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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 5  |  Page : 15-28

COVID-19 and head and neck cancer treatment


1 Department of Medical Oncology, Tata Memorial Center; Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Homi Bhabha National Institute; Department of Surgical Oncology, Tata Memorial Center, Mumbai, Maharashtra, India
3 Department of Radiation Oncology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
4 Department of Surgical Oncology, Tata Memorial Center, HBCH and MPMMCC, Varanasi, Uttar Pradesh, India

Date of Submission07-Apr-2020
Date of Decision08-Apr-2020
Date of Acceptance08-Apr-2019
Date of Web Publication25-Apr-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_135_20

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  Abstract 


The coronavirus disease 2019 (COVID-19) pandemic is exponentially increasing, as are the risks of COVID-related complications and fatalities. Hence, health-care resources are being allocated for its management. Cancer treatment has taken a back seat in multiple countries due to resource scarcity and the risk of COVID-19-related complications. Head and neck cancer is no different. Probably, by the time COVID-related data get generated specifically for head and neck cancers, either the pandemic will be over, or it will be too late. Hence, there is an urgent need for guidance for head and neck cancer treatment in this situation. In this review article, we have provided evidence-based guidance for selecting the most appropriate therapy in the current pandemic situation.

Keywords: COVID, COVID-19, guidelines, head and neck cancer, low-middle-income countries, India, SARS-CoV2, corona, HNSCC


How to cite this article:
Patil V, Noronha V, Chaturvedi P, Talapatra K, Joshi A, Menon N, Pandey D, Prabhash K. COVID-19 and head and neck cancer treatment. Cancer Res Stat Treat 2020;3, Suppl S1:15-28

How to cite this URL:
Patil V, Noronha V, Chaturvedi P, Talapatra K, Joshi A, Menon N, Pandey D, Prabhash K. COVID-19 and head and neck cancer treatment. Cancer Res Stat Treat [serial online] 2020 [cited 2020 May 30];3, Suppl S1:15-28. Available from: http://www.crstonline.com/text.asp?2020/3/5/15/283302




  Introduction Top


Head and neck squamous cell carcinoma (HNSCC) is an uncommon tumor globally, but one of the most common malignancies seen in the Indian subcontinent[1] and other low-middle-income countries (LMIC).[2] This disease is prevalent in older patients[3] and those with low socioeconomic status.[4] It is commonly associated with comorbidities (36.4%–88.9%).[5] Most of the patients have a history of long-term tobacco use and are thus naturally predisposed to chronic obstructive pulmonary disease (COPD), with 31% harboring it at the time of diagnosis.[6] Unfortunately, most patients (65%–90%) present in the locally advanced stage[7],[8] and require multimodality treatment. Standard guidelines have been developed nationally[9],[10] and globally[11],[12] to provide guidance in the management of these patients. However, most of these cancer-directed treatments require frequent hospital visits, are immunosuppressive, derange the metabolic profile and hence put the patient at a higher risk of coronavirus disease 2019 (COVID-19) mortality risk.[13]

The COVID-19 pandemic has reached most parts of the world.[14] The numbers are exponentially rising and even the centers with adequate state-of-the-art health facilities are stretched and unable to handle the caseload.[15] Analysis from China has suggested that the case fatality rate in cancer patients is 3.5 times that seen in noncancer patients.[13] In addition, patients with comorbidities such as diabetes, hypertension, COPD, and ischemic heart disease have a higher risk of mortality from COVID-19 infection.[16] Thus, it becomes necessary to tweak existing guidelines for every cancer during this pandemic. Here, we discuss evidence-based tweaking of HNSCC guidelines.


  Oral Cancer Top


What should the treatment options be in Stage I–II oral cancer?

Evidence

Although a well-conducted randomized study has never been performed to compare surgery with radiation, surgery is more accepted as a treatment modality in early-stage oral cancers. In an interim analysis of 35 participants in a randomized study (including Stage II–IV oral cancer) comparing surgery with radiation showed a hazard ratio for death of 0.24 (95% confidence interval [CI], 0.10–0.59), in favor of surgery.[17] The evidence is weak, and likely to have been inflated by small numbers and high violations in the study (incompliance with radiation schedule and allotted arm).[18] However, it provided a clue that surgery might be better, leading to durable control rates and a 10-year survival of approximately 30% in this setting.[19] As most of these surgeries are wide local excisions with primary closure, they should not be delayed. In patients whose disease is inoperable because of medical comorbidities or their own preference, radical radiotherapy can be offered without any delay. A delay of up to 30–37 days does not have any impact on outcomes[20],[21],[22] and is the usual waiting period in tertiary care centers.[21],[23],[24] Postoperative adjuvant treatment with radiation is administered in the presence of more than one high-risk feature, which includes perineural invasion, lymphovascular space invasion, or poor grade. This recommendation is based on a retrospective analysis by Chen et al., in 192 patients with at least 2 minor prognostic factors and without any major risk factors (margin positive or perinodal extension); postoperative radiation (RT), or chemoradiation (CRT) yielded a significantly better 5-year locoregional control (surgery + CRT: 76.7%, surgery + RT: 75.4% vs. surgery 66.3%, P = 0.044), disease-free survival (surgery + CRT: 58.6%, surgery + RT: 55.9% vs. surgery 41.7%, P = 0.006), and overall survival (surgery + CRT: 69.8%, surgery + RT: 62.1% vs. surgery 48.6%, P = 0.030) compared to the surgery only group.[25] As the recommendation for adjuvant CRT is based on retrospective evidence, therefore, radiation or CRT can be deferred in such a situation after an appropriate discussion with the patient. CRT is recommended if the margin is close or positive and this has been proven to lead to an overall survival improvement in two Phase III studies[26],[27] and subsequent meta-analysis.[28] This treatment is associated with grade 3 and above adverse events in 77% of the patients.[29] Hence, it should be used judiciously. It would be desirable that we avoid this treatment by ensuring wide local excision and performing a frozen section. If the margin is positive, consideration should be given for revision and avoidance of CRT.

Recommendation

Wide local excision should be offered. Adjuvant radiation can be deferred or judiciously used based on high risk features. A positive margin should be avoided by taking wide margins and confirming on frozen section. However, if margin status is positive, then CRT is warranted.

What should the treatment options be in locally advanced resectable oral cancer?


Evidence

Two randomized studies have addressed this issue. The one by Robertson et al. is included in the above discussion.[17] The second by Iyer et al. randomized patients with Stage III/IV resectable HNSCC to surgery followed by radiation or CRT.[30] Overall, the results were similar in terms of disease-free survival and overall survival. However, in oral cavity cancer, the disease-specific survival at 5 years was significantly better in those who underwent primary surgery (68% vs. 12%, P = 0.038). Although this was an unplanned subgroup analysis, the data suggest that probably surgery is the treatment of choice in resectable oral cancers. Adjuvant radiation needs to be offered to these patients except in T3N0 and T1–T2N1 without any major or minor risk factors.[31] The use of adjuvant radiation is based on a single small randomized study done in India where the use of RT improved the 3-year disease-free survival from 38% to 68% (P< 0.005).[32] However, the overall survival was similar, which suggests that probably these patients could be salvaged with radiation at recurrence. In patients with margin-positive status or the presence of perinodal extension[26],[27] or >2 lymph nodes positive, the use of concurrent CRT is associated with an overall survival benefit (hazard ratio [HR], 0.90; 95% CI, 0.86–0.94; P< 0.001).[33]

COVID-19 impact

The waiting period for surgery routinely in major hospitals is 4–6 weeks.[21],[23],[24] During the current COVID pandemic with resource allocation for COVID-19 patients (doctors, nurses, paramedical staff, intensive care unit beds, ventilators, and funds), this waiting period would be substantially longer.[34],[35] Hence, the risk of progression of disease during this waiting period is also significant and needs consideration. In a study done by Nair et al., 60% of the patients had progression during 21 days of waiting.[36] To counter this, one can use the strategy of neoadjuvant chemotherapy (NACT). In two Phase III randomized studies, the use of NACT failed to improve outcomes.[37],[38] However, both studies did show that outcomes with NACT were non-inferior to the standard treatment. The 10-year overall survivals were numerically higher in the NACT arm (46.5% vs. 37.7%; P = 0.3402; [HR] = 0.837).[39] Thus, the use of NACT would help in delaying surgery and avoid the risk of progression. Another aspect of NACT which was explored in the Licitra study was the decrease in the need for demolitive surgery (52% to 31%) and avoidance of adjuvant radiation (46% to 33%).[37] This suggests that in nearly 40% of patients both demolitive surgery and adjuvant radiation would be avoided by giving NACT. In this study, adjuvant radiation was administered to patients who had one or more of the following risk factors-margin positive status, perinodal extension, invasion of the soft tissues of the face (cheek and chin) and/or more than three nodal metastases. This will lead to less challenging surgery, hence a lower requirement of complex reconstructive techniques which translates into a lower incidence of adverse events.[40],[41] These results were validated by Chaukar et al., in the Mandibular Preservation Study. Contrary to the popular notion, NACT does not compromise the ability to deliver locoregional treatment and the postoperative complication rates are also not significantly different in patients who receive NACT followed by surgery compared to those who undergo surgery alone. In fact, a lower rate of locoregional complications has been noted amongst the patients who received NACT followed by surgery.[42] Avoidance of radiation in 40% of patients[37] in whom it is indicated would reduce a substantial burden on radiotherapy units. Hence, NACT for 3–4 cycles should be considered.

Selection of neoadjuvant chemotherapy

Chemotherapy

The three-drug TPF (Docetaxel, Cisplatin, 5FU) regimen has better outcomes compared to the 2 drug 5FU-platinum regimen.[43],[44] However, the use of both these regimens requires the administration of continuous infusion of 5FU and is associated with high risk of grade 3 or above adverse events. The situation is further complicated by the high incidence of dihydropyrimidine dehydrogenase (DYPD) mutation in India.[45],[46] From retrospective evidence, the three-drug TPF regimen led to better response rates than the two-drug taxane-platinum (50% vs. 22%) regimen;[47] however, these have never been tested in a randomized fashion. NACT leads to immunosuppression and increased hospital visits.[48] Hence, other alternative schedules are required in the current situation. Weekly paclitaxel-carboplatin regimen as NACT in HNSCC has been used in poor performance status patients and those with multiple comorbidities.[49] This regimen was found to be safe, has a response rate of 66% and produces limited immunosuppression. Hence, this schedule appears to be a good option in the current situation.

Metronomic

Patients who are not fit for intravenous chemotherapy can be offered oral metronomic chemotherapy. In a randomized study done by Nair et al., the use of celecoxib and erlotinib for 21 days followed by surgery versus upfront surgery, led to an 0% risk of progression versus 60% in the surgery arm at week-3.[36] In both arms, surgery was done in the 4th week. Although not powered for survival, the use of erlotinib and celecoxib led to an improvement in overall survival from 60% to 86% (P = 0.048). Similar improvement in disease-free survival was reported in a retrospective matched pair analysis in oral cancers by Pai et al.[50] The use of metronomic methotrexate and celecoxib in the waiting period for surgery led to a decrease in the risk of progression and improved the 2-year disease-free survival from 71.6% to 86.5%. The options of weekly paclitaxel-carboplatin, erlotinib-celecoxib, or weekly methotrexate-celecoxib seem to be viable in this situation as all of these therapies have low potential for immunosuppression and are affordable. The latter two schedules have the added advantage of being oral further limiting hospital visits.

Immunotherapy

In well-to-do patients, the option of using checkpoint inhibitors exists. CheckMate 358 explored the safety and feasibility of neoadjuvant nivolumab in patients with resectable squamous cell carcinoma of the oral cavity, pharynx, or larynx with T1 or greater primary lesions and N1 or greater nodal disease. Nivolumab resulted in preoperative tumor reduction in 48% evaluable patients. Nivolumab was well tolerated; treatment-related adverse events of grade 3–4 occurred in four patients (increased lipase and glossodynia) and did not result in surgery delays.[51] In a Phase II study of neoadjuvant pembrolizumab and adjuvant combined cisplatin and radiation with pembrolizumab in resected HNSCC, 47% of the patients had a pathological response >10% and 32% had a major response (>70%).[52] Uppaluri et al. explored neoadjuvant pembrolizumab in surgically resectable locally advanced head and neck cancer. Greater than 10% pathological downstaging was seen in 43% of patients and 48% had some pathological downstaging. Even in this study, no surgical delay was noted.[53]

Selection of radiation technique for postoperative radiation

While most of the guidelines recommend conformal/intensity modulated radiotherapy (IMRT) in the treatment of head and neck cancers with radiation, the primary benefit of IMRT is to minimize toxicities. [54,55] In the current setting, use should be judicious as it is resource and technology intensive[56] and should be advised to patients with clear benefits in terms of decreased toxicity/sparing critical organs. The Department should be encouraged to create alternative simpler plans with techniques like 3D conformal radiation wherever feasible as it decreases the burden on resources.

Selection of concurrent chemotherapy

Cisplatin fit

Cisplatin fitness should be assessed prior to planning cisplatin. The data on improvement in outcomes seen in the Radiation Therapy Oncology Group (RTOG) and the European Organisation for Research and Treatment of Cancer (EORTC) study were with 100 mg/m2 of cisplatin.[26],[27] In a Phase III randomized study by Noronha et al., the use of weekly 30 mg/m2 of cisplatin was found to be inferior to 100 mg/m2 administered 3 weekly in terms of lower locoregional control (difference - 14.6%; 95% CI, 5.7%–23.5%; P = 0.014). However, the disease-free survival and overall survival were similar. The use of 3 weekly cisplatin was associated with higher in-hospital admissions (31.1% vs. 11.3%) and adverse events (84.6% vs. 71.6%). In view of the lack of overall survival benefit and resource-consuming nature of the 3 weekly regimens, in the current pandemic, weekly cisplatin dosed at 30–40 mg/m2 can be used.

Cisplatin unfit

There is limited evidence for using any other chemotherapy regimen in this situation. In the RTOG 0234 study, docetaxel-cetuximab was used; however, the study was performed in cisplatin fit patients rather than unfit.[57] Docetaxel administered weekly is immunosuppressive and hence should preferably be avoided in the current situation.

Recommendation

Surgery is the mainstay of treatment. However, if delays are anticipated, NACT with paclitaxel + carboplatin or erlotinib + celecoxib or methotrexate + celecoxib or nivolumab or pembrolizumab can be offered. This would help decrease the risk of progression and would make possible less demolitive surgery. Adjuvant radiation can be deferred or can be used judiciously based on risk factors. In patients with high-risk features such as margin positive status or presence of perinodal extension or >2-node metastasis, adjuvant CRT should be administered with weekly cisplatin in cisplatin-fit patient and only adjuvant radiation in cisplatin-unfit patients.

What should the treatment options be in locally advanced borderline resectable oral cancer?


Evidence

With upfront surgery, the average time to recurrence is 2–6 months, depending on the locoregional spread of the disease.[58] The dismal nature of these results along with the morbidity of resection suggest that an alternative form of treatment needs to be developed for these tumors. No data exist in the literature for the use of upfront CRT in these patients. The high volume of the gross tumor and the proximity to or involvement of bony structures or critical organs at risk with radiation tolerance below 70 Gy make the delivery of curative doses of radiotherapy (70 Gy) near impossible. Unpublished data from our center confirm the poor prognosis in these patients treated with upfront CRT. The median progression-free survival was 4.40 (95% CI, 2.07–6.83) months and overall survival was 5.83 (95% CI, 2.73–9.60) months. The goals of NACT are to reduce the size of the tumor, make it potentially resectable and achieve negative margins. Patients identified as having technically unresectable disease can be selected for NACT. It is important to understand that patients with frank skull base invasion, prevertebral fascia involvement, and carotid encasement are considered inoperable and should not be clubbed along with technically unresectable cancers.[59] Patients are treated with NACT followed by an assessment for surgery after 2 cycles; patients considered resectable then undergo surgery while others are treated with radiation or chemotherapy. The estimated median overall survival with this strategy is 12.7 months. At a median follow-up of 18 months, the estimated median survival was not reached for patients undergoing postchemotherapy resection versus 8 months in nonsurgical modalities postchemotherapy (P = 0.0001). Multiple institutes from South India,[60],[61] North India,[62],[63],[64] Western India,[65],[66],[67] and Eastern India[68],[69] have reported similar results with different chemotherapy regimens including weekly paclitaxel with carboplatin. It can be concluded that NACT is effective in converting (23.8%–43%) technically unresectable oral cavity cancers into operable disease and is associated with significantly improved overall survival in comparison to nonsurgical treatment.

Selection of neoadjuvant chemotherapy

Please see the earlier section on chemotherapy under locally advanced resectable oral cancer. Metronomic chemotherapy and immunotherapy have not been evaluated in borderline resectable cancer but can be tried if the patient is not fit for weekly paclitaxel + carboplatin.

Surgery

Surgery needs to be performed according to the post-NACT tumor volume.[59],[70],[71] There is no difference in histopathological parameters with this approach.[71] Outcomes with this approach of post-NACT tumor resection are similar as compared to upfront surgery, as reported in a randomized study in resectable oral cancer from Tata Memorial Hospital.[37]

Adjuvant therapy postsurgery

Adjuvant CRT postsurgery is essential. In our experience, the median overall survival of patients who received NACT and surgical resection followed by adjuvant therapy was higher than that of patients who did not.[70] CRT with weekly cycles of cisplatin chemotherapy (30 mg/m2) is recommended. The dose of cisplatin is 30 mg/m2 and not 100 mg/m2 administered once-in-3-weeks or 40 mg/m2week ly to reduce the cumulative platinum exposure and avoid long-term complications. In patients who are unfit for cisplatin, carboplatin can be used.[44] NACT is not associated with a higher rate of adverse events or interruption in the delivery of adjuvant CRT.[72]

Recommendation

NACT should consist of weekly or 3-weekly paclitaxel + carboplatin. In patients in whom this is not an option or who are not fit for it, the options include erlotinib + celecoxib or methotrexate + celecoxib or nivolumab or pembrolizumab. Surgery should be performed 6–8 weeks after starting systemic therapy and can be done in accordance with the post-NACT tumor volume. Adjuvant CRT should be done with weekly cisplatin-30 mg/m2 in cisplatin fit patients and with carboplatin in cisplatin-unfit patients. In patients who are unresectable after systemic therapy, CRT can be attempted in patients with a good performance status and partial response to NACT. In all others, the treatment intent is palliative and suitable palliative therapy needs to be provided (Please refer to the palliative section).

What should the treatment options be in unresectable oral cancer?


Evidence

NACT followed by radiation was tested in the TAX 323 study.[43] The result suggested that the use of the TPF regimen was better than the 2-drug 5FU-cisplatin regimen. However, the number of patients with oral cavity cancer was small (17.6%). Hence, the results cannot be extrapolated. In the unpublished series from Tata Memorial Hospital which was discussed above, the results of CRT in borderline resectable cancers were dismal. Unresectable cancers have a higher gross tumor volume than borderline resectable cancers and hence it is unlikely that CRT as a treatment modality would be feasible in the large majority of patients. Considering the poor prognosis and limited treatment options in the current situation, it is preferable to treat these patients with palliative intent therapies.

Recommendation

Unresectable oral cancers should be offered palliative therapies. In a very select few patients with Eastern Cooperative Oncology Group Performance Status 0–1, young age without any comorbidities, radical CRT can be tried but outcome is dismal.


  Oropharynx Top


What should the treatment options be in Stage I–II oropharyngeal cancer?

Evidence

For treatment decisions, the staging system considered for oropharynx is the 7th edition of AJCC. Radiation and transoral robotic surgery are the two modalities for treatment. Only a single Phase II randomized study of 68 patients called ORATOR has compared them.[73] The progression-free and overall survival were similar. However, this study was not adequately powered for the comparison of these outcomes. The primary endpoint of the study was the swallowing-related quality of life score at 1 year; the study met its primary endpoint. The quality of life scores were statistically higher in the radiation arm but the difference was not clinically meaningful. In the current COVID-19 pandemic, both treatment modalities have their benefit. Surgery is a one-step procedure while radiation requires a treatment period of 7–8 weeks, thus, increasing hospital visits and the potential of getting infected with COVID-19. A delay in initiation of the treatment of >30 days is associated with a decrease in overall survival.[21],[74]

Recommendation

In the current situation, both radiation and transoral robotic surgery are valid options; however, radiation seems to be the preferred option, if a single modality is used.

What should the treatment options be in Stage III–IV oropharyngeal cancer?

Evidence

For treatment decisions, the staging considered for oropharynx is the 7th edition of the AJCC. CRT is the treatment of choice in this setting. This recommendation is based largely on retrospective studies; a randomized study comparing surgery with CRT has not been reported.[18] The choice of CRT is due to the anatomical preservation of the swallowing apparatus and limited morbidity as compared to open oropharyngeal surgeries.[75] The use of NACT followed by CRT has failed to improve outcomes over CRT[76],[77] except in the Italian study.[78] Thus, considering the requirement for the use of TPF and then cetuximab during radiation, the option of CRT with cisplatin seems more practical.

Selection of the radiation technique

Refer to comments in the previous section.

Selection of concurrent chemotherapy

Cisplatin-fit

As discussed in the earlier section on the selection of concurrent chemotherapy for locally advanced resectable oral cancer (cisplatin eligible patients), weekly chemotherapy is the preferred option in the current COVID-19 pandemic. This regimen has proven to have improved outcomes over radical radiation in a Phase III randomized study.[79] In another large study from our group, the addition of weekly nimotuzumab led to an improvement in progression-free survival (HR, 0.69; 95% CI, 0.53–0.89; P = 0.004), and locoregional control (HR, 0.67; 95% CI, 0.50–0.89; P = 0.006), but not overall survival (HR, 0.84; 95% CI, 0.65–1.08; P = 0.163) in the overall cohort.[80] However, in the HPV-negative oropharynx cohort, this regimen was associated with a large survival advantage (2-year OS, 39.0% [95% CI, 28.4–49.6] to 57.6% [95% CI, 46.3–67.4]), HR - 0.63, 95% CI, 0.43–0.92, P = 0.018).[81] This increment in outcome was without an increase in immunosuppression. It seems that the addition of nimotuzumab to weekly cisplatin achieves similar efficacy as that of 100 mg/m2 but with lower adverse events.

Cisplatin-unfit

The options in this setting are carboplatin+5FU,[82],[83] cetuximab,[84] and nimotuzumab.[85] Each of these has a proven survival benefit, however, the benefit was demonstrated in cisplatin-fit patients and whether this can be translated to cisplatin-unfit patients is an open question.

Recommendation

Radical CRT with weekly cisplatin ± nimotuzumab in cisplatin-fit patients. In cisplatin-unfit patients, radical radiation with carboplatin +5FU or cetuximab or nimotuzumab can be tried but with caution.


  Larynx-Hypopharynx Top


What should the treatment options be in Stage I–II laryngeal/hypopharyngeal cancer?

Evidence

Both radiation and surgery (with or without laser) are considered options in this setting. There is only one randomized study which has compared these two modalities in early glottic cancer.[86] In this study in T1 tumors, the 5-year OS was 91.7% following radiotherapy and 100% following surgery, while in T2 tumors, it was 88.8% following radiotherapy and 97.4% following surgery. This difference was not statistically significant. Based on this study and on retrospective evidence, both modalities seem to have equivalent oncological and functional outcomes in glottic, supraglottic, and hypopharyngeal cancers.[87],[88],[89],[90] Laser-based microsurgery is a procedure with very limited hospital visits as opposed to radical radiation which requires at least 30–35 visits to the hospital.

Recommendation

Both radiation and surgery are options; however, radiation should be preferred as surgery may cause aerosol exposure

What should the treatment options be in Stage III–IV laryngeal/hypopharyngeal cancer with a functional larynx?

Evidence

Conservation of a functional larynx is the objective of treatment. Radical CRT and NACT followed by radiation (RT) both have equivalent long-term outcomes, with numerically better 10-year overall survival in favor of NACT followed by radiation (38.8% vs. 27.5%, P = 0.08). Both modalities have similar adverse event rates (81% vs. 82%).[91] However, mucosal toxicity during radiation was doubled in the CRT arm. Further, Grade 3–4 hematological side effects occurred in 47% of patients during CRT and in 15% of patients during the radiation phase. Thus, even if NACT with cisplatin-5FU (CF) leads to 52% Grade 3–4 hematological adverse events, these do not necessarily require frequent hospital visits.[92] However, hospital visits are mandatory during the CRT/radiation phase and these visits will put the immunosuppressed patient at high risk of acquiring COVID-19 infection.

NACT followed by local treatment based on response assessment is another strategy and has shown similar outcomes as seen with upfront laryngectomy in laryngeal cancer. The 2-year outcome with this strategy is 68% and the larynx preservation rate is 64%.[93] Similar results were seen in the EORTC study in hypopharyngeal cancer. The early outcomes were higher in the NACT arm[94] with the median overall survival improving from 25 months to 44 months with a hazard ratio of 0.86 (log-rank test, P = 0.006). The 5- and 10-year results were similar.[95] The larynx-preservation rate at 5 years was 35%. These results have been validated in a 153 patients' retrospective review from Canada. In this study, primary surgery (S) and neoadjuvant bioselective approaches were superior to concurrent CRT (5-year OS for S - 78% [95% CI, 55%–90%] vs. 76% [95% CI, 63%–85%] vs. 61% [95% CI, 44%–75%] respectively); however, the highest laryngeal preservation rate was seen with primary CRT.[96]

Selection of the neoadjuvant chemotherapy regimen

The three drugs TPF regimen has better outcomes than the 2-drug cisplatin-5FU regimen. The 3 years laryngeal preservation rates were 70.3% versus 57.5% in favor of the TPF arm. However, there was no difference in overall survival (60% at 3 years in both arms).[97] Similar results with better outcomes in terms of progression-free survival and overall survival were reported in the TAX 324 study.[44] However, TPF is associated with a high adverse events rate, needs continuous infusion and is resource consuming,[48] hence needs to be avoided in the current situation. As opposed to this, weekly paclitaxel + carboplatin chemotherapy leads a response rate of 66%, a lower rate of adverse events with minimal immunosuppression,[49] hence needs to be considered in the current setting. The two drug regimen of taxane and platinum administered every 3 weeks has a response rate of 58% in a retrospective analysis performed by Joshi et al.[98]

Selection of radiation technique

Refer to comments in the previous section.

Selection of concurrent chemotherapy

Cisplatin-fit

As has been discussed earlier, weekly cisplatin with nimotuzumab is an appropriate schedule.[80] As the objective is to preserve the larynx, an increase in progression-free survival is an appropriate endpoint as this would lead to an increase in organ preservation. Hence, patients who can afford this schedule should be offered this. In patients who cannot afford nimotuzumab, cisplatin 40 mg/m2 is appropriate.

Cisplatin-unfit

The options in this setting are carboplatin + 5FU,[82],[83] cetuximab,[84] and nimotuzumab.[85] Each of these has a proven benefit in terms of improvement in locoregional control and hence are appropriate for organ preservation. However, these benefits were obtained in cisplatin-fit patients and whether this holds true for cisplatin-unfit patients is an open question.

Recommendation

NACT followed by radiation and CRT both have similar outcomes. However, NACT followed by radiation seems to be preferable as this would lead to a fewer hospital visits for the immunosuppressed patients. The NACT regimen of weekly or 3 weekly paclitaxel + carboplatin should be preferred. If CRT is selected, then in cisplatin fit patients-weekly cisplatin + nimotuzumab should be preferred, another option is weekly cisplatin. In cisplatin unfit patients, radical radiation with carboplatin + 5FU or cetuximab or nimotuzumab can be tried but with caution.

What should the treatment options be in Stage III–IV laryngeal/hypopharyngeal cancer with a dysfunctional larynx and resectable?

Evidence

Delay in treatment initiation has an impact in laryngeal cancer if the delay is beyond 46–73 days.[99] A delay beyond 73 days is associated with a 16.1 months decrease in median survival (P< 0.001) and hence, if required, surgery can be delayed for up to 6–8 weeks. However, whether this has an adverse impact in hypopharynx cancer is less clear.[100],[101] NACT can be offered in the meantime with the weekly paclitaxel + carboplatin regimen being preferred.[49] Oral therapy options are limited as the patient has a dysfunctional larynx and may aspirate the oral tablets or capsules. Nivolumab[51] and pembrolizumab[53] have similar response rate, progression-free survival and overall survival in oral cancer, pharynx, and laryngeal cancer. Hence, it is likely that the results seen in pharyngeal cancers with nivolumab and pembrolizumab would be similar those in oral cavity cancer. In case of inoperable tumor due to medical comorbidities, the patient should be treated with CRT or NACT followed by radiation as for patients with a functional larynx. Adjuvant radiation in patients with operated laryngeal cancer is based on retrospective series.[102] It has not shown to be associated with improvement in long-term outcomes and hence can be deferred. However, if there are high-risk features (margin positive status, perinodal extension, or >2 lymph nodes positive) then CRT needs to be offered.[26],[27]

Selection of neoadjuvant chemotherapy regimen

Refer to earlier section.

Selection of radiation technique

Refer to earlier section.

Selection of concurrent chemotherapy

Refer to earlier section.

Recommendation

Surgery should be performed. It can be deferred for 6–8 weeks for laryngeal cancer but should be done within 30 days in hypopharyngeal cancer. The NACT regimen of weekly or 3 weekly paclitaxel + carboplatin is preferred and can be administered in the interim waiting period. Adjuvant radiation after surgery can be deferred or can be use judiciously based on individual risk factors. If a patient is inoperable, then follow recommendations outlined under functional larynx.

What should the treatment options be in Stage IV unresectable laryngeal/hypopharyngeal cancer?

Evidence

Borderline resectable laryngeal cancers are those with mucosal extension of cancer until the tonsil. Hence, the achievement of R0 resection is difficult but possible after tumor shrinkage. A response rate of 58% is seen with NACT and resectability is achieved in 33.3% of patients. A 2-year overall survival of 78% was seen with this strategy at Tata Memorial Hospital.[98] This overall survival is similar to that seen with a dysfunctional larynx in Stage III–IV cancer. Adjuvant CRT with weekly cisplatin 30 mg/m2 is preferred after NACT. This would lead to a lower cumulative dose of cisplatin 200 mg/m2. Similar results were also published by Sittitrai et al.,[103] Semrau et al.,[104] and Wei et al.,[105] In patients with unresectable cancers, the management strategy remains either CRT or NACT followed by radiation or CRT. There is very limited evidence available to choose between the two strategies. In multiple studies comparing CRT to NACT followed by CRT, NACT failed to improve outcomes except in one Italian study.[76],[77],[78] The interpretation of the results however are limited as unresectable laryngeal-hypopharyngeal cancers constituted a very low proportion of patients in these studies. Hence, either approach can be used. In the current pandemic, probably, the use of CRT would be preferred in such a situation.

Recommendation

NACT followed by response-based treatment (surgery in resectable and CRT in unresectable) needs to be performed in this setting. Adjuvant CRT should be offered with weekly cisplatin. For unresectable laryngeal or hypopharyngeal cancer, either CRT or NACT followed by radiation can be used, with the former being preferred. The regimen for concurrent chemotherapy is weekly cisplatin with or without nimotuzumab based on the patient affordability.


  Nasopharynx Top


What should the treatment options be in Stage I nasopharyngeal cancer?

Evidence

Radiation alone is the recommended treatment.[106] No study has compared CRT to radiation alone in Stage I nasopharyngeal cancer. However, subgroup analyses from studies suggest that addition of chemotherapy might be essential.[107]

Recommendation

Radiation should be started without delay.

What should the treatment options be in Stage II–IV nasopharyngeal cancer?


Evidence

A delay in treatment of >4 weeks is associated with inferior outcomes.[108] NACT followed by CRT and CRT followed by adjuvant chemotherapy are considered equivalent. CRT followed by adjuvant chemotherapy has shown an improvement in outcomes over radiation alone.[109] NACT followed by CRT has shown improvement in outcomes over CRT.[110],[111],[112] To date, no trial has compared NACT followed by CRT versus CTRT followed by adjuvant chemotherapy; such a trial is ongoing with preliminary results showing no difference.[113] Hence, both modalities can be used. NACT allows the immediate start of treatment, ensures compliance and helps in prognostication while adjuvant chemotherapy does not delay or cause radiation interruptions. However, it is difficult to deliver adjuvant chemotherapy; compliance is only 60%–70%.[109] The NACT and adjuvant studies mainly included stage III–IV patients and representation of Stage II patients was lower. However, the benefit of concurrent CRT is proven even in Stage II.[114]

Selection of the neoadjuvant regimen

Multiple neoadjuvant regimens are described in the literature: TPF (full dose); mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL),[115] TPF (modified dose),[111] gemcitabine + cisplatin,[110] and PF regimen.[112] Out of these, the last three are associated with an improvement in overall survival. Hence, any one out of these 3 should be preferred. In view of the requirement of continuous infusion administration of 5FU, high rate of DYPD mutations in the Indian population[46] and lower rate of adverse events which is particularly important in the current situation, gemcitabine + cisplatin should be preferred. However, these regimens have never been tested against each other in the NACT setting in randomized studies. In the palliative setting, gemcitabine + cisplatin was found to lead to better outcomes than the PF regimen.[116]

Selection of radiation technique

IMRT has a survival advantage in nasopharynx[117] and hence should be used.

Selection of the chemotherapy schedule

Chemotherapy schedule of cisplatin at 100 mg/m2, cisplatin at 40 mg/m2 of and carboplatin[118] have all been used in randomized settings and found to have similar outcomes in head-to-head comparisons.[119] Weekly cisplatin schedule of 40 mg/m2 in nasopharyngeal cancer produces more hematological side effects than the 100 mg/m2 schedule. Hence, in the current situation, a weekly carboplatin schedule should be preferred.

Recommendation

NACT with gemcitabine + cisplatin followed by carboplatin with radiation (with IMRT) should be preferred.


  Palliative Therapy Top


What is the intent of treatment and goals in the palliative or salvage settings?

Evidence

Expectation and preferences of Indian patients undergoing palliative therapies were captured in a prospective study by Patil et al., in 200 patients.[120] Prolongation of life and symptom relief were the primary expectations in 41% (95% CI, 34.4%–47.9%) and 58.5% (95% CI, 51.6%–65.1%) of patients, respectively, suggesting that the overwhelming majority of patients want only symptomatic relief. The preferences for chemotherapy as expected were oral, minimally toxic, and affordable regimens. Considering the travel restrictions which make it difficult for the patient to consult the oncologist and financial instability due to the COVID-19 pandemic, these preferences are likely to be tilted more toward symptom relief.

Recommendation

The goals of the therapy should be set in a detailed discussion with the patient. The treatment regimens should be tailored to meet these goals.

What should the treatment options be for patients with residual-recurrent disease who are eligible for salvage surgery?

Evidence

No randomized trial has compared salvage surgery with systemic therapy. However, indirect comparison through flawed studies suggests that salvage surgery leads to an improvement in disease free and overall survival.[121],[122] Salvage surgery is associated with a high rate of postoperative complications and it cannot be delayed beyond 30 days.[121] Considerable proportion of patients (14.3%) progress in the waiting period. NACT has been tried as alluded to in the section on resectable oral cancers. However, it was not associated with any clinically meaningful improvement in outcomes.[123] Hence, salvage surgery should be performed without any delay. Post-salvage surgery, patients need to receive adjuvant chemotherapy with re-radiation in the presence of high-risk features. The high-risk features included clinical and/or radiologic evidence of deep infiltration (>1 cm); laryngeal tumors were included only in case of extralaryngeal spread or ≥1 node-positive disease. The administration of adjuvant CRT leads to an improvement in the 2-year disease-free survival with a hazard ratio of 1.68 (95% CI, 1.13–2.50; P = 0.01). However, there was no improvement in overall survival.[124] Hence, in the current situation, patients can undergo salvage surgery and chemotherapy with re-radiation can be deferred if the patient is not a candidate for re-radiation or there are no high risk features.

Recommendation

Patients, who are eligible, should undergo salvage surgery.

What should the treatment options be for patients with residual-recurrent disease who are not eligible for salvage surgery but are eligible for radiation or re-radiation?

Evidence

Re-radiation with chemotherapy provides sustained benefit in selected patients. The selection criteria are objective and take into account previous radiation plan, time interval since last radiation and presence of radiation sequelae.[125] However, it is associated with substantial adverse events but these are mainly late adverse events. There are no randomized studies in this setting and these recommendations are based on multiple retrospective and single arm prospective studies.[126] IMRT can be used if organs at risk make it difficult to deliver a tumoricidal dose. Selection of chemotherapy is dependent on the chemotherapy that was previous received and the cumulative dose. If chemotherapy was not received previously, then selection will be the same as discussed above for each site. If chemotherapy was received previously, then non-cross resistant schedules such as 5FU + hydroxyurea[124] or paclitaxel + carboplatin[11] can be used. However, these schedules have a high rate of adverse events and this needs to be discussed with the patient.

Recommendation

Re-radiation with chemotherapy should be administered within 1 month.

What should the treatment options be for platinum refractory disease?

Evidence

Nivolumab and pembrolizumab have both proven their benefit in large multicentric randomized studies.[127],[128] However, the applicability of these results in LMIC is questionable as <1% of patients can afford these drugs. In addition, the administration of these regimens might be complicated by the overlapping pictures of COVID-19-related pneumonia and pulmonary toxicity of these agents. Cytokine release syndrome (CRS) is considered central to the pathogenesis of COVID-19. Theoretically, it is considered that CRS might be more prominent in the presence of immune checkpoint inhibitors. Although these drugs are safe, and in normal circumstances they are associated with limited adverse events, in the current COVID-19 pandemic, these agents might rarely lead to a catastrophic event if a patient gets infected with COVID-19 and has pneumonia or CRS.[129] Hence, as it is rare, and would be limited to a minority of patients, the administration of these agents should be not be withheld but should be administered with caution. However, if a patient cannot afford immunotherapy, the use of triple oral metronomic chemotherapy is recommended. Triple metronomic chemotherapy (methotrexate, celecoxib, and erlotinib) has minimal immunosuppressive activity and hence can be safely administered in the current situation.[130]

Recommendation

In the <1% of patients who can afford them in India-nivolumab or pembrolizumab can be administered but with close watch for pulmonary toxicity and CRS. In patients with advanced age, preexisting lung damage, or multiple comorbidities even if they can afford these agents, these can be deferred by administration of triple metronomic chemotherapy. In all others, triple metronomic chemotherapy can be administered.

What should the treatment plan be for the rest of the patients?

Evidence

Pembrolizumab alone or pembrolizumab with cisplatin + 5FU or cetuximab with cisplatin + 5FU are the choices in normal settings for those who can afford them (below 1% in LMIC).[131] For patients with combined PD-L1 positive score of >20% - pembrolizumab single agent with the above-mentioned caution regarding pulmonary toxicity can be administered. However, in the rest of the patients, pembrolizumab or cetuximab with chemotherapy is required. These regimens are associated with a high rate of adverse events and immunosuppression. Hence, in these patients, single-agent pembrolizumab should be preferred.[131] In patients (99% of patients in LMIC) who cannot afford these regimens, the option of oral metronomic chemotherapy with methotrexate and celecoxib can be considered. This regimen is associated with an improvement in PFS and OS over intravenous single-agent cisplatin.[132] In HNSCC, there is no difference in overall survival between single agent or combination agents.[125] Hence, it can be safely assumed that metronomic chemotherapy with methotrexate and celecoxib may have a better or similar efficacy as intravenous combination chemotherapy. The symptom control and its ability to maintain quality of life are added benefits.[133]

Recommendation

Oral metronomic chemotherapy in all patients except in those who can afford pembrolizumab and have a combined positive score (CPS) of >20%.

What is the ancillary care for these palliative patients?

Evidence

Palliative care referral with holistic management of symptoms, counseling, and support system is shown to improve outcomes in few cancer sites.[134],[135] These data can be extrapolated to head and neck cancer and these can be offered

Recommendation

The integration of palliative care services early in the palliative treatment course is suggested even during the COVID-19 pandemic.[136]




  Premalignant Lesions Top


What should the management options be of premalignant lesions?

Recommendation

Premalignant lesions rarely cause immediate threat to life and hence the management of these lesions can be deferred.


  Virtual Tumor Board Top


How should be multidisciplinary board conducted?

Virtual meetings should be encouraged, especially when multidisciplinary decision-making is required.


  Conclusion Top


The COVID-19 pandemic requires a different approach toward management of head and neck cancer patients. An individualized approach taking into account the risk of COVID-19 infection, its fatality and cancer progression risk needs to be taken.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Oral Cancer
Oropharynx
Larynx-Hypopharynx
Nasopharynx
Palliative Therapy
Premalignant Lesions
Virtual Tumor Board
Conclusion
References

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