|Year : 2020 | Volume
| Issue : 1 | Page : 9-15
Precision onco-surgery for redefining resectability in head and neck cancer
BM Joshna1, G Abhijith1, S Anand1, K Akshay1, T Shalini1, R Vishal1, P Prasanth2
1 Department of Head and Neck Surgical Oncology, HCG Cancer Centre, Bengaluru, India
2 Department of Oncoplastics and Reconstructive Surgery, HCG Cancer Centre, Bengaluru, India
|Date of Submission||14-May-2020|
|Date of Decision||12-Jun-2020|
|Date of Acceptance||01-Jul-2020|
|Date of Web Publication||22-Oct-2020|
Dr. T Shalini
Department of Head and Neck Surgical Oncology HCG Cancer Centre, Bengaluru
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Joshna B M, Abhijith G, Anand S, Akshay K, Shalini T, Vishal R, Prasanth P. Precision onco-surgery for redefining resectability in head and neck cancer. J Precis Oncol 2020;1:9-15
|How to cite this URL:|
Joshna B M, Abhijith G, Anand S, Akshay K, Shalini T, Vishal R, Prasanth P. Precision onco-surgery for redefining resectability in head and neck cancer. J Precis Oncol [serial online] 2020 [cited 2021 May 14];1:9-15. Available from: https://www.jprecisiononcology.com/text.asp?2020/1/1/9/298271
| Introduction|| |
Defining the term unresectable is difficult, as resectability has evolved over time due to advances in surgical techniques and reconstruction Criteria for unresectability is varied ranging from structural and anatomical aspects to functional and co-existing medical conditions (1). We describe three cases, which in an usual circumstance would be deemed unresectable were treated with precision surgical techniques to offer best functional and quality of life outcomes.
| Case Series|| |
A 38year old non-smoker, presented with a diagnosis of Locally advanced Carcinoma Tongue. The tumour was involving the entire tongue extending to floor of mouth and tonsillar fossa with mandibular erosion. He had a fungating neck wound from a metastatic node [Figure 1]. Fearing portended outcomes, he refused standard treatment and opted for Ayurvedic medications alongside Geftinib. Three months later when he presented again, a re-assessment PET imaging was suggestive of progressive disease [Figure 2]1* with nodal infiltration and thrombosis of internal jugular vein (IJV) and common carotid artery (CCA)(cT4bN3bM0).
His case was discussed in Mutli Disciplinary Clinic (MDC) and a recommendation for 3cycles of chemotherapy with TPF (Cisplatin, Paxlitaxel and 5-FU) regimen was made. As he had partially responded (PERCIST 1.1) to Chemotherapy, his case was re-discussed in MDC and planned for Concurrent Chemoradiation therapy with weekly Cisplatin and 70Gy/35 fractions of radiotherapy (IMRT technique)2*.
A post treatment PET-CT scan after 6weeks showed interval regression of the primary lesion and neck mass. Although there was a favourable response in the primary, there was more than 2700 encasement of CCA3* with infiltration of IJV, sternocleidomastoid muscle and skin ulceration by the nodal mass [Figure 3]&[Figure 4]. Anticipating an impending carotid blowout a carotid stenting was done. A salvage neck surgery with palliative intent was planned. He underwent Left extended radical neck dissection with 360 degree dissection of CCA (sub-adventitial peel) with right selective neck dissection and antero-lateral thigh (ALT) flap reconstruction for the neck defect [Figure 5].
|Figure 3: Clinical response at primary site with ulcerative neck disease after CTRT|
Click here to view
The final histopathology report was suggestive of poorly differentiated carcinoma. Tissue sample over the carotid sheath showed no evidence of tumour4*.
The case discussed in MDC regarding further adjuvant therapy. In view of a weak carotid vessel wall, the option of radiotherapy boost/stereotactic radiosurgery was discarded. The clinic recommended adjuvant chemo-immunotherapy with Paclitaxel and Pembrolizumab immunotherapy5*.. It has been 4 months now, he is disease free and doing well.
A 14year old teenager presented to us with disfigurement of her facial profile and pain [Figure 6]. She was a case of recurrent myxoid liposarcoma and had undergone surgical excision twice in the past6*. At the last surgery she underwent wide local excision and reconstruction with pectoralis major myo-cutaneous (PMMC) flap. As the histopathology was inconclusive, the family was advised further molecular testing and radiotherapy. Financial constrains came in their way to seek further treatment.
At presentation to our centre, the tumour was disfiguring and involving right side of face and extending to pectoral region. She had right proptosis with diplopia. She was discussed in MDC and suggested to undergo 3 cycles of chemotherapy with Ifosfamide and Doxorubicin, response evaluation followed by surgical salvage. The residual tumour did not respond to chemotherapy and the disease progressed. Magnetic Resonance imaging (MRI), revealed a large exophytic predominantly fat attenuating mass lesion involving the maxillary, pre-maxillary, infra-temporal region, lower neck, orbit with proptosis and involvement of the intraocular muscles, optic nerve with enhancement of right cavernous sinus and partial encasement (<270 degree) of CCA and Internal carotid artery [Figure 7]. The case was discussed in MDC, as other options had exhausted and her pain was becoming unbearable, a bold decision to surgically salvage the tumour was made.
The family and the teenager were counselled by the Psycho-oncologist over several session before the surgical resection was to be attempted. Accepting the risk, and with the awareness of high propensity to recur the family and teenager gave their nod for surgery. This was a highly complex surgery and involved a team of head and neck Surgeons, Vascular Surgeon, Neurosurgeon, Thoracic Surgeon, Surgical Oncologist, Lateral Skull base surgeon and Reconstructive Surgeon. She underwent a wide local excision with right posterior segmental mandibulectomy, right extended maxillectomy, right orbital exenteration tumour with excision of the cavernous sinus extension [Figure 8]. The defect was reconstructed with an ALT Flap.
A 55 year old patient previously treated case of carcinoma right buccal mucosa with residual lesion in left mandible presented to us with complaints of ulcer in right side of mouth. The lesion was involving the right cheek, gingivobuccal sulcus floor of mouth and measured. PET CT scan showed a 6.4 x.2x 4.6cm metabolic active lesion involving the masticator space and the right infratemporal fossa (SUV max 49.2). There was no evidence of distant metastasis [Figure 9]. The residual lesion had extensive ITF involvement and are considered unresectable (2). The case was discussed in MDC and in light of bone erosion, an option of palliative chemotherapy versus salvage surgery was discussed. The house weighing the possible outcomes recommended a salvage surgery.
Patient underwent compartmental en-bloc resection with neck dissection and the defect reconstructed with flap reconstruction. Histopathology reported RpT3N1 with clear surgical margins, DOI of 25mm, with Lympho-vascular invasion (LVI) and peri-neural invasion (PNI). The case was brought up in MDC, and as she had received chemoradiotherapy within 6 months re-irradiation was ruled out. Considering her physical profile and performance status, adjuvant chemotherapy was not an option either. She was advised on metronomic chemotherapy7*and has been on meticulous follow up with us. At 1 year following the surgery, she is disease free, tolerating oral feeds leading a good quality of life [Figure 10].
| Discussion|| |
Advanced Head and Neck cancers have a propensity to recur locally (3). Early detection of recurrence holds the key to a successful salvage when feasible. 18F-Fluorodeoxy D glucose Positron emission tomography computed tomography is an important diagnostic tool for the evaluation of pre-operative staging, tumour response assessment, post therapy follow up in Head and neck SCC (4). PET CT scan is effective in detecting the loco regional recurrence in head and neck tumours earlier when compared to physical examination and/or conventional imaging modality (5). In our series, PET-CT gave an accurate assesement of the recurrences/ residual disease. This helped us make timely decisions to successfully salvage these cases.
An integrated approach towards the management of cancer is of paramount importance. Multi- disciplinary clinic(MDC) is one such outlook to deliver the essential and effective treatment based on scientific evidence. Inputs during the MDC from various disciplines of healthcare personnel help in achieving the co- ordinated patient care (6). It's a great portal for involving the patients and their kin in the decision making of treatment. Discussion of challenging cases, as in the case series provided an avenue to make rational decisions. The involvement of the family in the decision making could have long term impact on recovery and outcomes. NCCN guideline has suggested criteria to assess resectability in Head and Neck cancers, though not absolute. Involvement of the skull base, invasion or encasement of carotids, involvement of infratemporal fossa, direct extension of neck disease to external skin are considered technically inoperable and portend poor prognosis (7). All our cases were borderline operable tumours. As our surgical expertise improves, we set new boundaries. Operability in the authors view is a relative and dynamic term and keeps evolving.
Carotid space involvement is associated with poor survival rate and disease-free survival rate. Kennedy et.al. in a study reported the 5- year survival in carotid encased tumours as 7% and a dismal recurrence rate of 46% and a 68% rate of distant metastases (8). Hiranandani also reported similar outcomes and noted the operative mortality of 21.9 % with carotid resection (9). Treatment of cancer contiguous to the carotid artery becomes a challenge in recurrent or persistent disease secondary to fibrosis adjacent to carotid adventitia owing to previous radiation or surgical procedures (10). Similarly, previously untreated disease can present with various degrees of carotid artery encasement. In many of these cases, intraoperative assessment of the carotid adventitia can guide a surgeon to attempt a resection in a sub-adventitial plane (“curative peel”) (11). Additional factor of weakened vessel walls pose a threat of carotid blow out in perioperative period. Despite this there does seem to be a survival advantage to pursuing curative treatment. In special situations, resection of primary tumours in-toto with carotid space extension, salvage surgery and benign vascular tumours- Carotid artery dissection, resection and re anastomosis is recommended. Aggressive surgical treatment options have shown better survival rate when compared to non-surgical treatment (12- 14). Studies have shown similar outcomes to resection anastomosis when a sub-adventitial peel was feasible (11). In our experience, the decision regarding unrespectability can only be made intraoperatively by direct assessment of the arterial anatomy, and we could peel off the disease from over the carotid artery without any added complications. The stenting in one of the cases provided additional support to the vessel wall.
For advanced tumours of oral cavity resection of tumour in continuity with underlying surrounding structures including muscles, submandibular, sublingual glands with/without bone as a single unit termed “compartmental resection” offers better oncological outcomes [15-19]. Compartmental resection addresses the worry of in-contiguous microscopic spread without disturbing the lymphatic pathway to the neck nodes (18). In our case, the residual tumour was addressed using the concepts of compartmental resection. These resections, result in greater functional morbidity and demands a good and experienced reconstructive team to optimise outcomes.
| Conclusion|| |
Labelling a tumour as unresectable based on broad consensus fails to identify and precisely treat the select favourable borderline case. This is against the principles of precision oncology and personalised medicine. Our experience over the years suggests that operability is a dynamic entity and keeps evolving and improving as the surgeon, technology and treatment modalities get better.
- Tumour growth rate is widely used for prognostic purposes and assess therapeutic effects of different treatment modalities. When a tumour becomes larger, its growth rate decreases and change to nonexponential growth model (the Gompertzian model). These observations have been made by following the tumour for a long period with several volume measurements. However, in clinical studies, volume estimations of nontreated tumours are usually available only for short measurement time intervals where tumour growth is well explained by an exponential model (1).
- Induction chemotherapy (IC) has a proven role in organ preservation and in reducing distant failure, however, its ability to prolong OS has not been demonstrated. The MACH-NC study showed that IC cisplatin/5-fluorouracil (PF) followed by local treatment was associated with a small but significant improvement in OS and in distant failures. In a recent, MACH-NC update, induction PF plus a taxane increased progression free survival (PFS) and OS versus PF.
Adding induction TPF to concomitant treatment significantly improves CRs, PFS and OS. The degree of benefit may differ according to the type of the subsequent concomitant strategies. Currently. IC is not considered the standard of care for Locally Advanced HNSCC, nonetheless it a valid option for poor prognosis patients (2).
- Tumour involvement of select sites is associated with poor prognosis and some of them labelled unresectable on technical grounds. However, none of these sites of involvement is an absolute contraindication to resection (3).
- Involvement of the pterygoid muscles, particularly when associated with severe trismus or pterygopalatine fossa involvement with cranial neuropathy
- Gross extension of the tumour to the skull base (eg, erosion of the pterygoid plates or sphenoid bone, widening of the foramen ovale)
- Direct extension to the superior nasopharynx or deep extension into the Eustachian tube and lateral nasopharyngeal walls
- Invasion (encasement) of the common or internal carotid artery
- Direct extension of neck disease to involve the external skin
- Direct extension to mediastinal structures, prevertebral fascia, or cervical vertebrae
- Presence of subdermal metastases.
Resectability in oral cancers is decided primarily by the involvement of anatomical landmarks. Extension of the tumour to the base of the skull, prevertebral muscles and encasement or invasion of the carotid artery are absolute contraindications to surgery. However, involvement of other anatomical landmarks can limit the extent of resection and surgeons fail to clear margins (4).Planned neck dissection was carried out in the past in patients with N2 and N3 neck disease irrespective of treatment response to concurrent chemoradiation. The procedure was usually performed weeks after completion of chemoradiation before the onset of fibrosis, thereby making the surgery technically easier.
Evidence favouring planned neck dissection comes from studies showing the presence of tumour in neck dissection specimens done after complete or near-complete radiologic and clinical response to chemoradiation. Before the advent of fluorodeoxyglucose–positron emission tomography (FDG-PET) scanning, planned neck dissection was a commonly performed. Today, most centres now reserve neck dissection to salvage recurrent/residual neck disease.
The18 FDG-PET is usually carried out at 12 weeks after completion of chemoradiation. Salvage neck dissection is done in patients who have persistent neck disease as detected by PET. This has reduced the number of planned neck dissection, but has the disadvantage of making the operation technically more challenging with the onset of fibrosis (5).
Patients with viable tumour in neck dissection specimens after chemoradiation have poorer outcomes as compared with patients without viable tumour in neck dissection specimen. Failure of chemoradiation to sterilize the neck reflects the biologic aggressiveness of the tumour. It is the identification of patients who do not get benefit that remains the challenge.
Limitations of defining a viable tumour cell are severalfold. There is no established, standardized proven method that can objectively measure them in a treated lymph node. The quantification of viable cells and the number necessary for the tumour to continue growth is not firmly established.
One may expect that the number of viable tumour cells immediately after completion of chemoradiation may be much higher in neck dissection specimen. However, it is not always true. Even these viable cells may be in the process of dying at a molecular level, but the visible hallmarks of cell death may be absent. The presence of viable cells is better assessed after several weeks of completion of chemoradiation, ensuring the process of cell death to be complete. During this period any remaining viable cells will have had the chance to grow making detection more feasible (6).
The CPS is given by summing the number of PD-L1–stained cells (tumour cells, lymphocytes, macrophages) and dividing the result by the total number of viable tumour cells, multiplied by 100 (7).
Pembrolizumab plus chemotherapy has demonstrated superior OS than pembrolizumab monotherapy. Tumour PD-L1 expression generally correlates with improved efficacy with anti-PD-1/PD-L1 immune checkpoint inhibitors (ICIs) in recurrent/metastatic HNSCC, with increased predictive value when including PD-L1 expression on tumour infiltrating immune cells. The predictive value of PD-L1 expression is however not absolute (8).
As such, new methods of disease evaluation and surveillance have been developed, including immunotherapy- centric response metrics, such as the immune-related response criteria (irRC) and immune-related Response Evaluation Criteria in Solid Tumours (irRECIST) The conventional response criteria may underestimate the therapeutic benefit of ICIs due to the initial appearance of tumour flare. Key differences between immune-based response criteria and RECIST v1.1 focus on initial evaluation of disease progression which accounts for delayed response and tumour flare through standardized imaging. irRC and irRECIST require confirmation of initial evidence of progressive disease and new lesions Under irRECIST, if tumour flare is followed by tumour shrinkage on a subsequent check up, the bar is reset and the flare would be considered immune unconfirmed progressive disease (9,10).
Head and neck sarcomas being rare tumours (1% of all H&N tumours), pose a challenge in the management due to close proximity to vital structures. All except Rhabdomyosarcoma and Ewing's sarcoma need surgery as the primary modality of treatment. The local recurrence rates for high-grade soft tissue sarcomas after surgical excision have been reported to be as high as 50%. The survival and incidence of the local recurrence, however, depends on the extent and adequacy of the excision. Local excision with wide margins are necessary to remove the microscopic pseudopodia else may lead to local recurrence. With advances in reconstructive techniques, including free tissue transfer, have made more aggressive surgical resection a reality. A multidisciplinary meeting is advised to help in the decision making of adjuvant radiotherapy and/or chemotherapy (11-15).Traditional maximum tolerable dose, single-agent palliative chemotherapy in head and neck cancer has shown marginal improvement in survival. The effect of this treatment on quality of life (QOL) is an issue considering the side effects. Efforts of improving survival by use of combination chemotherapy have not been successful either. Combination chemotherapy regimens increase the toxicity. The addition cetuximab to the combination chemotherapy has shown improved survival, but this is not a cost effective option. Metronomic chemotherapy was developed as an option in such situations for improvement in efficacy in a cost effective manner. The efficacy of oral metronomic chemotherapy (OMCT) consisting of low-dose methotrexate (15 mg/m 2 weekly) and celecoxib, in terms of progression-free survival (PFS), QOL, and OS, was better than single-agent cisplatin and with a favorable toxicity profile.
OMCT has shown encouraging results, especially in the context of patients who are not able to take cetuximab- based therapy in the palliative setting. These results need to be improved with various innovative ways. OMCT, however, has limited activity in platinum refractory patients. The site and subsite influence the outcomes to metronomic chemotherapy in head and neck cancer (16).
| References|| |
- Mehrara, E., Forssell-Aronsson, E., Ahlman, H., & Bernhardt, P. (2007). Specific Growth Rate versus Doubling Time for Quantitative Characterization of Tumour Growth Rate. Cancer Research, 67(8), 3970 LP – 3975. https://doi.org/10.1158/0008-5472.CAN-06-3822
- Ghi MG, Paccagnella A, Ferrari D, et al. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial. Ann Oncol. 2017;28(9):2206-2212. doi:10.1093/annonc/mdx299
- NCCN Guidelines
- Patil VM, Prabhash K, Noronha V, et al. Neoadjuvant chemotherapy followed by surgery in very locally advanced technically unresectable oral cavity cancers. Oral Oncol. 2014;50(10):1000-1004. doi:10.1016/j.oraloncology.2014.07.015
- Mehanna H, McConkey CC, Rahman JK, et al. PET-NECK: a multicentre randomised Phase III non-inferiority trial comparing a positron emission tomography-computerised tomography-guided watch-and-wait policy with planned neck dissection in the management of locally advanced (N2/N3) nodal metastases in patients with squamous cell head and neck cancer. Health Technol Assess. 2017;21(17):1-122. doi:10.3310/hta21170
- Ganly I, Bocker J, Carlson DL, et al. Viable tumour in postchemoradiation neck dissection specimens as an indicator of poor outcome. Head Neck. 2011;33(10):1387-1393. doi:10.1002/hed.21612
- Kulangara, K., Zhang, N., Corigliano, E., et al.(2019). Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer. Archives of Pathology & Laboratory Medicine, 143(3), 330–337. https://doi.org/10.5858/arpa.2018-0043-OA
- Cohen, E.E.W., Bell, R.B., Bifulco, C.B. et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). j. immunotherapy cancer 7, 184 (2019). https://doi.org/10.1186/s40425-019-0662-5
- Wolchok JD, et al. Guidelines for the evaluation of immune therapy activity in solid tumours: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20.
- Seymour L, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143–52.
- Rabindra P. Singh et al. Adult Head and Neck Soft Tissue Sarcomas: Treatment and Outcome. Hindawi Publishing Corporation- Sarcoma (2007), Volume 2008, Article ID 654987, doi:10.1155/2008/654987.
- W. M. Mendenhall, C. M. Mendenhall, J. W. Werning, C. E. Riggs, and N. P. Mendenhall, “Adult head and neck soft tissue sarcomas,” Head & Neck, vol. 27, no. 10, pp. 916–922, 2005.
- W. F. Enneking, S. S. Spanier, and M. A. Goodman, “A system for the surgical staging of musculoskeletal sarcoma,” Clinical Orthopaedics and Related Research, vol. 153, pp. 106–120, 1980.
- R.A. Eelesl et al. Head and neck sarcomas: prognostic factors and implications for treatment. British Journal of Cancer (1993), 68, 201-207.
- Sturgis, E. M., & Potter, B. O. (2003). Sarcomas of the head and neck region. Current Opinion in Oncology, 15(3), 239–252. doi:10.1097/00001622-200305000-00011.
- Patil V M, Noronha V, Joshi A, Nayak L, Pande N, Chandrashekharan A, Dhumal S, Bhattacharjee A, Banavali S, Prabhash K. Retrospective analysis of palliative metronomic chemotherapy in head and neck cancer. Indian J Cancer 2017;54:2
| References|| |
Culliney B, Birhan A, Young AV, et al
. Management of locally advanced or unresectable head and neck cancer. Oncology (Willis- ton Park) 2008; 22: 1152 – 1161.
Liao CT, Ng SH, Chang JT, et al.
T4b oral cavity cancer below the mandibular notch is resectable with a favorable outcome. Oral Oncol. 2007;43(6):570-579. doi:10.1016/j.oraloncology.2006.06.008.
Brockstein B, Haraf DJ, Rademaker AW, et al.
Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience. Ann Oncol 2004; 15:1179.
Oyen WJ, Marres HA, Kaanders JH. Progress in nuclear medicine procedures in head and neck oncology. Q J Nucl Med Mol Imaging. 2011;55:485–486.
Lowe V J.et al (2000). Surveillance for Recurrent Head and Neck Cancer Using Positron Emission Tomography. Journal of Clinical Oncology, 18(3), 651–651. doi:10.1200/jco.2000.18.3.651 ).
Abdulrahman GO Jr. The effect of multidisciplinary team care on cancer management. Pan Afr Med J. 2011;9:20. doi: 10.4314/pamj.v9i1.71195. Epub 2011 Jun 17. PMID: 22355430; PMCID: PMC3215542.
National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology. NCCN guidelines version 1.2019. Head and neck cancers. NCCN; 2019.
Kennedy JT, Krause CJ, Loevy S. The Importance of Tumour Attachment to the Carotid Artery. Arch Otolaryngol. 1977;103(2):70–3. doi:10.1001/archotol.1977.00780190050002
Hiranandani LH: Management of cervical metastases in head and neck cancers. J Laryngol Otol 85:1097-1126, 1971.
Freeman SB, Hamaker RC, Borrowdale RB, Huntley TC. Management of neck metastasis with carotid artery involvement. Laryngoscope. 2004;114(1):20-24.
Loré, J. M., & Boulos, E. J. (1981). Resection and reconstruction of the carotid artery in metastatic squamous cell carcinoma. The American Journal of Surgery, 142(4), 437–442. doi:10.1016/0002-9610(81)90370-6
Ozer, E., Agrawal, A., Ozer, H. G., & Schuller, D. E. (2008). The Impact of Surgery in the Management of the Head and Neck Carcinoma Involving the Carotid Artery. The Laryngoscope, 118(10), 1771–1774. doi:10.1097/mlg.0b013e31817f6dc7.
Roh, J.-L., Ra Kim, M., Choi, S.-H., Hyun Lee, J., Cho, K.-J., Yuhl Nam, S., & Yoon Kim, S. (2008). Can patients with head and neck cancers invading carotid artery gain survival benefit from surgery? Acta Oto-Laryngologica, 128(12), 1370–1374. doi:10.1080/00016480801968518.
Manzoor NF, Russell JO, Bricker A, et al.
Impact of Surgical Resection on Survival in Patients With Advanced Head and Neck Cancer Involving the Carotid Artery. JAMA Otolaryngol Head Neck Surg. 2013;139(11):1219–1225. doi:10.1001/jamaoto.2013.4917
Modified in-continuity resection is advantageous for prognosis and as a new surgical strategy for management of oral tongue cancer Li, Bo et al.
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 129, Issue 5, 453– 460.
Feng Z, Xu QS, Qin LZ, Li H, Li JZ, Su M, Han ZX. Risk factors for relapse of middle-stage squamous cell carcinoma of the submandibular region and floor of mouth: the importance of en bloc resection. Br J Oral Maxillofac Surg, (2016) 54(1):88-93. doi: 10.1016/j.bjoms.2015.09.024.
Leemans CR, Tiwari R, Nauta JJ, Snow GB. Discontinuous vs incontinuity neck dissection in carcinoma of the oral cavity. Arch Otolaryngol Head Neck Surg, (1991) 117(9):1003-6.
Tesseroli MA, Calabrese L, Carvalho AL, Kowalski LP, Chiesa F. Discontinuous vs. in-continuity neck dissection in carcinoma of the oral cavity. Experience of two oncologic hospitals. Acta torhinolaryngol Ital, (2006) 26(6):350-5.
Prabhash K, Noronha V, et al.
Neoadjuvant chemotherapy followed by surgery in very locally advanced technically unresectable oral cavity cancers. Oral Oncol. 2014;50(10):1000-1004. doi:10.1016/j.oraloncology.2014.07.015
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]