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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 35-38
 

Induction chemotherapy in locally advanced T4b oral cavity squamous cell cancers: A regional cancer center experience


Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. T Chaudhuri
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_131_17

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 » Abstract 

OBJECTIVES: The present study aimed to investigate the efficacy, toxicity, and impact of induction chemotherapy (IC) in locally advanced T4b oral cavity squamous cell cancers (OSCCs). MATERIALS AND METHODS: Patients diagnosed with locally advanced T4b OSCC from January 2013 to October 2016 at our center, who received 2–3 cycles of IC and then assessed for resectability, were reviewed retrospectively. Patients' profile, response, and toxicity of IC, resectability status, and overall survival (OS) were evaluated. Statistical analyses were performed by SPSS software version 17. RESULTS: A total of 116 patients received IC, and out of them 90 (77.6%) were males. Median age at diagnosis was 43 years (range 31–62 years). Nearly 103 (88.8%) of our patients received doublet chemotherapy and the rest of the patients received triplet regimen. Majority of the patients had buccal mucosa cancers (71.6%), followed by gingivobuccal complex (21.6%) and oral tongue (6.9%) primaries. After IC, partial response was achieved in 20 (17.3%) patients, stable disease in 68 (58.6%) patients, and disease progression was noted in 28 (24.1%) patients. Post-IC, resectability was achieved in 22 (19%) of 116 patients, but 6 of them did not undergo surgery due to logistic and personal reasons. The median OS of patients who underwent surgery followed by adjuvant local therapy (n = 16) was 19.7 months (95% confidence interval [CI]: 16.0–22.8 months) and for those treated with nonsurgical local therapy (n = 100) was 7.1 months (95% CI: 5.8–8.2 months) (log-rank P = 0.000). CONCLUSIONS: IC had a manageable toxicity profile and achieved resectability in 19% of our patients with T4b OSCC. Patients underwent resection had a significantly better median OS than those who received nonsurgical local treatment.


Keywords: Induction chemotherapy, oral cavity squamous cell cancers, resectability


How to cite this article:
Rudresha A H, Chaudhuri T, Lakshmaiah K C, Babu K G, Dasappa L, Jacob L A, Suresh Babu M C, Lokesh K N, Rajeev L K. Induction chemotherapy in locally advanced T4b oral cavity squamous cell cancers: A regional cancer center experience. Indian J Cancer 2017;54:35-8

How to cite this URL:
Rudresha A H, Chaudhuri T, Lakshmaiah K C, Babu K G, Dasappa L, Jacob L A, Suresh Babu M C, Lokesh K N, Rajeev L K. Induction chemotherapy in locally advanced T4b oral cavity squamous cell cancers: A regional cancer center experience. Indian J Cancer [serial online] 2017 [cited 2020 Mar 29];54:35-8. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/35/219535



 » Introduction Top


Squamous cell carcinoma is the most common type of tumor of the oral cavity.[1] The majority of oral cavity squamous cell cancers (OSCCs) are locally advanced and have a relatively poor prognosis with 5-year overall survival (OS) <50%–60%.[2],[3],[4] The current standard of care for resectable locally advanced OSCC is surgical resection followed by adjuvant radiotherapy or chemo-radiotherapy, as indicated.[5] For the purpose of achieving a negative pathological margin, extensive surgical procedures are required in these locally advanced tumors which are associated with the significant amount of cosmetic deformity and functional morbidity.[6] As per the present American Joint Committee on Cancer (AJCC) staging system, involvement of infratemporal fossa and masticator space in a case of OSCC are considered as a very advanced local disease and staged as T4b.[7] Despite recent advances in surgical and reconstructive techniques, surgery with an aim to remove all gross tumors with a negative margin from these sites is extensive and extremely morbid. As a consequence, conventionally T4b OSCCs are considered unresectable. The current standard of management for T4b OSCCs is definitive chemoradiation alone. However, the results of this nonsurgical local treatment modality in T4b OSCCs are disappointing with a reported 1-year disease-free survival ranging from 10% to 40% in various studies.[8],[9],[10],[11],[12],[13],[14]

Two large landmark trials, the TAX323 and TAX 324, had highlighted the role of induction chemotherapy (IC) using triplet regimen in unresectable and locally advanced head and neck cancers.[15],[16] The use of TPF (docetaxel, cisplatin, and 5-fluorouracil [5-FU]) regimen in these trials led to an overall response rate (ORR) of about 68%. However, these two landmark studies were not exclusively designed for OSCC and <15% of the included patients had oral cavity cancers. In Phase III randomized controlled trial, Licitra et al. showed that the use of IC in resectable OSCCs was associated with 33% clinical complete response (CR) and 82% ORR.[17]

We believe that a proportion of patients with T4b OSCCs who would be considered unresectable otherwise might be made resectable by the use of IC and this may improve the overall outcome. To examine the validity of such a hypothesis, we performed a retrospective analysis of our patients with unresectable T4b OSCCs who were treated with IC.


 » Materials and Methods Top


Patient selection, evaluation, and treatment

All consecutive cases diagnosed with locally advanced T4b OSCCs and having Eastern Cooperative Oncology Group performance score ≤2, between January 2013 and October 2016 at the Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India, were investigated retrospectively. All the patients underwent a detailed history and physical examination. The locoregional disease extent was investigated by contrast-enhanced computed tomography scans, and the diagnosis was confirmed by microscopic examination of the biopsy specimens. These patients were considered inoperable upfront at a multidisciplinary clinic due to very advanced local disease and offered IC with an aim to achieve resectability. Patients received either a triplet regimen of docetaxel 75 mg/m 2 on day 1, cisplatin 75 mg/m 2 on day 1, and 5-FU 750 mg/m 2/day on day 1–5 (DCF regimen) or a doublet combination of paclitaxel 175 mg/m 2 on day 1 and carboplatin area under the curve 5 on day 1 (PC regimen). Primary granulocyte colony-stimulating factor (G-CSF) prophylaxis from day 6 to day 10 was given to all patients of DCF chemotherapy arm, and secondary G-CSF prophylaxis was given to the patients who received PC regimen. A 25% dose reduction in subsequent cycles was done in patients developing any Grade IV or life-threatening toxicity. Responses to IC were reported according to the Response Evaluation Criteria in Solid Tumors (version 1.1). The adverse events were classified based on the Common Terminology Criteria for Adverse Events version 4.0. After the completion of 2–3 cycles of IC, all patients were evaluated clinicoradiologically for response assessment. In patients who had adequate downstaging of the tumor, surgery had been offered as an option. Following surgery, all patients received adjuvant radiation with or without concurrent chemotherapy (cisplatin 40 mg/m 2/weekly) depending on the histopathological report of the operated specimen. Patients with unresectable disease even after IC were treated with either definitive chemoradiation or radical radiation or palliative radiation or best supportive care (BSC) depending on the performance status, locoregional disease extent after IC, patients choice, and logistics.

Statistical analysis

Duration of progression-free survival (PFS) was defined by the time from the treatment initiation until the documented recurrence or disease progression, and OS was calculated from the date of diagnosis until death. Kaplan–Meier survival analysis was used for estimation of median OS in the whole cohort. Impact of prognostic factors and therapeutic strategies on survival was tested using the log-rank test. OS was taken as the primary end point for this retrospective analysis, and the secondary end points were PFS, response, and toxicity profile of IC. All statistical analyses were performed using SPSS software version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).


 » Results Top


A total of 116 cases of locally advanced T4b oral cavity cancers treated with IC over the mentioned time period were retrospectively reviewed. The baseline patients' characteristics are shown in [Table 1]. Majority of our patients (88.8%, n = 103) received doublet IC with PC regimen, and the rest of the patients received DCF regimen. All the patients in the DCF arm (n = 13) received two cycles of IC and 69% (n = 71) of patients in the doublet arm received three cycles of IC. Sixteen patients (15.5%) in the PC arm received only one cycle of IC due to rapid disease progression.
Table 1: Patients' profile at baseline

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According to the assessment of response to IC, stable disease (SD) was documented in 68 patients (58.6%), followed by a partial response (PR) in 20 patients (17.3%) and disease progression in 28 patients (24.1%). None of our patients achieved a CR after IC. Almost 53.8% (7 of 13) of patients in the DCF arm achieved a PR as opposed to 12.6% (13 of 103) in the doublet chemotherapy arm, and the difference was found to be statistically significant by Fisher's exact test (two-tailed P = 0.0119). All the seven patients who achieved a PR in the triplet IC arm became resectable and 15 patients (including the 13 patients, who achieved PR) in the doublet IC arm became resectable. This difference of achieving resectability status between triplet and doublet IC regimens was also found to be statistically significant (Fisher's exact two-tailed P = 0.0198). On univariate analysis, use of triplet IC regimen was found to be a significant factor for the achievement of resectability (P = 0.01).

The rate of febrile neutropenia was 23% (n = 3) with DCF regimen (in spite of primary G-CSF prophylaxis) and 16.5% (n = 17) with PC regimen. All Grade III–IV toxicities were significantly higher with the triplet IC regimen in comparison to the doublet regimen: Hematological toxicity – 30.8% versus 21.3%; mucositis – 15.3% versus 0%, and diarrhea – 15.3% versus 0% (P = 0.00). Two patients in the DCF arm required 25% dose reduction in the next cycle due to severe diarrhea and mucositis.

After IC, 22 patients (19%) achieved resectability but 6 of them did not undergo surgery due to logistic and personal reasons. Two of these six patients opted for definitive chemoradiation, and the rest of four patients defaulted after IC and received palliative radiation latter. All the 16 patients, who underwent surgery post-IC, had a R0 resection and received adjuvant chemoradiation at standard doses. Among the 94 patients who had not achieved resectability after IC, 44 received definitive chemoradiation, 11 received definitive radiation, 20 received palliative radiation, and 19 patients received BSC alone.

At the time of last follow-up, 79 patients (68%) had disease failure, either in the form of locoregional recurrence/progression (n = 71) or as distant recurrence (n = 2) or as both (n = 6). The median PFS and OS for the whole cohort were 6.1 and 8.4 months, respectively. The median OS of patients who underwent surgery followed by adjuvant local therapy (n = 16) was 19.7 months (95% confidence interval [CI]: 16.0–22.8 months) and for those treated with nonsurgical local therapy (n = 100) was 7.1 months (95% CI: 5.8–8.2 months) (log-rank P = 0.000) [Figure 1]. Among the 100 patients, who received nonsurgical local treatment post-IC, the median OS for patients receiving definitive chemoradiation, definitive radiation, palliative radiation, and BSC was 9.4, 7.3, 5.6, and 4.3 months, respectively [Figure 2].
Figure 1: Kaplan–Meier curve of overall survival (in months) of patients with T4b oral cavity squamous cell cancers. The median overall survival of patients who underwent surgery followed by adjuvant local therapy (n = 16) was 19.7 months and for those treated with nonsurgical local therapy (n = 100) was 7.1 months (log-rank P = 0.000)

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Figure 2: Kaplan–Meier curve of overall survival (in months) of patients with T4b oral cavity squamous cell cancers, who received nonsurgical local treatment postinduction chemotherapy (n = 100). The median overall survival for patients receiving definitive chemoradiation, definitive radiation, palliative radiation, and best supportive care was 9.4, 7.3, 5.6, and 4.3 months, respectively

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 » Discussion Top


AJCC staging 2010 defines very advanced local disease or unresectable T4b OSCC as tumor invading the masticator space, pterygoid plates, and skull base or encasement of the internal carotid artery.[7] However, “resectability” remains a controversial term with limited consensus among the surgical teams.

The role of IC in head–neck cancers is being explored with the premise of reducing the extent of surgical resection, improving locoregional control (LRC), and decreasing distant metastasis, thereby improving treatment outcomes by decreasing mortality and morbidity. However, indications of IC in oral cancers are not clearly defined. Majority of studies have failed to demonstrate a significant benefit of IC in terms of LRC and OS in resectable OSCC.[17],[18],[19],[20],[21],[22] However, they have shown encouraging results in terms of achieving high ORR with IC.

The results of definitive chemoradiation or definitive radiation alone in T4b OSCCs are not satisfactory.[9] A few small studies showed encouraging results in terms of achieving good LRC using upfront compartmental resections in OSCC patients with infratemporal fossa or masticator space involvement.[23],[24] However, these are single institutional reports and are not generally reproducible in routine practice. A rationale for proposing IC in these very advanced local diseases is to improve the overall outcome by facilitating possible resection following tumor downstaging. Interestingly, there are a few published retrospective reports also from our country to support this hypothesis.[25],[26]

In a study reported by Joshi et al., the role of IC followed by resection in T4b OSCCs was tested in 110 patients.[25] Almost 92.7% of their patients had involvement of the masticator space. Twenty percent of patients received three-drug regimens whereas the rest received various combinations of two-drug regimen. PR was achieved in 28 patients, SD in 49 patients, and progression was noted in 23 patients. None of the patients had a CR to IC. Resectability was achieved in 34 (30.9%) of 110 patients. The estimated median OS in patients who underwent surgery was 18.0 months and for those treated with nonsurgical treatment was 6.5 months (P = 0.0001). In a follow-up article by the same group, Patil et al. retrospectively analyzed 721 patients with T4a and T4b OSCC deemed as technically unresectable who received IC.[26] Nearly 43% of these patients had sufficient reduction in tumor size that made them resectable. Three drug regimen achieved resectability in 66.21% and two-drug regimen in 40.34%. The LRC rate was 20.6% for the overall cohort. For patients undergoing surgery, the LRC was 32% and 15% for the nonsurgical group. The median estimated survival was 19.6 and 8.16 months, respectively.

In our study, the response rates and resectability after IC are lower than previously reported,[25],[26] which could be explained by differences in the patient profile and IC regimens. Moreover, the assessment of resectability is dependent on the surgical skills available in any oncology center. Hence, our results need to be validated by other centers.


 » Conclusions Top


In the current study, the use of IC in T4b oral cavity cancers is feasible with a manageable toxicity profile. In a subset of patients with locally very advanced/unresectable OSCC, IC has been shown to cause significant tumor shrinkage and improve resectability. Clearly, these hypothesis-generating findings of improved resectability and overall outcomes with IC in patients with T4b OSCCs need further validation through large prospective randomized trials.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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