6]. The predominant pattern of failure was local 53 out of 64 failures (82.8%).
Table 6: Failure pattern post neoadjuvant chemotherapy


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The estimated median PFS was 5.07 months for the overall population. On univariate analysis among the tested variables, age (below 40 years vs. above and equal to 40 years), sex, regimen used (2 drug vs. 3 drug), whether regimen contained Docetaxel or not, space involved (tumor restricted to lower MS vs. those extending above) and type of local treatment (surgical vs. non-surgical). Female sex (P = 0.043), those regimens which had Docetaxel (P = 0.034) and those patients who underwent surgery (P = 0.0001) had statistically significant impact on survival.

The estimated median OS was 7.7 (95% confidence interval [CI]: 6.64-8.88 months) for the overall population. On univariate analysis among the tested variables age (below 40 years vs. above and equal 40 years), sex, regimen used (2 drug vs. 3 drugs), whether regimen contained Docetaxel or not, space involved (tumor restricted to lower MS vs. those extending above), response to chemotherapy and type of local treatment (surgical vs. non-surgical). Variables that had statistically significant impact on survival were those who had Docetaxel in their regimen (P = 0.021), those patients who had at least a partial response (P = 0.020) and those patients who underwent surgery (P = 0.0001). The estimated median OS in patients who underwent surgery was 18.0 months (95% CI: 13.6-22.46 months) and for those treated with non-surgical treatment was 6.5 months (95% CI: 5.6-7.4 months) [Figure 2]. On performing Cox regression analysis, the only independent predictor of survival was seen in those patients in whom surgery was performed. The hazard ratio was 8.437 (95% CI: 3.536-20.131) (P = 0.0001) in favor of surgical intervention.
Figure 2: A Kaplan Meier plot showing the overall survival curve of patients undergoing resection versus those treated with non-surgical approach. The survival curve depicted by light green color is that of patients undergoing resection while the one in blue is of patients not undergoing resection. The median survival have been depicted

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 » Discussion Top


T4b oral cavity cancers are considered unresectable and so recognized in the 6 th edition of AJCC staging classification. [8] Radical radiation, with or without chemotherapy is the standard therapy for such patients. However, several studies from India have documented poor results with this approach. [11],[14],[15],[22] Consequently, expert guidelines for the management of T4b oral cavity tumors issued by the Indian council of Medical research recommend that the intent of treatment in these patients be palliative from the outset. [23] Investigators have reported different approaches to improve the poor outcomes in T4b tumors. Liao et al. studied the role of meticulous surgery in those patients where the tumor involvement of the MS was restricted to a plane below the jugular notch. The results were impressive with 5 year OS rate of 47%. [17],[18] However, these results have not been replicated elsewhere.

Neoadjuvant or induction chemotherapy is another modality that has been reported in various studies. Okura et al. published a retrospective review of induction chemotherapy in patients with operable oral cavity cancers. The induction chemotherapy comprised of two cycles of cisplatin, vincristine and peplomycin, with or without mitomycin C. The overall response rate was 51.5% and there was a documented decrease in the rates of distant metastases. Surprisingly, the loco regional relapse rates were higher in patients with stage II and N0 tumors receiving induction therapy. The type of surgery performed, the response to chemotherapy as per the T stage, the impact of effective chemotherapy and the adequacy of surgical margins achieved have not been reported. [24] Licitra et al. in their study have reported the results of a randomized trial of induction chemotherapy in operable oral cavity cancer. Around 20% of the patients had T4 disease in this study. The response rate was 82%. Chemotherapy did not have any benefit with respect to OS. However, there was a benefit in terms of morbidity related to lesser number of morbid procedures such as segmental mandibulectomy (31% in chemotherapy arm vs. 52% in the control arm). [25] The TA Χ 323 trial has reported on the use of induction chemotherapy in unresectable head and neck cancers. [19] However, oral cavity constituted < 15% of the tumors and using induction therapy for facilitating respectability was not an objective of this trial. To the best of our knowledge as is the first report dealing with the use of induction chemotherapy and assessment for surgery in T4b oral cancers.

At our institute, NACT is used in patients where lesions are deemed unresectable due to their anatomic spread. The intent of treatment is to make the lesions amenable to resection with adequate margins. An interesting hypothesis in this regard could be the potential difference in the biological activity of oral cavity tumors compared with other sites in the head and neck region. Yeole et al. have demonstrated that the response of oral cavity cancers especially buccal mucosa cancers to radiation is inferior when compared with pharyngeal cavity cancers. [26] Hence, surgery upfront or following chemotherapy should conceivably be the preferred paradigm of therapy. Further, this approach seems promising as patient undergoing surgery had a survival advantage in our analysis.

There are limitations to our study. This is a retrospective analysis and there is no randomization or a comparator arm to decide the true benefit of NACT. The response rates in our study are lower than previously reported, which could be explained by differences in the patient profile. Though objective criteria were used as much as possible along with discussion in a multidisciplinary clinic, inherently the assessment of resectability is dependent on the surgical skills available in any center. Hence, our results need to be validated by different centers.

An intriguing finding from our study is the unexpectedly weak association of the response evaluation criteria in solid tumor criteria with the achievement of respectability. Many patients had stable disease on imaging which implies a change of < 30% in the sum of longest diameters. Such a decrement might often be sufficient for a surgeon to achieve resection with adequate margins especially where the lesion was border line to begin with. Thus, a discussion with the radiologist and surgical oncologist in a multidisciplinary clinic is essential in all cases. Another important finding relates to the selection of patients and the protocol for induction chemotherapy. In the logistic regression analysis, it was seen that patients with involvement of MS with tumor restricted below the axial plane passing through jugular notch had better response to this approach. In our study, 38.35% (28 out of 73) of these patients achieved resectability. Further, regimens containing 3 drugs appear to be better and if only 2 drugs are used, Docetaxel appears to be better than paclitaxel.

The OS advantage demonstrated in our analysis from use of surgical modality post neoadjuvant treatment is encouraging. However, it should be considered that patient in whom there was tumor regression could only undergo surgery as response to induction chemotherapy is a known important prognostic factor in head and neck cancers. [25],[27],[28] The likely benefit of this approach has also been pointed out by Paterson et al. [29] Our results prior to use in clinical practice need prospective randomized evaluation where in patients post induction chemotherapy are considered resectable, undergo a randomization between surgery versus radical chemo radiation.


 » Conclusion Top


The use of induction chemotherapy in T4b cancer is safe and feasible and may lead to complete surgical resection, especially in patients with involvement of MS below the jugular notch. This approach is likely to lead to a survival advantage in patients who undergo surgery.

 
 » References Top

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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