|MINI SYMPOSIUM: HEAD NECK CANCER
|Year : 2013 | Volume
| Issue : 1 | Page : 1-8
Induction chemotherapy in technically unresectable locally advanced oral cavity cancers: Does it make a difference?
VM Patil1, V Noronha1, VK Muddu1, S Gulia1, B Bhosale1, S Arya2, S Juvekar2, P Chatturvedi3, DA Chaukar3, P Pai3, A D'cruz3, K Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radio-Diagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||20-May-2013|
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Locally advanced and unresectable oral cavity cancers have a poor prognosis. Induction might be beneficial in this setting by reducing tumor bulk and allowing definitive surgery. Aim: To analyze the impact of induction chemotherapy on locally advanced, technically unresectable oral cavity cancers. Materials and Methods: Retrospective analysis of patients with locally advanced oral cavity cancers, who were treated with neoadjuvant chemotherapy (NACT) during the period between June 2009 and December 2010. Data from a prospectively filled database were analyzed for information on patient characteristics, chemotherapy received, toxicity, response rates, local treatment offered, patterns of failure, and overall survival. The statistical analysis was performed with SPSS version 16. Results: 123 patients, with a median age of 42 years were analyzed. Buccal mucosa was the most common subsite (68.30%). Three drug regimen was utilized in 26 patients (21.10%) and the rest received two drug regimen. Resectability was achieved in 17 patients treated with 3 drug regimen (68.00%) and 36 patients receiving 2 drug regimen. Febrile neutropenia was seen in 3 patients (3.09%) receiving 2 drug regimen and in 9 patients (34.62%) receiving 3 drug regimen. The estimated median OS was not reached in patients who had clinical response and underwent surgery as opposed to 8 months in patients treated with non-surgical modality post NACT (P = 0.0001). Conclusion: Induction chemotherapy was effective in converting technically unresectable oral cavity cancers to operable disease in approximately 40% of patients and was associated with significantly improved overall survival in comparison to nonsurgical treatment.
Keywords: Head and neck neoplasm, induction chemotherapy, locally advanced, oral cancers, unresectable
|How to cite this article:|
Patil V M, Noronha V, Muddu V K, Gulia S, Bhosale B, Arya S, Juvekar S, Chatturvedi P, Chaukar D A, Pai P, D'cruz A, Prabhash K. Induction chemotherapy in technically unresectable locally advanced oral cavity cancers: Does it make a difference?. Indian J Cancer 2013;50:1-8
|How to cite this URL:|
Patil V M, Noronha V, Muddu V K, Gulia S, Bhosale B, Arya S, Juvekar S, Chatturvedi P, Chaukar D A, Pai P, D'cruz A, Prabhash K. Induction chemotherapy in technically unresectable locally advanced oral cavity cancers: Does it make a difference?. Indian J Cancer [serial online] 2013 [cited 2019 Nov 21];50:1-8. Available from: http://www.indianjcancer.com/text.asp?2013/50/1/1/112263
| » Introduction|| |
Surgical excision is the mainstay of treatment for oral cavity cancers. ,,,,, The aim of surgery in oral cancers is to remove all visible tumor with a wide margin, in order to have a complete excision of the tumor.  However, the achievement of pathologically negative margins is significantly decreased with increasing T stage of the tumor.  More extensive procedures are required which are associated with a substantial amount of cosmetic deformity and functional morbidity. The balance between the extent of surgery required to achieve negative margins and acceptable cosmetic and functional impairment defines the resectability of a tumor. , The American Joint Committee on Cancer (AJCC) has included resectable tumors in T4a and unresectable tumors in T4b. However, certain T4a oral cavity tumors with features like extensive skin edema up to the zygomatic arch, tongue carcinomas with extensive soft tissue involvement up to the hyoid cartilage and tumors reaching and involving the pterygoid muscles are generally considered unresectable with substantially increased functional and cosmetic morbidity. Furthermore, the possibility of getting a positive or close margin is much higher in these patients. Pathologically positive and close resection margins is associated with a poorer outcome among patients with oral cavity cancers. ,
The patients who are considered locally advanced and technically unresectable are usually treated with nonsurgical modalities. There is considerable heterogeneity in the intent and type of treatment offered to these patients. The reported 3-year disease-free survival (DFS) with definitive radiation has been reported to be 15%  In contrast, patients who have been offered palliative treatment alone have survival in the range of 200 days in different series. 
Two large landmark trials, the TAX323 and TAX 324, had highlighted the role of induction chemotherapy in unresectable and locally advanced head and neck cancers. The use of three drug regimens in these trials led to response rates of around 68%. However, less than 15% of the patients included had oral cavity cancers. There was distinct ambiguity related to the definition of unresectability. , Locally advanced head and neck cancers, which included stage IV and even stage III were deemed unresectable by a multidisciplinary team. Lictria et al. showed that the use of induction chemotherapy in resectable oral cavity cancers was associated with 27% clinical complete response (CR) and 82% overall response rate.  We believe that a proportion of patients with borderline unresectable tumors who would not be offered surgery might be made resectable by the use of induction chemotherapy. This may improve the overall outcome and lead to an increase in the overall survival.
To examine the validity of such an approach, we performed a retrospective analysis of our patients with borderline unresectable oral cavity cancers who were treated with induction chemotherapy.
| » Materials and Methods|| |
This is a retrospective analysis of patients with technically unresectable oral cavity cancer treated at a tertiary care cancer institute from June 2009 to December 2010. The data on all patients receiving NACT are prospectively maintained in our database.
These patients were considered technically unresectable in a multidisciplinary clinic, which included surgical oncologists, radiologists, medical oncologists and radiotherapists. The tumors were deemed unresectable by virtue of any of the following clinical factors [the first two factors are highlighted in [Figure 1]]
Disease reaching up to the zygoma and/or soft tissue swelling up to the zygoma.
|Figure 1: The extension of tumor up to or beyond these planes shown was considered as borderline unresectable, as surgery with margins was considered too morbid a procedure in the Head and Neck - Disease Management Group clinics|
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Extensive soft tissue involvement reaching up to the hyoid cartilage and extensive skin infiltration.
Involvement of the infratemporal fossa.
Those patients without any uncontrolled comorbidity and with adequate hematological, renal and hepatic reserve parameters were offered chemotherapy.
Patients received either three drug combination (Platinum + 5FU+Docetaxel) or two drug combination chemotherapy (Platinum + Taxane). The major deciding factor was socioeconomic-patients who could afford the anticipated costs were offered three-drug regimen while the other patients were given two-drug therapy. Cisplatin was the first choice for all patients with normal renal parameters. Patients with serum creatinine clearance below 60 ml/min as calculated by the Cockcroft-Gault formula were treated with carboplatin.
Docetaxel was administered at a dose of 75 mg/m 2 over 2 hours on day 1, cisplatin was administered at a dose of 75 mg/m 2 over 1 hour on day 1 and 5 FU was administered at a dose of 750 mg/m 2 /day as continuous infusion for 5 days. Patients were administered standard premedications prior to chemotherapy. All patients received primary G-CSF prophylaxis and oral antibiotic prophylaxis (Levofloxacin) from day 6 till day 12. In the 2 drug combination, either docetaxel at a dose of 75 mg/m 2 over 2 hours or paclitaxel at a dose of 175 mg/m 2 over 3 hours was administered on day 1 with either cisplatin at a dose of 75 mg/m 2 or carboplatin at a dose of AUC (area under curve) of 6 on the same day. Standard premedication was used. However, this regimen was given on outpatient basis in the daycare. The chemotherapy was given once every 21 days in both the regimens.
All patients were assessed midcycle on day 8 and before each successive cycle for toxicity and clinical response. Chemotherapy was administered only if hemoglobin was above 8.0 mg/dl, absolute neutrophil count was more than 1500/cu.mm and platelet count was more than 100 000/cu.mm. The serum creatinine clearance was calculated before each cycle and was required to be above 60 ml/min for administration of cisplatin. All Grade 3-4 (Gr 3-4) toxicity except alopecia should have decreased to at least grade 1 prior to next cycle. In patients receiving 2-drug regimens who had febrile neutropenia (any grade) in the first cycle, secondary G-CSF prophylaxis was administered in the subsequent cycles. In patients who developed febrile neutropenia after primary G-CSF prophylaxis or had any Gr 4 life threatening toxicity, a dose-reduction of 25% was done in subsequent cycles. The maximum grade of toxicity in all cyclesaccording to the Common Terminology Criteria for Adverse Events [CTCAE version 4.02] is reported. All patients after the completion of the 2nd cycle were reassessed by radiology and clinical examination. The response and potential for resectability was decided in the multidisciplinary joint clinic. Patients who were considered to have resectable disease underwent surgical resection. Patients whose surgery was delayed by more than 5 weeks due to any reason (operative waiting list, anesthetic fitness, logistic issues) were given one more cycle of chemotherapy. Patients who did not achieve resectability after chemotherapy were treated based on the final extent of disease and the response to neoadjuvant chemotherapy. These patients underwent radical chemoradiation, radical radiation, palliative radiation, palliative chemotherapy or best supportive care as decided in the clinic.
Statistical analysis was performed using SPSS software version.16. Descriptive analysis has been performed for tumor characteristics. The response rates and percentage of patients achieving resectability at the end of the second cycle were calculated. Overall survival was defined from the date of the first day of chemotherapy till the date of death or last day of follow-up. The overall survival of the patients who underwent surgery was compared to the patients who remained unresectable. Univariate and multivariate analysis was performed to find predictors of achievement of resectability and overall survival
| » Results|| |
There were 123 patients identified with borderline unresectable oral cavity cancer who were offered neoadjuvant chemotherapy. The baseline characteristics, the reason for unresectability and the chemotherapy regimen given are shown in [Table 1].
The median number of cycles delivered was 2 (1-4). The number of cycles delivered was 1 in 4 patients, 2 in 87 patients, 3 in 30 patients and 4 in 2 patients. The total number of cycles received in all patients was 276. More than 2 cycles was required in 32 patients on account of delay in dates of local treatment. Planned chemotherapy was completed in all patients except 4. Three patients had progression after the 1st cycle and one patient refused chemotherapy. Dose reduction was done in three patients; all received 25% dose reduction.
The response rate with the three drug and two drug regimens was 32.00% and 27.37%, respectively. Resectability was achieved in 17 patients with 3 drug regimen (68.00%) and 36 patients with 2 drug regimen (37.89%). Univariate analysis with Chi-square test was performed to assess factors associated with resectability. Among the tested variables of age, site, drug regimen, nodal status, only use of three drug regimen was significantly associated with resectability (P = 0.029).
The details of grade 3-4 toxicity can be seen in [Table 2].
|Table 2: Response rates achieved, resectability at the end of 2 cycles and toxicity analysis. 3 patients are not included in response and resectability analysis as one died (3 drug recipient) prior to the response assessment and 2 (both 2 drug regimen recipient) defaulted post completion of 2 cycles due to logistic reasons. However the details of grade 3-4 hematological, gastrointestinal and cardiac toxicity included all patients|
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There was one death in the patients receiving three drug regimen due to febrile neutropenia. Two patients reported chest pain during the 5-FU infusion; the infusion was stopped immediately in both the patients. Neither of the patients had electrocardiograph changes or raised cardiac enzymes on serial monitoring. The chest pain was attributed to 5-FU induced coronary vasospasm.
The treatment plan following neoadjuvant chemotherapy as decided in the joint clinic is highlighted in [Table 3]. A consort diagram detailing the actual treatment received is shown in [Figure 2] and [Figure 3].
|Figure 2: Consort diagram of buccal mucosa primary patients. CR-complete response, PR-partial response, SD-stable disease, PD-progressive disease, NRD-NO response assessment done, Sx-surgery, CTRT-Chemoradiation, Pall RT-Palliative radiation, Pall chemo-Palliative chemotherapy, Supp C-Supportive care.|
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|Figure 3: Consort diagram of non-buccal mucosa primary patients. CR-complete response, PR-partial response, SD-stable disease, PD-progressive disease, NRD-NO response assessment done, Sx-surgery, CTRT-Chemoradiation, Pall RT-Palliative radiation, Pall chemo-Palliative chemotherapy, Supp C-Supportive care|
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|Table 3: Postneoadjuvant treatment offered. 3 patients are not included as one died (3 drug recipient) prior to the response assessment and 2 (both 2 drug regimen recipient) defaulted postcompletion 2 cycles due to logistic|
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Local therapy (surgery)
Out of 53 patients who were deemed resectable, 43 patients actually underwent resection. Three patients had progression of disease while waiting for surgery. One of them then received palliative radiotherapy; the other two patients were given best supportive care only. Two patients did not consent for surgery and were treated with radical chemoradiation. The remaining five patients defaulted after the completion of NACT and did not follow-up for definitive treatment.
The median duration between last day of chemotherapy and surgery was 43 days (15-122 days). The histopathological details of the tumor are shown in [Table 4].
After surgery, all patients (43 patients) received adjuvant radiation in accordance with the institute standards (60 Gy/30#/6 weeks). Concurrent chemotherapy with weekly cisplatin 30 mg/m 2 was given in 35 patients.
Local therapy (radiation)
Radical chemoradiation and radiation were delivered with conventional parallel opposed two field technique covering the tumor and regional lymph nodes at risk. The median dose delivered was 66 Gy44-70 Gy. The fraction size used was 2 Gy. The treatment was completed by all except four patients who developed severe reactions. All these patients were in the chemoradiation group.
Palliative radiation was delivered with varying doses; the median biologically equivalent dose being 39 Gy 10 (39-79.2 Gy 10 ).
The median duration of follow up is 15 months. Seventy-seven events had taken place during this time. In the majority, i.e., 71 patients, these were loco-regional events. Fourteen patients had only nodal failure while the rest had both local and regional failure. Distant metastases were seen in six patients. The sites of distant metastases were the lung in three patients and skin nodules in the rest.
The estimated median overall survival for the whole population is 12.7 months The estimated median survival was not reached for patients undergoing post-chemotherapy resection. This was statistically significant compared to patients treated with nonsurgical modalities postchemotherapy. The estimated median OS in these patients was 8 months (P = 0.0001) [Figure 4]. This was the only variable that was significant among the tested variables (age, site, lymph node status, drug regimen, duration of treatment, and modality of local treatment).
| » Discussion|| |
Guidelines on treatment of buccal mucosa from the Indian council for medical research (ICMR) have highlighted the fact that nearly 70%-80% of patients in India present with locally advanced stage and majority are treated with palliative intent.  Other epidemiological differences exist between the Western and the Indian patients with Indian patients reporting a higher percentage of oral cavity tumors compared to pharyngeal primary. 
The existing treatment options in the patients with locally advanced borderline resectable oral cavity cancers are limited. The usual therapeutic options include concurrent chemoradiation, radical radiation, palliative radiation and best supportive care. However, as highlighted previously, the nonsurgical modalities rarely achieve a lasting cure. In the present analysis, we have attempted to downstage the malignancy with induction chemotherapy so that surgical resections with negative margins could be achieved. To the best of our knowledge, the use of induction therapy in a patient population with borderline resectable oral cavity cancers alone has not been reported to date.
In our study, 65.53% of patients receiving three drug regimen and 37.11% of patients receiving 2 drug regimen had cancers of the oral cavity that became resectable following induction chemotherapy. Three-drug regimen was significantly more effective than 2-drug regimens. The use of taxanes as the other agent with platinum as opposed to 5-FU in previous studies was logistically favorable and enabled chemotherapy on day care basis and obviated the need for long-term intravenous catheters. The overall response rate seen in our study is lower when compared to that reported for 2 drug and 3 drug regimens in the TAX 323 and TAX 324. However, it should be noted that less than 15% of patients in these trials had oral cavity cancers. , Biologically, oral cancers may be less sensitive to chemotherapy than pharyngeal malignancy. This was demonstrated in a single-institution study where induction chemotherapy was shown to be associated with deterimental effects.  In another trial by Lictria et al. in resectable oral cavity cancers, the addition of induction chemotherapy failed to produce a survival advantage. However, in this trial all patients had resectable cancer and only 20% of patients with T4 stage. 
Induction followed by surgery, if effective, can be an important strategy as oral cavity cancers have poor response radiation alone. ,,, There is some evidence that patients who undergo surgery have a better outcome than patients who did not undergo resection in oral cavity cancer. ,, In light of these studies, our approach of using induction chemotherapy to convert potentially unresectable tumors to resectable disease could theoretically produce better results than nonsurgical treatment. The value of this approach has been highlighted previously. ,,,
Our analysis demonstrates the effectiveness of neoadjuvant chemotherapy in downstaging tumors and enabling radical surgery. The 2-year overall survival for stage IV cancers in our study is comparable to other studies in which upfront surgery was done. ,,,,,
Another important finding is that even in patients with radiologically defined (as per RECIST) stable response after chemotherapy (68 patients), a significant number could still undergo therapy with radical intent. Twenty four patients had disease amenable to radical surgery, 14 could undergo definitive concurrent chemoradiation and 1 patient was eligible for radical radiation. Significantly, the high proportion (35%) of patients with stable response who subsequently underwent surgery successfully with negative margins also highlights the fallacies of using RECIST criteria to assess responses in oral cavity cancer, especially after neoadjuvant therapy. A rigid cut-off of 30% reduction in sum of long dimensions may not be an accurate measure for response in head and neck cancers where critical structures are quite close and a reduction in diameter just sufficient to undergo surgery may be clinically more relevant.
Though Paccagnella et al, have previously reported response even till the 4th cycle of chemotherapy,  we felt that that 2 cycles would be sufficient to select patients for surgery or other definitive treatment. Furthermore, it was felt that doing surgery as soon as resectability is achieved would reduce the risk of tumor progression on neoadjuvant chemotherapy. Two cycles for assessing response has been used in a previous study for a separate cohort of patients. 
The grade 3-4 hematological and gastrointestinal toxicity of induction chemotherapy with three drug regimen was 41.66% and 70.83%. This toxicity was seen despite primary G-CSF prophylaxis and oral quinolone prophylaxis. The incidence of toxicity is higher than reported previously in literature. , The two drug regimen was associated with significantly lesser toxicity than three drug regimen. The poor tolerance of chemotherapy in our setting needs further exploration. Potential reasons which could explain these results include poorer nutritional status of our patients, the less advantaged socioeconomic profile and putative differences in drug metabolism.  Since the data collection was done on outpatient basis as part of routine treatment, the supportive care and documentation of toxicity might not be as rigorous as seen in prospectively designed and controlled trials
| » Conclusion|| |
The use of induction chemotherapy, whether two or three drugs, achieved resectability in technically unresectable oral cavity cancers in approximately one-third and two-third of patients, respectively. The three drug regimen (DCF) may lead to greater degree of achievement of respectability at the cost of significantly increased toxicity. Overall, surgery remains the most important modality of treatment in such cohort of patients. Larger prospective randomized trials with three drug and two drug regimens are needed in borderline resectable cancers of the oral cavity to establish the benefit of neoadjuvant chemotherapy.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]
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