Role of addition of chemotherapy to palliative radiotherapy protocol: A review of literature and experience from a tertiary cancer center of India

Pavan Deepak Mandigala Venkata Ramana; Gulafshan Jabi; Mohsin Khan

doi:10.4103/jrcr.jrcr_31_22

REVIEW ARTICLE

Year : 2023 | Volume : 14 | Issue : 1 | Page : 8-13

Role of addition of chemotherapy to palliative radiotherapy protocol: A review of literature and experience from a tertiary cancer center of India

Pavan Deepak Mandigala Venkata Ramana, Gulafshan Jabi, Mohsin Khan
Department of Radiotherapy, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Date of Submission	25-Apr-2022
Date of Decision	08-Jun-2022
Date of Acceptance	09-Jun-2022
Date of Web Publication	02-Nov-2022

Correspondence Address:
Dr. Pavan Deepak Mandigala Venkata Ramana
Department of Radiotherapy, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jrcr.jrcr_31_22

Abstract

Unresectable head-and-neck cancers (HNCs) pose a significant challenge to clinical oncologists. Radiotherapy (RT) has a pivotal role in palliation of symptoms in advanced unresectable stage. Palliative RT protocols generally employ hypofractionated regimes in an attempt to reduce the overall treatment time and acute toxicities. Concurrent chemoradiotherapy (CCRT) may improve local control facilitating faster palliation of symptoms. Yet the role of chemotherapy with hypofractionated schedules is unclear in palliative settings due to the fear of increased toxicities. The literature review was hence conducted to validate the tolerability and efficacy of CCRT in the palliative setting. The literature search was performed on electronic databases using appropriate keywords. Studies evaluating untreated patients, treated recurrent cancers, second primaries localized in the head and neck or metastatic HNC were all chosen. Five studies were selected which met our selection criteria. Palliation of symptoms, response rates, and toxicities of these studies was evaluated. Role of such concurrent regimes at other sites have also been discussed. All the evaluated studies demonstrated good rates of symptom palliation and response rates with tolerable adverse effects. In addition, our literature review has identified a paucity of evidence that warrants large-scale longitudinal studies to derive conclusive remarks on the use of palliative CCRT.

Keywords: Chemoradiotherapy, concurrent, head-and-neck cancer, palliative

How to cite this article:
Venkata Ramana PD, Jabi G, Khan M. Role of addition of chemotherapy to palliative radiotherapy protocol: A review of literature and experience from a tertiary cancer center of India. J Radiat Cancer Res 2023;14:8-13

How to cite this URL:
Venkata Ramana PD, Jabi G, Khan M. Role of addition of chemotherapy to palliative radiotherapy protocol: A review of literature and experience from a tertiary cancer center of India. J Radiat Cancer Res [serial online] 2023 [cited 2023 Jun 7];14:8-13. Available from: https://www.journalrcr.org/text.asp?2023/14/1/8/360385

Introduction

Worldwide, head-and-neck cancers (HNCs) account for approximately 900,000 new cases diagnosed annually.^[1]

Almost two-thirds of the patients with cancer were diagnosed at the locoregional stage for HNC in India.^[2] Unresectable diseases are generally managed by palliative intent. The role of radiation in palliation is established with various trials evaluating advanced malignancies.

The role of the addition of chemotherapy concurrently to radiation in the palliative setting is not completely understood and remains controversial. Setbacks to the use of concurrent regimens include fear of increased and intolerable toxicities and worsening of quality of life (QoL). There is a paucity of data on chemoradiation in palliative care, in terms of tolerability, objective response, and symptomatic improvement. Hence, we have performed a review focusing on studying the role of concurrent chemoradiation in the palliative management of advanced-stage HNCs.

Results

Through electronic searches in the above-mentioned databases, we have selected five studies which have incorporated chemotherapy with radiotherapy (RT) in palliative settings in HNC.

Literature search strategy

A comprehensive search was performed on electronic databases such as PubMed-MEDLINE, Cochrane, EMBASE, and SCOPUS. The search terms used were “Head and Neck” “Cancer,” “Carcinoma,” “Palliative,” “Chemoradiation,” “chemoradiotherapy,” “Concomitant,” and “Concurrent” with appropriate BOOLEAN “AND” or “OR” search algorithms. All eligible studies were required to meet the following predefined criteria:

Must include the diagnosis of HNC
Can include previously untreated patients, treated recurrent cancers, second primaries localized in head and neck, or metastatic HNC.

Parameters assessed

The studies were selected such that the patient characteristics, especially performance status was included. The other parameters included symptoms before commencing RT. Treatment-related parameters included fractionation regime and technique employed, concurrent chemotherapy dose, and schedule.

Outcome assessment

Information on the parameters, namely, symptom palliation rate, overall response, and survival data were recorded after analyzing the studies.

The study findings are tabulated in [Table 1].

Table 1: Characteristics and outcomes of the studies analyzed

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Treatment Approach In Palliative Care

HNC account for more than 3% of the global cancer burden.^[1] There is significant heterogeneity in the incidence and prevalence of HNCs across the world. In India, HNCs constitute 66.6% and the vast majority of them belong to the locally advanced stage at presentation.^[2]

According to a multi-institutional study by Nandakumar and Nandakumar^[8] conducted in India, estimated that 65% of patients with locally advanced stage did not receive optimal treatment. This observational study demonstrated the requirement of concurrent chemoradiation, especially in the cancers of the oropharynx and hypopharynx. Absolute increase in Three Year cumulative survival percent (TCS) 17% and Five-year cumulative survival percent (FCS) of 14.5% was noted with the addition of concurrent chemotherapy in locally advanced oropharyngeal. A similar advantage in TCS and FCS was observed in locally advanced hypopharyngeal cancer were 17.4% and 15.3%, respectively.

The survival of patients with incurable HNC is short, with a mean of 5 months which can range from days to more than 3 years.^[9] Incurability of HNC can be due to several reasons: inoperability plus no other curative treatment options, distant metastasis, the presence of severe comorbidity, and/or poor performance status of the patient or if the patient denies curative intervention.

HNC in the palliative phase can cause specific end-of-life issues because of its local anatomy and the consequences of treatment such as intense pain, airway complications, bleeding or pus discharge from a local site, communication difficulties, dysphagia, facial disfigurement, and psychosocial complaints.

Approaches to treat these subsets of patients will be to improve the QoL by attempting to palliate the symptoms. RT has been tried and has succeeded in providing effective palliation in HNC. Paris et al.^[10] used the RTOG 8502 protocol in HNC, which was originally devised for advanced pelvic malignancies. The study participants had inoperable or metastatic disease and few were denied surgery. About 28% had complete response (CR); 49% lesions had partial response (PR); 10% lesions had no response; and 8% lesions progressed under treatment. Palliation was achieved in 85% of cases. The regimen of RTOG 8502, called QUAD SHOT, consists of 3.7 Gy twice-daily fractions given over two consecutive days per cycle with a rest period of 2–4 weeks between the three prescribed cycles for a total dose of 44.4 Gy. Corry et al.^[11] used the same fractionation schedule and demonstrated 44% improvement in overall QoL (EORTC QLQ-C30) compared to their pretreatment levels. Pain severity and dysphagia were improved in 56% and 33% of patients, respectively.

Concurrent chemoradiotherapy (CCRT) has been the standard approach in the locally advanced head-and-neck carcinoma due to the radiosensitizing properties of chemotherapy. Its role in palliative schedules is unclear. The hypothesis of better local control translating to better palliation of symptoms relative to RT alone and the ability to address distant metastasis drives its utilization in very advanced cancers requires palliative intent therapy. Palliative chemoradiation was superior to chemotherapy alone in poor prognosis non-small-cell lung cancer, as evidenced by a randomized trial by the Norwegian lung cancer study group. The median overall survival was 9.7 and 12.6 months (P < 0.01), respectively, for chemotherapy alone and chemoradiation. At the end of the treatment, patients in chemotherapy alone had a significant decline in QoL as opposed to the chemoradiation arm.^[12]

Carrascosa et al.^[13] conducted a prospective phase 2 study that included pelvic and HNC subjects to a total of 20, of which 7 were of the head and neck primary. All of them had advanced stages and were not candidates for conventional radiation because of disease extent and comorbid medical problems. The symptoms that prompted treatment included bleeding, pain, dysphagia, and foul odor. QUAD SHOT regimen along with radiosensitizing IV paclitaxel 60 mg/m² was given 1 h before 1^st day of each radiation cycle. Five out of 7 patients had PR and one patient had CR. The complete symptomatic response was seen in 3 and PR was seen in three patients. Pain and bleeding were the symptoms with more clinical improvement. There were no Grade 4 toxicities. This study concluded that the palliative schedule used has provided good tumor response and palliation of symptoms with good tolerance to concurrent paclitaxel. Although the number of participants was few in this study, the prospective design, tolerability, and promising outcomes warrants further evaluation and adoption of this protocol to extrapolate the results.

All of the studies analyzed have selected patients with good performance status where patients were able to take care of their personal requirements. In most of the studies evaluated, over 90% of patients belonged to either Stage IV or recurrent lesions.^[3],[5],[6] Ghosh et al.^[4] included some patients of Stage III with poor PS. 28% of patients had metastatic disease in Gamez et al.^[7]

In the selected studies, pain at the local site was the most common presenting complaint among patients of advanced HNC, followed by dysphagia and dyspnea. Bleeding was not a common presentation reported by these studies, possibly because single fraction treatment would be preferred in such scenarios.

There is uncertainty in adopting a palliative schedule which has largely limited the use of CCRT in the palliative setting. Few studies have used hypofractionation by modifying the QUAD SHOT regimen to reach a near tumoricidal dose. In Indian studies by Ghosh et al.^[4] and Arvind Kumar et al.,^[6] treatment time was kept short with no planned gaps.

Cisplatin or carboplatin, bleomycin, methotrexate, and cetuximab have been the routine agents used concurrently in various combinations. As expected, the majority of studies have most commonly used platinum agents. Chemotherapy was administered twice weekly by Minatel et al.^[3] and Monnier et al.,^[5] while Gamez et al.^[7] and Arvind et al.^[6] gave triweekly and daily, respectively.

Increased risk of toxicities has concerned the physicians to opt out of concurrent protocol. However, studies have shown that it is well tolerated if dose, combination, and schedule being properly computed. Minatel et al.^[3] studied the addition of IV concurrent bleomycin and radiation of 50 Gy delivered in 20 fractions. Grade 3 RTOG stomatitis and dysphagia were seen in 46% and 3% of patients, respectively. There were no Grade 4 toxicities. Overall treatment was observed to be feasible. Monnier et al.,^[5] Ghosh et al.^[4] and Gamez et al.^[7] however reported fewer to no severe grade toxicities. Arvind Kumar et al.^[6] reported significantly higher rates of Grades 3–4 acute dysphagia in the CRT arm (68%) as compared with the RT alone arm (7.7%), which eventually subsided at the end of 6 months.

A comparative study analyzing the outcomes of RT alone and CRT was done by Arvind Kumar et al.^[6] QoL was assessed with EORTC QLQ-C15-PAL and HN-35 questionnaire. At just 1 month posttreatment, there was a significant improvement in emotional functioning, global health status, pain, and insomnia as rated with C-15 in the CRT arm. In assessment using HN-35 also there was a better improvement in pain, social contact, speech, dental complaints, and mouth opening. Analysis at 6 months showed more alleviation in pain, dysphagia, and dental problems in the CRT arm. Because these are the most common presentations of advanced head-and-neck malignancies, these results are convincing using a concurrent regimen.

Minatel et al.^[3] reported improvement in pain severity in 77.8% of patients, while that for RT alone study of Corry et al.^[11] was 56%.

Modest local control benefit is expected with the addition of chemotherapy in the palliative setting, which helps in achieving durable relief of symptoms. Four of the 5 studies analyzed provided more than 50% overall response rates (ORR). Monnier et al. demonstrated that response rates were higher for nodes than for primary tumors. This is consistent with Corry et al.^[11] data of RT alone, where ORR was 53%. Ghosh et al. however reported contradictory results that had fewer ORR in the CRT arm and RT arm as compared to best supportive care. Because the statistical significance value is not known, it is difficult to draw conclusions regarding the response from this particular study.

Although the main objective of any palliative protocol is no the improvement in survival outcomes, this additional benefit is welcomed if only a few or tolerable side effects are produced by such protocol. Carvalho et al.^[14] studied 90 patients and classified into three groups equally – Group 1 treated with RT alone, Group 2 with neoadjuvant chemotherapy, followed by RT, and Group 3 with concomitant chemoradiation. The patients selected had unresectable HNC, age under 65 years, not previously treated, KPS above 50, and had no pulmonary or cardiac comorbidities. Concurrent cisplatin and bleomycin were given by intravenous means triweekly with radiation of 2 Gy per fraction accounting to 70 Gy. The median survival of Groups 1, 2, and 3 are 11.7 months, 12.1 months, and 14.5 months, respectively (P < 0.0001). This study also compared these three groups with a fourth group with no treatment. The median survival in this untreated group was only 3.9 months. This study attempted to establish the fact that radiation either alone or in combination, even in the intent of palliation is associated with improved survival.

The average median survival of all studies we have selected was 9.25 months (ranging from 7 to 12.9 months). This is higher than the median survival data of RT alone reported by Corry et al.^[11] (5.7 months) which enrolled patients of similar performance status and stage.

Our Institutional Experience

After carefully selecting patients with advanced-stage disease, we have administered palliative chemoradiotherapy to patients not amenable to curative intent therapy. The fractionation regime, we use in this setting is usually 30 Gray in 10 fractions with 2 Gray per fraction delivered over 2 weeks with concurrent administration of weekly intravenous cisplatin 35 mg/m². We have observed that the regimen is well tolerated with manageable toxicity, even in patients with poor performance status. The outcomes were promising with good ORR and significant palliation of symptoms leading to improvement in QoL. Furthermore, this regime was tolerable with few severe grade toxicities. After obtaining approval statement from the ethics committee for use of patient data, we have enlisted a few cases who have been treated as per the protocol during the period of 2018–2021 at our institution [Table 2].

Table 2: Summary of case series of palliative concurrent chemoradiotherapy – our experience

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Conclusions

The evaluated studies have demonstrated that hypofractionated palliative CCRT schedules are tolerable and are associated with good response rates and palliation of symptoms. Hence, the addition of chemotherapy to palliative RT protocols should strongly be considered in good performance status patients with advanced, relapsed or metastatic HNC patients not amenable to curative intent therapy. Selection of chemotherapy is critical in this scenario and the dose and combination should be such that the toxic effects are tolerable and manageable with less aggressive interventions. Because the evaluated studies were mostly of nonrandomized and retrospective nature, prospective adequately powered randomized studies are warranted to mitigate this paucity of data.

Toxicity: assessed as RTOG toxicity criteria

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

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