|Year : 2015 | Volume
| Issue : 4 | Page : 632-636
Does the use of induction chemotherapy in oral cavity cancer compromise subsequent loco-regional treatment delivery: Results from a matched pair analysis
VM Patil1, G Muttath2, S Babu3, ST Kumar3, J Jones2, S Sen4, S Chakraborty2
1 Department of Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Thalassery, Kerala, India
2 Department of Radiation Oncology, Malabar Cancer Centre, Thalassery, Kerala, India
3 Department of Surgical Oncology, Malabar Cancer Centre, Thalassery, Kerala, India
4 Division of Clinical Research and Biostatistics, Malabar Cancer Centre, Thalassery, Kerala, India
|Date of Web Publication||10-Mar-2016|
Department of Radiation Oncology, Malabar Cancer Centre, Thalassery, Kerala, India
Source of Support: None, Conflict of Interest: None
BACKGROUND: Neoadjuvant chemotherapy is being increasingly used in patients with unresectable oral cavity cancers to make them resectable. However, its impact on locoregional treatment delivery in such setting remains poorly studied.
AIMS: To evaluate the impact of neoadjuvant chemotherapy on delivery of further locoregional treatment.
DESIGN: Mono institutional retrospective audit of patients with oral cavity squamous cell cancers treated with neoadjuvant triplet chemotherapy in India.
MATERIALS AND METHODS: Patients receiving neoadjuvant chemotherapy (n = 14) from May 2012 to April 2014 were matched 1:2 to patients undergoing upfront surgery (n = 28) based on age (>60 or 60 and less), gender (male or female) and subsite site (tongue and floor of mouth or buccoalveolar complex). Data regarding factors related to the delivery of locoregional treatment and toxicities were compiled.
ANALYSIS: Descriptive analysis in the form of median (range) for continuous variables and frequencies for categorical variables.
RESULTS: Patients undergoing neoadjuvant chemotherapy required more extensive resections and had greater operative time (460 vs. 415 min, P < 0.001). A greater incidence of locoregional wound complications was seen as a consequence (57.1% vs. 14.3%, P, 0.01). However, toxicities during radiotherapy were not substantially different between the two groups and compliance to radiation was also similar. Total package time of 100 days or less, was maintained in 90% of patients in both groups.
CONCLUSIONS: Delivery of neoadjuvant chemotherapy does not impair the ability to deliver locoregional treatment.
Keywords: Adjuvant radiotherapy, induction chemotherapy, Intensity Modulated Radiotherapy, locoregional treatment, neoadjuvant chemotherapy, oral cavity cancer, surgery,technically unresectable
|How to cite this article:|
Patil V M, Muttath G, Babu S, Kumar S T, Jones J, Sen S, Chakraborty S. Does the use of induction chemotherapy in oral cavity cancer compromise subsequent loco-regional treatment delivery: Results from a matched pair analysis. Indian J Cancer 2015;52:632-6
|How to cite this URL:|
Patil V M, Muttath G, Babu S, Kumar S T, Jones J, Sen S, Chakraborty S. Does the use of induction chemotherapy in oral cavity cancer compromise subsequent loco-regional treatment delivery: Results from a matched pair analysis. Indian J Cancer [serial online] 2015 [cited 2019 Dec 12];52:632-6. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/632/178442
| » Introduction|| |
Induction chemotherapy (IC) is a new weapon in the armamentarium against head neck cancer. Results from the TAX 323 and TAX 324 trials have shown the activity of triplet IC in locally advanced head neck cancers., Two trials conducted by Zhong et al. and Licitra et al. have evaluated the role of IC in operable oral cavity cancers., While both these trials failed to show any significant improvement in overall survival in patients receiving IC as compared to upfront surgery, encouraging response rates were obtained.
Unlike other forms of head neck cancer, an R0 resection remains the cornerstone of management of advanced oral cavity cancers.,, Hence, patients in whom a R0 resection cannot be achieved are usually treated with definitive radiotherapy with or without chemotherapy. However, results of series treating patients of oral cavity cancers with definitive chemoradiation are dismal.,
Induction chemotherapy has been used in locally advanced oral cavity cancers who are deemed technically unresectable in view of the loco-regionally advanced nature of the disease. The goal of IC in this setting is to downstage the disease and make it operable. In such a setting use of IC resulted in nearly one-third of patients undergoing surgery as reported from a tertiary cancer center in India. We have previously reported our experience with chemotherapy related toxicities in oral cavity cancer patients who have received triplet IC.
While the high activity of IC has been shown in multiple studies, its impact on subsequent delivery of locoregional treatment in unresectable oral cavity cancers remains poorly studied. In order to investigate if IC lead to a delay in the delivery of locoregional treatment or poor treatment tolerance, we undertook a match paired analysis of patients undergoing IC followed by surgery and postoperative radiotherapy versus those undergoing upfront surgery and adjuvant radiotherapy.
| » Materials and Methods|| |
Patients with oral cavity cancers treated with IC with triplet chemotherapy regimen (docetaxel, cisplatin, and 5 fluorouracil) between August 2013 and August 2014 were selected for this audit. Patients were matched 1:2 according to the following criteria with oral cavity cancer patients treated with upfront surgery and adjuvant radiotherapy:
- Age (<60 or 60 or more)
- Gender (male/female)
- Disease subsite (tongue and floor of mouth/buccoalveolar complex).
Patient receiving IC underwent chemotherapy with docetaxel (75 mg/m 2 D1), cisplatin (75 mg/m 2 D1) and 5 fluorouracil (750 mg/m 2 D1–D5) every 3 weeks for 2–3 cycles. Further details of the patient selection criteria, schedule employed, dose reductions and toxicities encountered have been presented separately. Following this patient underwent surgery and adjuvant radiotherapy with rapidarc intensity modulated radiotherapy (IMRT).
Surgery included wide local excision along with appropriate neck dissection and reconstruction. All patients underwent preoperative speech and swallowing assessments as well as counseling from a dietician.
All patients underwent planning computed tomography with intravenous (IV) contrast with 3 mm slices from vertex of the skull to the mid chest with a custom made thermoplastic immobilization shell. Target volume delineation was done following our departmental guidelines (Appendix I). Two clinical target volumes (CTVs) were delineated for each patient - high-risk CTV which included tumor bed and adjacent areas along with involved nodal levels and a low-risk CTV which included the elective nodal volume. Organs at risk delineated included the brainstem, spinal cord, internal ear, parotid glands, mandible, pharyngeal constrictors, larynx and cervical esophagus. Of these, the spinal cord and brainstem were considered priority 1 structures. CTVs were expanded isotropically by 5 mm to generate the respective planning target volumes (PTVs).
Rapidarc IMRT plans consisted of two coplanar mono-isocentric arcs (arc angle was decided as per the target geometry) optimized using the PRO algorithm (version 10). Dose was calculated on a 0.25 cm grid using the anisotropic analytical algorithm (version 10). Plans were normalized so that both the PTVs received 100% of the prescribed dose to at least 95% of the volume and maximum dose did not exceed 115% of the prescribed dose for the respective PTV. Plan homogeneity index as defined by ICRU 83 was kept at 0.2 or less. The QUANTEC recommendations were followed for organ at risk doses. Individual plan quality assurance was performed for all patients, and plans were accepted if they had pass percentage of ≥95% at 3% and 3 mm distance-to-agreement.
Radiation treatments were delivered on 5 days a week, and all patients underwent image guidance during the first 3 fractions and then at least three weekly depending on residual setup errors. Patients with high-risk features like nodal extracapsular extension or positive margins underwent concurrent chemotherapy. In patients receiving IC without these adverse features, the decision to use concurrent chemotherapy was left to the treating physician. Platinum based weekly chemoradiation using cisplatin (40 mg/m 2 weekly) or carboplatin (area under the curve - 2) was used in patients undergoing chemoradiation. During the period of radiation, all patients underwent weekly assessments, and toxicities were recorded prospectively in a toxicity chart following the Common Terminology Criteria for Adverse Events (CTCAE version 4.0) schema (National Cancer Insitu te, NCI).
The audit was approved by the institutional Institutional Review Board and requirement for informed consent waived off in view of the retrospective nature of the study. The following parameters related to the delivery of loco-regional treatment were collected for all patients:
Duration between the last cycle of chemotherapy and surgery Operating time Postoperative complications (CTCAE v 4.0) Gap between surgery and radiation Acute toxicities experienced during radiation/chemoradiation (CTCAE v 4.0) Hospitalizations during radiation Cumulative dose of chemotherapy delivered (if concurrent chemoradiation was delivered) Radiation breaks if any including duration and cause(s) Total package time (defined as the duration between the date of surgery and date of radiation). Statistical analysis
Patients receiving IC were matched 1:2 to patients receiving upfront surgery based on the aforementioned criteria. Matching was done manually. Descriptive statistics included median and range for continuous variables and frequencies for categorical variables. Mann–Whitney U-test was used to test for difference of medians and distribution for continuous variables while Chi-square test was used to test for association for categorical variables. Statistical analysis was done using the R software versions 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria) and the R studio IDE (version 0.98, Boston, MA, USA).
| » Results|| |
Out of 17 patients who had received neoadjuvant chemotherapy at our institute for advanced unresectable oral cavity cancers since May 2012, 14 patients were eligible for analysis. One patient was excluded as he developed rapidly progressive lung metastases during radiation and died within 10 fractions of radiotherapy. Two patients had refused surgery despite extensive counseling. In one patient the disease progressed after 4 months, and she was treated with palliative radiotherapy. The second patient elected to take curative intent radiotherapy outside and is presently doing well.
The 14 patients receiving IC were matched to 28 patients undergoing upfront surgery followed by adjuvant radiotherapy (Sx). Demographic characteristics of the patient population are noted in [Table 1]. 16 (57.1%) patients in the Sx group had pathological stage IVA disease. All patients of IC group had clinical stage IV disease, with 6 patients having stage IVB disease and 8 patients having stage IVA disease.
The median gap between the last cycle of chemotherapy and surgery was 26 (15–55) days. Patients in Sx group had a median delay of 26 (9–42) days between their dates of registration and date of surgery (P = 1.0). Wide local excision was performed in all patients. Some form of mandibulectomy was required in 5 (35.7%) patients and 13 (46.4%) patients in the IC and Sx groups respectively (P = 0.53). Ipsilateral neck dissection consisted of selective neck dissection and modified radical neck dissection in 1 (4.6%) and 12 (85.7%) patients in IC group versus 10 (35.7%) and 16 (57.1%) patients in the Sx group respectively (P = 0.13). Primary reconstruction with flaps was done in all patients in the IC and in 24 (85.7%) patients in Sx groups respectively (P = 0.35). PMMC (Pectoralis Major Myo-Cutaneous) flap and SAIF (Submental Artery Island Flap) were utilized for reconstruction in 11 (78.5%) and 1 (7.1%) patients in the IC group respectively. The corresponding figures for the Sx group were 11 (39.3%) and 4 (14.3%) patients respectively. The median time taken for surgery in the IC group was 460 (140–715) min versus 415 (150–899) min in Sx group (P < 0.001).
The grade 3–4 postoperative complications encountered in the patient population is indicated in [Table 2] below. None of the patients developed postoperative cardiovascular complications or deep venous thrombosis. Infectious complications were observed in 6 (42.8%) and 5 (17.8%) patients in the IC and Sx groups respectively (P = 0.10). Postoperative wound resuturing was required in 8 (57.1%) and 2 (7.1%) patients in the IC and Sx groups respectively (P = 0.001). Postoperative wound re-exploration was required in 3 (21.4%) and 2 (7.1%) patients respectively in the IC and Sx groups (P = 0.39). The median duration of hospitalization in the postoperative period in the IC and Sx groups were 14.5 (5–28) and 7 (4–27) days respectively (P = 0.04).
|Table 2: The incidence of Grade 3 and Grade 4 complications in the IC versus the Sx group|
Click here to view
The median delay to start of radiation from the day of surgery was 41.5 (27–63) days and 41 (28–83) days in the IC and Sx groups respectively (P = 0.78). [Table 3] shows the parameters related to radiation therapy and concurrent chemotherapy given in these groups. Only 1 patient received concurrent chemotherapy with carboplatin after NACT due to reduced creatinine clearance (54 ml/min). A package time of <100 days was maintained in 13 (92.8%) patients in IC group and 26 (92.8%) patients in the Sx group.
|Table 3: The radiation related parameters with significant P values noted in bold|
Click here to view
2 (14.2%) patients in the IC group and 7 (25.0%) patients in the Sx group had breaks during radiation due to toxicities (P = 0.64). The most common toxicities resulting in treatment breaks were grade 3 mucositis in 3 patients followed by vomiting and dehydration in 2 patients. Concurrent chemotherapy was not given to 7 patients in the IC group because of the following reasons-old age (2) and lack of formal departmental protocol in 5. Hospitalizations were required in 3 (21.4%) patients of the IC group and 3 (10.7%) patients in the Sx group due to toxicities (P = 0.57). All patients in the IC group and 27 patients in Sx group completed their planned course of radiotherapy.
[Table 4] shows the grade 3–4 toxicities encountered by these patients during radiotherapy. Median weight loss during treatment was 6% (0–17%) in the IC group and 8% (0–19%) in the Sx group (P = 0.21). Feeding tube insertion to maintain nutrition during RT was required in 10 (71.4%) patients in IC group and 11 (39.3%) patients in Sx group (P = 0.10). The actuarial median duration of feeding tube dependence was 34 days post-RT (34 days in IC versus 31 days in Sx group, P = 0.24). Both patients with grade 2–3 vomiting in Sx group had not received chemotherapy. In the IC group 3 patients with grade 2–3 vomiting had received concurrent chemotherapy while 3 had not.
| » Discussion|| |
To the authors' knowledge this is the first study that evaluates the impact of neoadjuvant chemotherapy on subsequent locoregional treatment in patients with advanced unresectable oral cavity cancers from India. Severe life-threatening toxicities were not observed, and all patients who were started on radiation completed the planned course of treatment. Total package time was maintained below 100 days for 90% of the patients.
Previous studies have reported conflicting results regarding the impact of neoadjuvant chemotherapy on subsequent locoregional treatment. In a study reported by Licitra et al. 94% of the patients underwent surgery after neoadjuvant chemotherapy and only 33% received adjuvant radiotherapy. In a study conducted by Zhong et al. 85% of the patients completed locoregional treatment along with IC. However, both these studies were conducted in a population with upfront resectable oral cavity cancers. In the present study, 82% of the patients completed the planned locoregional treatment which is comparable to the results reported by Zhong et al. using triplet neoadjuvant chemotherapy.
Success of surgery in oral cavity cancers depends on the ability to achieve negative margins in resection., It is uncertain as to how completely neoadjuvant chemotherapy sterilizes the periphery of the tumor. Hence in our setting resections are planned according to the initial extent of the tumor and care is taken that all margins are confirmed negative by FS. In the present series, none of the patients had a positive margin after surgery.
Both studies by Licitra et al. and Zhong et al. have shown that there is no increase in postoperative wound complications after neoadjuvant chemotherapy., In the present series, however patients needed a more extensive resections to achieve clear margins. This is reflected in the increased time taken for surgery, more extensive neck dissections as well as the greater wound complication rates. However from the present study we cannot completely exclude the possibility that use of neoadjuvant chemotherapy may lead to delayed wound healing by altering collagen remodeling in the wound. The use of neoadjuvant chemotherapy did not result in an increase in biochemical toxicity rates in the postoperative period.
Despite some increase in the wound complications, the delivery of local radiotherapy was not hampered. As shown above most toxicities were comparable between the two groups with the exception of vomiting. The reason for the higher incidence of vomiting may be related to the higher use of concurrent chemotherapy in this patient population. Nonetheless, the compliance to chemotherapy was equal or better than in patient receiving upfront surgery and chemoradiation. In our institute, concurrent chemoradiation is delivered by radiation oncology department. We feel the closer cooperation between the medical oncology department while delivering chemoradiation for the patients receiving IC may have been one reason for their apparently better tolerance.
The present study is limited by its small sample size. It is difficult to compare patients with resectable and unresectable cancers as the volume of disease and extent of resection/radiation involved are different. The study employed a matched pair analysis method to minimize problems related to selection bias. In addition, all patients had received a triple drug chemotherapy regimen. However, the very nature of the population prevented us from matching the patients as per the stage. This is reflected some extent in the difference in the radiation volumes for the groups. Toxicity data for surgery was coded retrospectively that may result in a lower toxicity estimate than actual. However, radiation toxicity data was collected prospectively. Our policy regarding concurrent chemoradiation after neoadjuvant chemotherapy was not uniform as a result of which several patients did not receive the chemoradiation. However after extensive intra-departmental discussion we have decided to adopt concurrent chemoradiation as the standard adjuvant treatment in such patients in future.
| » Conclusion|| |
Although the use of patients receiving neoadjuvant chemotherapy had a higher incidence of locoregional wound complications after surgery, this did not impact their ability to tolerate adjuvant radiotherapy (with chemotherapy) within a defined time period. Results of this study need to be verified in larger cohorts with prospectively collected data.
| » Acknowledgment|| |
The authors acknowledge the support of all the nursing staff which enabled us to deliver the therapy to these patients.
| » References|| |
Mumme AM, Laban S, Knecht R. New aspects of induction chemotherapy for head and neck cancer: POSTASCO 2011. Eur Arch Otorhinolaryngol 2012;269:2303-8.
Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, et al.
Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695-704.
Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, et al.
Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: Long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011;12:153-9.
Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr, Sun J, et al.
Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. J Clin Oncol 2013;31:744-51.
Licitra L, Grandi C, Guzzo M, Mariani L, Lo Vullo S, Valvo F, et al.
Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J Clin Oncol 2003;21:327-33.
Loree TR, Strong EW. Significance of positive margins in oral cavity squamous carcinoma. Am J Surg 1990;160:410-4.
Binahmed A, Nason RW, Abdoh AA. The clinical significance of the positive surgical margin in oral cancer. Oral Oncol 2007;43:780-4.
Vikram B, Strong EW, Shah JP, Spiro R. Failure at the primary site following multimodality treatment in advanced head and neck cancer. Head Neck Surg 1984;6:720-3.
Sher DJ, Thotakura V, Balboni TA, Norris CM Jr, Haddad RI, Posner MR, et al.
Treatment of oral cavity squamous cell carcinoma with adjuvant or definitive intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2011;81:e215-22.
Studer G, Brown M, Bredell M, Graetz KW, Huber G, Linsenmeier C, et al.
Follow up after IMRT in oral cavity cancer: Update. Radiat Oncol 2012;7:84.
Patil VM, Noronha V, Joshi A, Muddu VK, Dhumal S, Arya S, et al.
Weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer for patients ineligible for 3 weekly maximum tolerable dose chemotherapy. Indian J Cancer 2014;51:20-4.
Joshi A, Patil VM, Noronha V, Juvekar S, Deshmukh A, Chatturvedi P, et al.
Is there a role of induction chemotherapy followed by resection in T4b oral cavity cancers? Indian J Cancer 2013;50:349-55.
Patil VM, Chakraborty S, Shenoy PK, Manuprasad A, Sajith Babu TP, Shivkumar T, et al
. Tolerance and toxicity of neoadjuvant docetaxel, cisplatin and 5 fluorouracil regimen in technically unresectable oral cancer in resource limited rural based tertiary cancer center. Indian J Cancer. 2014;51:69-72.
5. Planning aims, prescription, and technical data. J ICRU 2010;10:55-9.
Priya SR, D'Cruz AK, Pai PS. Cut margins and disease control in oral cancers. J Cancer Res Ther 2012;8:74-9.
Hada M, Omura K, Hirano Y, Watanabe G. Changes in bowel mucosal permeability and wound healing after neoadjuvant chemotherapy. Oncol Lett 2010;1:161-65.
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||Outcome of patients following neo-adjuvant chemotherapy for unresectable cervical nodes in head and neck squamous cell carcinomas
| ||Akshat Malik,Burhanuddin N. Qayyumi,Manish Mair,Hitesh Singhavi,Yash Mathur,Deepa Nair,Sarbani Ghosh-Laskar,Jai Prakash Agrawal,Kumar Prabash,Pankaj Chaturvedi |
| ||European Archives of Oto-Rhino-Laryngology. 2019; 276(2): 567 |
|[Pubmed] | [DOI]|
||Effect of neoadjuvant chemotherapy and its correlation with HPV status, EGFR, Her-2-neu, and GADD45 expression in oral squamous cell carcinoma
| ||Manoj Pandey,Krishna Kiran Kannepali,Ruhi Dixit,Mohan Kumar |
| ||World Journal of Surgical Oncology. 2018; 16(1) |
|[Pubmed] | [DOI]|