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  Table of Contents  
Year : 2014  |  Volume : 51  |  Issue : 2  |  Page : 89-94

Guidelines for treatment of recurrent or metastatic head and neck cancer

1 Medical Oncologist, Mumbai, India
2 Medical Oncologist, Malabar Cancer Center, Kerala, India
3 Radiation Oncologist, Tata Memorial Hospital, Mumbai, India
4 Surgical Oncologist, Tata Memorial Hospital, Mumbai, India
5 Medical Oncologist Tata Memorial Hospital, Mumbai, India
6 Radiation Oncologist, Pakistan
7 Medical Oncologist, Calcutta, India
8 Medical Oncologist, RGCI, Delhi, India
9 Medical Oncologist, Ahmedabad, India
10 Medical Oncologist, Ramchandra Medical College, Chennai, India
11 Medical Oncologist, Medanta Hospital, Delhi, India
12 Surgical Oncologist, Mumbai, India
13 Medical Oncologist, Pune, India
14 Medical Oncologist, Max Hospital, Delhi, India
15 Medical Oncologist, Nepal
16 Radiation Oncologist, Bangladesh
17 Oncologist

Date of Web Publication7-Aug-2014

Correspondence Address:
K Prabhash
Medical Oncologist Tata Memorial Hospital, Mumbai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.137896

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How to cite this article:
Parikh P, Patil V, Agarwal J P, Chaturvedi P, Vaidya A, Rathod S, Noronha V, Joshi A, Jamshed A, Bhattacharya G S, Gupta S, Desai C, Advani S H, Pai P, Laskar S, Ramesh A, Mohapatra P N, Vaid A K, Deshpande M, Ranade A A, Vora A, Baral R, Hussain M A, Rajan B, Dcruz A K, Prabhash K. Guidelines for treatment of recurrent or metastatic head and neck cancer. Indian J Cancer 2014;51:89-94

How to cite this URL:
Parikh P, Patil V, Agarwal J P, Chaturvedi P, Vaidya A, Rathod S, Noronha V, Joshi A, Jamshed A, Bhattacharya G S, Gupta S, Desai C, Advani S H, Pai P, Laskar S, Ramesh A, Mohapatra P N, Vaid A K, Deshpande M, Ranade A A, Vora A, Baral R, Hussain M A, Rajan B, Dcruz A K, Prabhash K. Guidelines for treatment of recurrent or metastatic head and neck cancer. Indian J Cancer [serial online] 2014 [cited 2021 May 16];51:89-94. Available from: https://www.indianjcancer.com/text.asp?2014/51/2/89/137896

  Introduction Top

Head and neck cancers are frequently seen in our country in locally advanced stage. [1],[2] Many of these patients are treated upfront with palliative therapy. Even if treatment is given with curative intent a significant proportion of patients have recurrent disease. [1],[2] Due to the high burden of locally advanced head neck cancers seen in India, number of patients with recurrent and metastatic head and neck cancer are also increasing proportionately. [1] Not many guidelines deal with such patients and those which deal with such scenarios many not be appropriate in our country scenarios and situations. Hence, a consensus panel of experts was formed to formulate the first such Indian guideline dealing with recurrent and metastatic head and neck cancers. It is aimed at helping a low volume community practice oncologist. The primary objective is to share current practices and come out with consensus recommendations for management of recurrent and metastatic head neck cancer (squamous cell cancers).

  Materials and Methods Top

A panel of expert across India meets during the 29 th Indian Cooperative Oncology Network (ICON) meeting in Mumbai. Prior to the meeting, the panel experts were divided into five groups as shown in [Table 1]. Each of these groups did the literature search in each of their respective assigned domains and came up with their recommendations. These recommendations then were debated over and reviewed during the 29 th ICON meeting first by the each assigned group and then by the whole of the panel expert. Following this, a consensus was reached and then the following guideline was formulated. The guideline is been formulated in the following sections.{Table 1}

  • Consensus flow chart
  • Surgery in recurrent and metastatic tumors
  • Radiation in recurrent and metastatic tumors
  • Chemotherapy in recurrent and metastatic tumors
  • Molecular therapy in recurrent and metastatic tumors
  • Supportive care in recurrent and metastatic tumors.

  Role of Surgery in Metastatic or Recurrent Head Neck Cancers Top

Salvage surgery may be feasible only in a small proportion of these patients, in up to 16% in one study. [3] It is known that the prognosis of recurrent cancer depends upon: Time to recurrence, site of recurrence, performance status (PS) and recurrence stage. [4] Efficacy of salvage was better for stage I/II patients, who had 2-year disease free survival of 70%, and a stable quality of life in about 60%. [5]

Factors contributing to complications

  • Previous irradiation
  • Surgery in salvage setting
  • Methicillin resistant Staphylococcus aureus infection
  • Age, malnutrition and uncontrolled medical comorbidities
  • Postoperative hemoglobin <12.5 g/dl.

Measures to prevent operative complications

  • Nutritional build-up and treatment of coexisting infections
  • Meticulous surgical techniques e.g., appropriate incisions, careful raising of flaps, introduction of nonirradiated vascularized tissue, separation of mucosal and visceral surfaces and adequate cover to vessels.

General principles

  • While salvage surgery provides the best chance of long-term cure in the setting of recurrence it is difficult and associated with higher rates of postoperative mortality and morbidity
  • Wherever possible, organ preserving surgery should be attempted
  • In selected patients, who have exhausted other treatment options, photodynamic chemotherapy can lead to clinical benefit and improvement in quality of life. [6]

  Surgery in Metastatic Head and Neck Squamous Cell Carcinoma Top


  • Metastases at presentation (synchronous): If small primary (rare), metastasectomy may be done in good PS
  • Late distant metastases (metachronous): Metastasectomy considered if controlled primary, good PS, resectable metastases.

Consensus [7],[8],[9]

  • Carefully Selected patients with single or oligometastases should be operated on if the primary head and neck cancer is under control
  • No definite evidence or randomized trials to show benefit of metastasectomy.

  Role of Re-radiation in Metastatic or Recurrent Head Neck Cancers Top

Re-radiation consensus

Factors involved in decision making

  • Patient factors: PS, comorbidity
  • Tumor factors: Disease type, extent of recurrence, metastatic status
  • Treatment factors: Initial Rx, sequelae of initial Rx, disease-free time interval.

It is preferable to undertake re-irradiation at the center where initial radiation therapy was offered.

Prognostic factors in re-irradiation [10],[11],[12],[13],[14]

  • Good PS
  • Long interval since index radiation (>1 year)
  • Low tumor volume (<27 cm 3 )
  • Greater dosage delivered (>58 Gy)
  • Use of intensity modulated radiotherapy (IMRT) (enabling higher tumoricidal dose).


  • Risk of complication (normal tissue toxicity) - Acute and chronic dysphagia, osteoradionecrosis/soft tissue necrosis, trismus/fibrosis, carotid rupture, 6-7 weeks of treatment plus 2-3 months of recovery
  • Lack of data (animal/human) - extrapolation bias.


  • Definite radiation ± chemotherapy or biological agent
  • Brachytherapy
  • Postoperative adjuvant radiation ± chemotherapy or biological agent.

Minimal data set required prior to re-irradiation

  • Type of previous radiation - definitive/adjuvant
  • Time interval since previous radiation
  • Radiation planning details: Including energy, dose, fractionation, time, portals, and technique
  • Details of previous adjuvant/concurrent treatment offered.


  • Modern radiotherapy techniques three-dimensional conformal RT (3DCRT)/IMRT are preferred. Image guidance can be useful
  • Modern radiotherapy techniques deliver higher and more conformed dosage while minimizing
  • Radiation to normal tissue (a prior bottleneck in treatment planning)
  • Stereotactic body RT and brachytherapy can also be offered in selected cases.


  • The optimal treatment volume for re-irradiation is uncertain. In an effort to limit the toxicity many reported experiences with re-irradiation have targeted the recurrent gross disease with limited margin and not added elective nodal re-irradiation.

Dose and fractionation

• In terms of the dose delivered in the second treatment course, data suggest a greater likelihood of local control with administration of a dose of at least 50-60 Gy in re-irradiation [15],[16],[17]

• Several recent reports with 3DCRT/IMRT have used doses between 66 and 70 Gy with acceptable morbidity. Doses >58 Gy are recommended. [17] Other options include

  • 1.5 Gy BID split course protocols with chemotherapy
  • Conventional fractionation 1.8-2 Gy OD (±concurrent chemotherapy)
  • Hyper fractionated RT 1.1-1.2 Gy BID (±concurrent chemotherapy)

• With stereotactic body RT techniques, doses of 30-50 Gy [3-5 Fr] can be delivered over 8-10 days [18]

• Doses of 30-34 Gy can be offered with HDR brachytherapy application of 300-400 cGy per fractions. [18]


Radiation Therapy Oncology Group and other groups have limited the cumulative spinal cord dose to 50-60 Gy, [ 11],[18],[19],[20] whereas some have allowed for normal tissue recovery and delivered somewhat higher cumulative doses all with a risk of myelopathy of <1%. [21] Quantitative Analyses of Normal Tissue Effects in the Clinic guidelines suggest that a cumulative equivalent dose 2 of ≤60 Gy can be considered safe. [22]

Time interval for re-irradiation

It is not preferable to re irradiate to curative doses within 1 year as therapeutic window is negligible and risk of complications is very high.

Re-irradiation toxicity


  Role of Chemotherapy in Metastatic or Recurrent Head Neck Cancers Top

Chemotherapy consensus

Baseline evaluation

  • Nutritional status-body mass index (BMI), albumin
  • Renal function tests - creatinine clearance
  • Comorbidities: Diabetes mellitus, cardiac status- electrocardiography/two-dimensional echo
  • Anemia - evaluation of cause essential - rule out vitamin B12 deficiency, International Development Association, evaluate sources of blood loss
  • Social and monetary support system
  • Potential problems with adherence to treatment - distance for commuting, cost of treatment, and source of funding.

Monitoring during treatment

  • Weight-loss of weight during treatment is common - evaluation of oral intake, nutritional advice essential
  • Monitoring creatinine clearance after every cycle of chemotherapy, especially Certified Demand Driven Planner (CDDP) based essential
  • Hematological toxicities necessitating dose reduction if required
  • Monitor peripheral neuropathy, especially with CDDP, carboplatin, paclitaxel
  • Serum electrolytes.

Treatment guidelines

In a patient with PS 0/1 with no comorbidities, the following regimens can be used

  • Platin/5-fluorouracil (5-FU)/taxane-based regimen (as per physician choice) + cetuximab
  • In extremely fit patients, may consider three drug regimen cetuximab (carboplatin + ifosfamide + taxane) [23],[24],[25],[26],[27],[28],[29],[30],[31]
  • The patient should be re-evaluated after three cycles for either stable disease (SD) or partial response or complete response - in case of any of these responses, to continue chemotherapy for a maximum of six cycles. If the patient has progressive disease, to plan for best supportive care
  • If a 5-FU based regimen is used, it is preferable to use a PICC line.

In a patient with PS >1, comorbidities, frail, poor nutritional status, not amenable for surgery/RT, evaluate the cause of poor nutrition status - consider Ryle's Tube/feeding jejunostomy as well as status of comorbidities. If the patient is to be under close follow-up with monitoring for toxicities, comorbidities and nutritional status, consider the following options:

  • Certified Demand Driven Planner single agent
  • Metronomic chemotherapy with capecitabine/celecoxib + methotrexate/etoposide/cyclophosphamide [32],[33]
  • Erlotinib/geftinib [34]
  • Keep a close watch on toxicities, tolerance, and response to treatment - minimal toxicity, stable or responsive disease. If the patient is not responding to treatment or cannot be kept under close follow-up, plan for best supportive care
  • All patients should have a follow-up every 3 months for 1 st year - physical exam, local examination, infectious diseases laboratory (if required).

  Role of Molecular Therapy in Metastatic or Recurrent Head Neck Cancers Top

Epidermal growth factor receptor (EGFR) is a member of the human epidermal receptor (HER)/Erb-B family cell proliferation, apoptosis, angiogenesis and the capacity of tumor cells to metastasize. EGFR-overexpression as well as increased messenger ribonucleic acid levels of TGF-a in tumors are usually associated with poorer responses to radiotherapy and have been shown to be strong predictors of decreased disease-free survival. [35]

• Cetuximab is a chimeric human/murine monoclonal antibody of the IgG1 isotype that binds to the EGFR with a higher affinity than its endogenous ligands. Panitumumab is a fully human, IgG2 EGF-R-targeting antibody that is already approved for metastatic colon cancer and is tested in locally advanced disease in combination with radiotherapy [36],[37]

• Zalutumumab, also a fully human antibody of the IgG1 type, is currently being evaluated in a randomized phase III trial concerning best supportive care for advanced platinum refractory patients [38]

• Cetuximab is approved in combination with irradiation in locally advanced disease based on a multinational, randomized phase III trial comparing radiotherapy plus cetuximab with radiotherapy alone. Nine-month increase in median locoregional control overall survival could be prolonged to a median of 49 months (vs. 29 months) laryngeal function preservation better in cetuximab arm. Extreme study (Erbitux in First-line Treatment of Recurrent or Metastatic Head and Neck Cancer) III trial, 442 patients who were not amenable to local therapy and had not received any systemic treatment received either cisplatin or carboplatin, together with 5-FU or a combination of this chemotherapy with cetuximab cetuximab prolonged OS from 7.4-10.1 months and disease-free survival from 3.3-5.6 months [39]

• Cetuximab monotherapy might then offer a second-line option with significant antitumor activity to these platin-resistant patients. Vermorken absolute increase of 2.5 months in median overall survival in cetuximab-treated patients compared to historical controls treated with best supportive care only [40]

• Combination of cetuximab and weekly paclitaxel was active and well-tolerated by patients who present with low PS2, medically unfit, platin resistant or for whom platin is contraindicated. [40] Gefitinib/erlotinib phase I/II trials as monotherapies in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with response rates of 4-10%. Phase III study involving 486 patients with recurrent HNSCC reported no improvement in response rates and overall length of survival with the addition of gefitinib at different dosing schedules to methotrexate when compared to methotrexate treatment alone [41]

• Lapatinib-induced ERB1 and HER2 blockage showed disease stabilization rates of about 20% in patients pretreated with antiEGFR compounds [42]

• Bevacizumab: Small phase I/II study in combination with erlotinib in metastatic or incurable recurrent disease showed an overall response rate of about 15% and a median survival of 7.1 months [43]

• Promising early clinical results were obtained in a small trial in refractory or metastasizing HNSCC patients, with a single agent sorafenib achieving stable disease in 10/26 patients and a median overall survival of 8 months [44]

• Vandetanib, Src kinases inhibitors like dasatinib, proteosome inhibitors such as borteozomib, etc., are being explored currently in RMHNSCC[Figure 1]. [44]
Figure 1: Decision making tree - Consensus Guidelines for recurrent and/or metastatic HNSCC

Click here to view

  Role of Supportive Care in Metastatic or Recurrent Head Neck Cancers Top

Foul smell

  • Foul smell producing ulcers are usually superinfected with anaerobic bacteria such as bacteroides, Enterobacter, or Escherichia coli species hence a systemic antibiotic is required [45],[46],[47]
  • For control of the smell, a local antibiotic solution is required. Use of topical application of antibacterial essential oil is supported by literature [45],[46],[47]
  • Antibacterial essential oils are tea tree oil or Eucalyptus oil. In addition to being antibactericidal, these can mask foul smell and can promote re-epithelization of tissue [45],[46],[47]


Evaluation of dysphagia (causes in the head and neck cancers)

  • No approximation of lips or the alveolus
  • Defective mobility (due to ankyloglossia) of the anterior 2/3 or posterior 1/3 of the tongue
  • Pharyngeal insufficiency (tumor-related destruction of uvula)
  • Defective laryngeal functioning leading to both dysphagia and aspiration
  • Hypopharyngeal tumor.

These causes have implication in treatment

  • In case of moderate to severe dysphagia with inadequate nutrition then a nasogastric tube insertion and feeding is appropriate [48],[49],[50]
  • Use of gastrostomy (feeding jejunostomy) is controversial in recurrent and metastatic setting. Though in occasional patient if radical intent chemoradiation is offered it can be used if grade 3-4 mucositis is anticipated, the patient BMI is below 20 Kg/m 2 and the dose of radiation exceeds 60 Gy with anticipation of a high-dose above the tolerance limits to the salivary gland. [48],[49],[50]

Bleeding control [51]

  • Packing: Nonadherent dressing material or hemostatic dressing like nonabsorable gelatin can be used. Use of vasoconstrictor coating if local practice can be used, but there is no evidence to support its benefit over simple dressing. Similarly, use of hemostatic gelatin or other expensive hemostatic dressing materials have not shown a benefit over simple nonadherent dressing
  • Uncontrolled bleeding: If bleeding is compromising hemodynamic status then intervention radiology guided embolization of the feeder vessel can be done. Alternatively patient can be taken up for surgical ligation of the vessel supplying the tumor site. If bleeding is in the form of oozing then hemostatic radiation or a short course of radiation can be given. It has shown to provide 80% control
  • Systemic agents: Although routinely used large controlled studies in cancer patient are lacking.

Trismus [52]

  • Exercises using a therabite device or tong blades significantly increase mouth opening on short-term, the effect sizes were large
  • Pentoxifylline increased mouth opening on short-term and electrotherapy increases mouth opening (follow-up: 3 months), but the effect sizes are small
  • Radiotherapy involving the structures of the temporomandibular joint and or pterygoid muscles reduces mouth opening with 18% (standard deviation: 17%)

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