|Ahead of print publication
“Christie Regimen” palliative radiotherapy in advanced head-and-neck cancer: A single-center experience
Anurita Srivastava, Narayan Adhikari, Deepak Raj Sonkar, Kishore Singh, Arun Kumar Rathi
Department of Radiation Oncology, Lok Nayak Hospital and associated Maulana Azad Medical College, New Delhi, India
|Date of Submission||26-Feb-2020|
|Date of Decision||01-May-2020|
|Date of Acceptance||06-Aug-2020|
|Date of Web Publication||03-Nov-2020|
Room No. 116, Department of Radiation Oncology, Lok Nayak Hospital and Associated Maulana Azad Medical College, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None
Background: Relevance of aggressive treatment in advanced head neck squamous cell cancers(HNSCC) is debatable in view of expected poor outcome. Long treatment duration only adds up to the cost of treatment without any improvements in outcomes.
Aims and Objectives: To assess the outcomes of hypofractionated “Christie” palliative radiotherapy regimen in advanced HNSCC
Materials and Methods: Patients of advanced HNSCC registered from June 2015 to June 2019 were treated by parallel pair field technique on Cobalt60 machine (Theatron 780E) to total dose of 50 Gray/16 fractions over 3.2 weeks. Toxicity was scored using Radiation Therapy Oncology Group (RTOG) criteria and response was evaluated as per WHO criteria.
Results: Records of 110 patients of HNSCC with mean age of 56.19 years were analysed. Evaluation at 4-8 weeks after radiotherapy resulted in a complete response (CR) in 19.1%, partial response (PR) in 32.7%, stable disease (SD) in 29.1% and progressive disease (PD) in 3.6%, while 15.5% patients did not report for post treatment evaluation. Median progression free survival was 9.52 months (95% CI 5.9 – 13.1 months). The median overall survival was 12.7 ± 2.2 months (95% CI 8.2 – 17.2). Median time to progression after completion of radiotherapy was 84 days. Grade IV dermatitis and mucositis was encountered in 2.7% and 1.8% cases respectively, requiring hospitalization.
Conclusion: Christie regimen for advanced HNSCC is a clinically viable option with acceptable outcomes in a resource constrained setting.
Keywords: Head-and-neck squamous cell carcinoma, hypofractionated radiotherapy, palliative
|How to cite this URL:|
Srivastava A, Adhikari N, Sonkar DR, Singh K, Rathi AK. “Christie Regimen” palliative radiotherapy in advanced head-and-neck cancer: A single-center experience. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 2]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299883
| > Introduction|| |
Head-and-neck squamous cell cancer is one of the most common cancers in developing countries like India with population-based cancer registry data predicting 2, 18, 421 cases of head-and-neck cancer in India by the year 2020., Rampant use of tobacco-related products is one of the most common risk factors for the high prevalence. Factors such as poverty, illiteracy, lack of access to health care, and limited health-care resources all contribute to the fact that most head-and-neck cancers present at an advanced stage. Patients presenting in locally advanced stage have fewer chances of cure with high failure rates of 50%–70%. The treatment is challenging because of extensive locoregional involvement, aggressive biological behavior, and inoperability that is further compounded due to poor general condition of patients and co-existing comorbidities. In addition, the limited health-care infrastructure and the heavy patient burden result in substantial delay in treatment, further compounding the chances of cure. Due to the involvement of the upper aerodigestive tract, these patients are burdened with severely debilitating symptoms in the form of pain, dysphagia, swelling, bleeding, etc., which need to be addressed promptly even if complete cure is not possible. Aggressive treatment approaches with chemoradiotherapy or altered fractionation radiotherapy schedules in such locally advanced cases have failed to produce satisfactory results with 5-year survival rates being <20% and a median survival of <12 months.,, Thus, the intent of treatment is focused on alleviating symptoms and improving quality of life keeping in mind the poor socioeconomic condition of the patient and resource constraints of the hospital. There are several fractionation schedules in use that vary considerably in total dose, daily fraction size, and overall treatment time, making it difficult to choose an optimal strategy. The rationale guiding the choice is either rapid symptom relief using high daily dose per fraction delivered over a short span of days or delivering higher total doses in various fraction sizes in the hope of prolonging duration of palliation.
This study retrospectively analyzed the outcomes of the patients treated with the hypofractionated palliative radiotherapy regimen popularly known as “Christie Regimen.”
| > Materials and Methods|| |
Between May 2015 and June 2019, 2991 cases of head-and-neck cancer were registered in our department, of which 110 were treated with Christie Regimen. Criteria for inclusion into this palliative protocol were as follows: Stage IV B/IV C disease and Stage III with significant comorbidities or poor performance status. Nonsquamous histology, salivary gland primary, nasopharyngeal primary, and paranasal sinus tumors were not included. Each case was individually assessed before being assigned for palliative protocol. Patients who had received prior neoadjuvant chemotherapy and not responded were also included, however, no concurrent chemotherapy was performed.
Treatment was given with palliative intent to effect symptom palliation and adequate local tumor control in a short time interval, and this was explained to the patient and family as part of the informed consent. Before treatment, a complete oral and laryngopharyngeal evaluation along with radiological imaging (contrast-enhanced computed tomography) was performed for disease mapping. Complete hematological, biochemistry profile assessment, preradiotherapy dental prophylaxis, and nutritional counseling were performed for all patients. Pain clinic referrals and surgical interventions in the form of tracheostomy/feeding tube placements were performed as indicated. At the time of analysis, all patient records were scrutinized and restaged as per the AJCC 8th edition.
Radiotherapy planning was performed on a simulator taking care to cover all gross disease with a 1–1.5 cm margin along with the involved lymph nodal regions. Parallel opposed fields (lateral/anteroposterior) were used to deliver 37.5 Gy in 12 fractions, 5 fractions per week, in first phase on a telecobalt machine (Theratron 780E). Off-cord field reduction was performed after 12 fractions to spare the spinal cord, and another 4 fractions were delivered to the gross disease up to a total dose of 50 Gy/16 fractions over 3.1 weeks. For cases with nodes overlying spinal cord, angled beams as per treatment planning system-based plan were used, and when the same was not possible, treatment was stopped due to lack of conformal radiotherapy at our center.
Weekly evaluations were performed to assess response and document acute toxicities. Analgesics and other symptomatic medications were used as indicated. All patients were encouraged to maintain oral nutrition, and feeding tubes were used only when necessary. Toxicity was scored as per RTOG and response assessment at ≥4 weeks as per the WHO criteria (complete response [CR] = disappearance of all known diseases, partial response [PR] = >50% decrease from baseline, stable disease [SD] = neither PR or progressive disease [PD] criteria met, PD = >25% increase of one or more lesions, or appearance of new lesions).
Patients who progressed during treatment were offered symptomatic care alone, whereas those who responded to treatment and progressed later were offered salvage chemotherapy if they were fit for the same. Time from hospital registration to starting treatment (chemotherapy/radiotherapy) was called as “initial treatment time;” time to start radiotherapy was defined as time from registration to starting of radiotherapy, whereas overall radiotherapy treatment time was defined as the duration of radiotherapy. Time to progression (TTP) was defined as the length of time from the start of radiotherapy till disease progression (after achieving complete disappearance of disease (CR), PR, or SD). Treatment time was taken as prolonged if it extended beyond 1 week from the stipulated completion date.
Statistical analysis was performed using SPSS Statistics for Windows, version 22.0 (SPSS Inc., Chicago, Ill., USA). Categorical variables were assessed using frequency distribution, whereas continuous variables were analyzed using descriptive statistics. Survival analysis was performed using Kaplan–Meier method. The time to event for progression-free survival (PFS) was calculated from the 1st day of radiotherapy. Overall survival was calculated from the date of diagnosis to the date of death or last known follow-up in the department. Every attempt was made to contact the patients lost to follow-up to ascertain the current status of the patients. Thereafter, considering a worst case scenario, both death and lost to follow-up status were deemed as events for survival analysis.
| > Results|| |
The demographic data of patients are shown in [Table 1].
There was a male predominance with a mean age of 56.19 years (22–85 years), and 30% of the patients had ages 65 years or more. Most patients at presentation had Eastern Cooperative Oncology Group performance status 1. The average weight (±standard deviation) was 51.68 ± 11.3 kg, ranging from 28 to 93 kg, and 11.8% of the patients weighed <40 kg. Most patients did not have comorbidities. The use of tobacco either chewable or smoked was prevalent in at least 70% of the patients. Chronic alcohol use was reported by 15.5%. All patients evaluated in this study belonged to the lower socioeconomic status and had limited financial resources. The majority of the patients reported to our center from remote areas, traveling >200 km. In this study, only 48.2% of the patients belonged to the state of Delhi, whereas all others had come for treatment from adjoining regions as far as Jharkhand. The average time from first symptom to establishing a diagnosis was 5.18 ± 4.1 months (range, 1–24 months) with 77% reporting within 6 months of initial symptom.
The disease characteristics of the patients are represented in [Table 2]. Oropharynx was the most common site of involvement (40.9%), followed by oral cavity (26.4%), larynx (23.6%), and hypopharynx (9.1%). Disease was often extensive involving more than a single site in 44.5% of the cases, and these patients had received upfront chemotherapy, and in case of poor response, they were subsequently taken up for palliative radiotherapy. Ninety percent of the cases had unresectable Stage IV disease, whereas the remaining 10% were considered for palliative treatment on account of either poor general condition, advanced age, or comorbidities.
The treatment details of the patients are depicted in [Table 3]. Every attempt was made to start treatment early, however, due to long waiting time on treatment machines, 55 patients were started on chemotherapy till radiotherapy could be started, resulting in an average of 5.5-week delay in starting initial treatment from the time of registration and an average duration of 10.7 weeks till the start of radiotherapy. 75.4% (83) of the patients completed the prescribed treatment, with 48% completing it without interruptions, whereas 27% had treatment prolongation due to interruptions. Treatment was not completed in 24.5% of the patients with 20.9% and 3.6% receiving a radiation dose between 30–40 Gy and 40–50 Gy, respectively. Major reasons for incomplete treatment and treatment prolongation are enlisted in the table.
Evaluation at 4–8 weeks after radiotherapy resulted in a CR in 19.1%, PR in 32.7%, SD in 29.1%, and PD in 3.6%, whereas 15.5% of the patients did not report for posttreatment evaluation. The median PFS was 9.52 months (95% confidence interval [CI]: 5.9–13.1 months) [Figure 1]. The median overall survival was 12.7 months (95% CI: 8.2–17.2). The median TTP after completion of radiotherapy was 84 days. Responders (CR/PR) had a longer median PFS (12.3 months) as compared to patients having SD/PD (6.6 months). At the time of analysis, 13.6% of the patients continued to be disease free. Although the median overall survival of patients who received neoadjuvant chemotherapy (NACT) was 12.7 months as compared to 9.5 months for patients who were not exposed to any chemotherapy, it was not statistically significant.
For the majority of the patients, the treatment was uneventful with manageable toxicities. ≥ Grade 3 acute toxicity resulting in protocol violation was on an average reported at 20.7 days and resulted in treatment prolongation in 4.5% (5) of the cases and incomplete treatment in 3.6% (4) of the cases. Grade IV dermatitis and mucositis was encountered in 2.7% and 1.8% of the cases, respectively, requiring hospitalization. 6.4% of the cases reported considerable swallowing difficulty, requiring nasogastric tube insertion for short interval. All patients recovered completely on an average of 5.5 weeks of treatment completion. In 8.2% of the cases, extensive nodal disease made off cord reduction technically not feasible due to nonavailability of conformal radiotherapy techniques at our center, preventing further radiotherapy treatment. Overall, 24.5% (n = 27) of the patients did not complete the treatment, due to self-default (8.2%), logistic inadequacies (8.2%), poor health (4.5%), and toxicity (3.6%). Frequent treatment interruptions on account of patient self-default (12.7%), poor health (5.4%), planned break (4.5%), and toxicity (4.5%) resulted in treatment prolongation in 27.3% (n = 30) of the patients.
Salvage chemotherapy was given to 23.6% of the cases at the time of disease progression.
| > Discussion|| |
In the current study, patients of locally advanced head-and-neck cancer deemed unfit for curative treatment were treated with the “Christie Regimen,” delivering 50 Gy in 16 fractions, 5 days a week over 3.1 weeks. Although there are several other palliative radiotherapy regimens (20 Gy/5 fr, Quad shot, 30 Gy/10 fr) being practiced at our center for past few decades, this study intended to report the outcomes of the recently introduced Christie Regimen for routine treatments in advanced head-and-neck cancer. The overall clinical response rate (CR/PR) in our study was 51.8% with 19% CR and 32.7% PR; 29% had SD and 3.6% had PD. In this study, the median PFS was 9.52 months (95% CI: 5.9–13.1 months), whereas the median overall survival was 12.7 months (95% CI: 8.2–17.2). The median TTP after completion of radiotherapy was 84 days. Responders (CR/PR) had a longer median PFS (12.3 months) as compared to patients having SD/PD (6.6 months).
Aggressive treatments in locally advanced head-and-neck cancers have significant toxicity and result in 5-year survivals rarely beyond 20%, with a median survival of only about 6 months in most studies.,, On the contrary, best supportive care in such cases results in median survival of about 100 days only. The use of hypofractionated radiotherapy regimens to palliate symptoms is practiced based on several large retrospective or small prospective trials.,,,,, Several dose fractionation schedules are in use for palliative treatments in head-and-neck cancer. However, it is quite difficult to draw comparative conclusions because of the heterogeneity of data on stages included, head-and-neck sites treated, dose-fractionation schedules, chemotherapy use, reported outcomes, and toxicities. Shorter regimens often are chosen for symptom relief, whereas attempt to deliver higher doses is aimed at achieving longer tumor control in the irradiated area.
Mohanti et al. in 2004 delivered 20 Gy/5 fr/week (BED 28 Gy10) to palliate patients of Stage IVa (78%) and IV b (22%) and achieved a PR rate of 37% at 1 month after radiotherapy. Thirty percent of these patients received further dose escalation up to 70 Gy, with a modal dose of 42 Gy in 21 fractions. The overall median survival reported was 200 days for the patients who received 20 Gy versus 400 days for patients receiving further dose escalation, indicating the favorable impact of a higher radiation dose.
Delivering a higher BED 50 Gy10, using 40 Gy/16 fractions over 4 weeks, Agarwal et al. achieved 10% CR, 63% PR, 16% SD, and 11% PD. The overall 1-year PFS was 55% (95% CI: 40.3%–69.9%), with the PFS being superior in responders (100%) compared to nonresponders (46.6%). Ghoshal et al. have reported results of two different fractionation schedules. Significant symptom relief with 30 Gy/10 fractions/2 weeks (BED 39 Gy10) was documented in 91% of the patients, whereas using the Quad shot regimen (BED 38 Gy10) >50% objective response was recorded in 86% of the patients.,
Christie Regimen (BED 66 Gy10) as reported by Al-mamgani et al. in 158 patients (81% Stage IV) resulted in 45% CR and a median OS of 17 months at a median follow-up of 16.4 months. The reported results are one of the best outcomes reported for palliative head-and-neck cancer. Compared to Al-mamgani et al., response rates reported in our study are inferior, more akin to the data reported in Indian studies. Possible reasons could be different biology, poor compliance, different spectrum of disease, and logistics.
Treatment noncompliance in radiotherapy has been implicated in inferior outcomes, and head-and-neck cancer radiotherapy treatments have the highest incidence of noncompliance attributed to combined effect of socioeconomic factors, treatment side effects, lack of communication, lack of education, and advanced stage of disease., Since all our patients belonged to the lower socioeconomic class with severe financial constraints and though treatment was offered at no extra cost, the additional cost of staying away from home affected compliance resulting either in treatment interruptions when they went back home to arrange for finances or resulted in incomplete treatments leading to considerable “lost to follow-up” in this study. Compromised nutritional status of these patients severely affected tolerance. Toxicity resulted in prolonged or incomplete treatment in 8% of the patients. The use of 4 fractions per week as used by Al-mamgani et al. in patients with poor general condition and the use of conformal radiation could have increased the compliance and that could have translated into better response rates eventually. Extensive/bulky disease that has not responded to neoadjuvant chemotherapy portends a poor outcome overall. Such patients comprised roughly 50% of the patients in this study compared to 14% for Al-mamgani et al. Nonavailability of conformal treatment technique compromised the total dose that could be delivered in 8.2% cases, further compromising outcomes.
The heavy patient load at our hospitals contributes to significant treatment delays that do affect the overall outcomes. In the current study, the average time to treatment initiation with chemotherapy alone was 5.5 weeks and almost doubled to 10.7 weeks for radiotherapy validating the observation by Fareed and Galloway. This delay for radiotherapy at our center is much larger than the average time of 42 days as reported by Murphy et al. and is reflected in the much inferior outcomes.
In India, where more than two-thirds of the head-and-neck cancer cases present in a locally advanced stage with a significant proportion being inoperable, there is a need to formulate uniform guidelines for the management of these patients while considering the limited resources.
The small number of patients in our study makes it difficult to draw any significant conclusions from a multivariate analysis to help bring out the subset of patients benefiting from this regimen.
| > Conclusion|| |
Locally advanced head-and-neck cancer is a major burden in our country and any delay in treatment along with lack of appropriate facilities makes them unsuitable for any curative treatment, which contributes in significant morbidity/ mortality. Hypofractionated schedules delivered over a short period of time are acceptable high palliation in advanced head-and-neck cancer in resource-constrained countries.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Murthy NS, Chaudhry K, Rath GK. Burden of cancer and projections for 2016, Indian scenario: Gaps in the availability of radiotherapy treatment facilities. Asian Pac J Cancer Prev 2008;9:671-7.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Satija A, Lorenz K, DeNatale M, Spruyt O, Deo SV, Bhatnagar S. Role of early palliative care in advanced head-and-neck cancers patients. Indian J Palliat Care 2019;25:153-5.
] [Full text]
Overgaard J, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E, et al
. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003;362:933-40.
Dobrowsky W, Naudé J. Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers. Radiother Oncol 2000;57:119-24.
Carvalho AL, Salvajoli JV, Kowalski LP. A comparison of radiotherapy or radiochemotherapy with symptomatic treatment alone in patients with advanced head and neck carcinomas. Eur Arch Otorhinolaryngol 2000;257:164-7.
Grau C, Prakash Agarwal J, Jabeen K, Rab Khan A, Abeyakoon S, Hadjieva T, et al
. Radiotherapy with or without mitomycin c in the treatment of locally advanced head and neck cancer: Results of the IAEA multicentre randomised trial. Radiother Oncol 2003;67:17-26.
Al-mamgani A, Tans L, Van rooij PH, Noever I, Baatenburg de jong RJ, Levendag PC. Hypofractionated radiotherapy denoted as the “Christie scheme”: An effective means of palliating patients with head and neck cancers not suitable for curative treatment. Acta Oncol Stockh Swed 2009;48:562-70.
Laursen M, Specht L, Kristensen CA, Gothelf A, Bernsdorf M, Vogelius I, et al
. An extended hypofractionated palliative radiotherapy regimen for head and neck carcinomas. Front Oncol 2018;8:206.
Mohanti BK, Umapathy H, Bahadur S, Thakar A, Pathy S. Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study. Radiother Oncol 2004;71:275-80.
Porceddu SV, Rosser B, Burmeister BH, Jones M, Hickey B, Baumann K, et al
. Hypofractionated radiotherapy for the palliation of advanced head and neck cancer in patients unsuitable for curative treatment – “Hypo Trial”. Radiother Oncol 2007;85:456-62.
Kowalski LP, Carvalho AL. Natural history of untreated head and neck cancer. Eur J Cancer 2000;36:1032-7.
Agarwal JP, Nemade B, Murthy V, Ghosh-Laskar S, Budrukkar A, Gupta T, et al
. Hypofractionated, palliative radiotherapy for advanced head and neck cancer. Radiother Oncol 2008;89:51-6.
Das S, Thomas S, Pal SK, Isiah R, John S. Hypofractionated palliative radiotherapy in locally advanced inoperable head and neck cancer: CMC vellore experience. Indian J Palliat Care 2013;19:93-8.
] [Full text]
Talapatra K, Gupta T, Agarwal JP, Ghosh-Laskar S, Srivastava S, Dinshaw K. Palliative radiotherapy in head and neck cancers: Evidence based review. Indian J Palliat Care 2006;12:44-50. [Full text]
Nguyen NT, Doerwald-Munoz L, Zhang H, Kim DH, Sagar S, Wright JR, et al
. 0-7-21 hypofractionated palliative radiotherapy: An effective treatment for advanced head and neck cancers. Br J Radiol 2015;88:20140646.
Ghoshal S, Patel F, Mudgil N, Bansal M, Sharma S. Palliative radiotherapy in locally advanced head and neck cancer: A prospective trial. Indian J Palliat Care 2004;1;10:19.
Ghoshal S, Chakraborty S, Moudgil N, Kaur M, Patel FD. Quad shot: A short but effective schedule for palliative radiation for head and neck carcinoma. Indian J Palliat Care 2009;15:137-40.
] [Full text]
Gupta S, Rastogi K, Bhatnagar AR, Singh D, Gupta K, Choudhary AS. Compliance to radiotherapy: A tertiary care center experience. Indian J Cancer 2018;55:166-9.
] [Full text]
Rangarajan R, Jayaraman K. Barriers affecting adherence to radiation treatment and strategies to overcome those barriers. Indian J Cancer 2017;54:458-60.
] [Full text]
Fareed MM, Galloway TJ. Time abides long enough for those who make use of it. Cancers Head Neck 2018;3:11.
Murphy CT, Galloway TJ, Handorf EA, Wang L, Mehra R, Flieder DB, et al
. Increasing time to treatment initiation for head and neckcancer: An analysis of the National Cancer Database. Cancer 2015;121:1204-13.
[Table 1], [Table 2], [Table 3]