Unscheduled treatment gaps in head and neck cancer radiotherapy

Deep Chakrabarti; Mranalini Verma; Abigail Veravolu Resu; Divya Kukreja; Madan Lal Brahma Bhatt

doi:10.4103/bjoc.bjoc_5_23

ORIGINAL ARTICLE

Year : 2022 | Volume : 2 | Issue : 1 | Page : 25-30

Unscheduled treatment gaps in head and neck cancer radiotherapy

Deep Chakrabarti¹, Mranalini Verma¹, Abigail Veravolu Resu², Divya Kukreja¹, Madan Lal Brahma Bhatt¹
¹ Department of Radiotherapy, King George’s Medical University, Lucknow, India
² Department of Radiation Oncology, Super Speciality Cancer Institute & Hospital, Lucknow, Uttar Pradesh, India

Date of Submission	28-Jan-2023
Date of Decision	07-Feb-2023
Date of Acceptance	15-Feb-2023
Date of Web Publication	31-Mar-2023

Correspondence Address:
Deep Chakrabarti
Department of Radiotherapy, King George’s Medical University, Lucknow 226003, Uttar Pradesh
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bjoc.bjoc_5_23

Abstract

Unscheduled treatment gaps are a recurring problem faced by radiotherapy units worldwide. During the times of a global emergency like the coronavirus pandemic, the problem was further potentiated. This article describes the treatment breaks experienced by our radiotherapy unit during the initial nine months of the pandemic in a tertiary-care academic university hospital. Head and neck cancers are a priority for radiation oncologists and gaps in treatment lead to reduced local control. Sound knowledge of tumor repopulation and timely corrections using the biologically effective dose are essential to mitigate such effects.

Keywords: Accelerated repopulation, biologically effective dose, clinical oncology, head and neck cancer, head and neck squamous cell carcinoma, novel coronavirus, radiobiology, radiotherapy, repopulation, SARS-CoV-2, unscheduled gaps

How to cite this article:
Chakrabarti D, Verma M, Resu AV, Kukreja D, Bhatt ML. Unscheduled treatment gaps in head and neck cancer radiotherapy. Bengal J Cancer 2022;2:25-30

How to cite this URL:
Chakrabarti D, Verma M, Resu AV, Kukreja D, Bhatt ML. Unscheduled treatment gaps in head and neck cancer radiotherapy. Bengal J Cancer [serial online] 2022 [cited 2023 Jun 7];2:25-30. Available from: http://www.bengaljcancer.org/text.asp?2022/2/1/25/373315

Background

The novel coronavirus pandemic continued to wreak havoc on health-care systems worldwide for the best part of more than two years whereby cancer care was delivered based on individualization, prioritization, and multidisciplinary team decisions.^[1] Unscheduled breaks during radiotherapy treatment correlate with poor local control owing to accelerated repopulation.^[2],[3],[4] For those patients in developing nations, the threat of the coronavirus was compounded by inequalities in social and economic factors that entails that a large proportion of patients are at risk of delayed or missed treatments.^[5] Government-enforced lockdown and curfews in a background of the unavailability of accommodation and personal transport, and the need to travel large distances to obtain cancer care, represented unique challenges. In the past two years, we have seen a sharp spike in the incidence of unscheduled treatment breaks in our radiotherapy unit. In this article, we describe the experience of unscheduled treatment breaks in a series of five patient scenarios of head and neck squamous cell cancers (HNSCC) and possible means to compensate for the delay [Table 1].

Table 1: Table showing characteristics of patients with unscheduled treatment breaks

Click here to view

Materials and Methods

This report deals with a series of five scenarios causing treatment disruptions of patients with HNSCC of various subsites, treated with definitive or palliative intent at a tertiary-care academic university facility between April 2020 and December 2020. All the patients were treated using an Elekta Synergy® linear accelerator system following standard dose recommendations^{[6],[7],[8],[9]} and usual constraints to the organs at risk.^[10] All patients had unscheduled gaps during treatment due to logistical issues. The issue of unplanned treatment gaps is being analyzed with the evidence of the biologically effective dose (BED) and tumor repopulation.

The BED represents the biological effect of the prescribed dose of radiotherapy. It is used to quantify the biological effect of radiotherapy based on the linear-quadratic model.^[11] This is represented by

where N is the number of well-spaced fractions and d is the dose prescribed per fraction. The generic tumor α/β value is usually taken to be 10 Gy for HNSCC and 3 Gy for most normal tissues, except the spinal cord, for which a value of 2 Gy is generally appropriate. While these nominal values are useful for the calculation of BED, in reality α/β ratio is not one single value but a range of values. To account for the loss of biological effect of radiation due to tumor repopulation, the formula is slightly modified as in^[12],[13]

K × (T − T_delay) is the tumor repopulation factor, where T represents the overall treatment time and T_delay is the time from the onset of treatment at which accelerated repopulation is presumed to begin. This has an average value of 21–28 days. K is the daily BED-equivalent (Gy·day⁻¹) of repopulation and is taken as 0.9 Gy·day⁻¹ for this report, as recommended by the Royal College of Radiologists, United Kingdom (RCR).^[13] The estimates for tumor BED₁₀, normal tissue BED₃, α/β ratio, overall treatment time, and time for accelerated repopulation are also in accordance with the recommendations of the RCR. BED calculations are approximated up to one place of decimal, while radiotherapy fraction sizes are approximated up to two places of decimals, as per convention.

Results

Between April and December 2020, out of 63 treated head and neck cancer patients treated by radiotherapy (24—definitive intent, 24—postoperative adjuvant, and 15—palliative intent), 12 patients (19%) had their planned treatment scheduled extended beyond 2 days. The following five scenarios causing delays were seen. The following serve as illustrative examples.

Patient 1

Patient 1 was a healthy 57-year-old gentleman with a cT3N2a tumor of the hypopharynx extending to the supraglottic larynx with hemilarynx fixation and had been planned for definitive chemoradiotherapy to a dose of 70 Gy in 35 fr. over 46 days with an effective tumor BED₁₀ of

and a normal tissue BED₃ of

After receiving 20 fr. of treatment, he defaulted for 3 weeks. So for the time that he defaulted, his treatment should have been completed. Any compensation that will be planned for such a patient will involve a prolongation of the initial planned treatment time and will lead to a loss of tumor BED₁₀ or an undue increase of normal tissue BED₃.

Option 1

Twice daily fractions from Monday to Saturday beginning on week 8, no treatment on Sunday, then in week 9, 2 fr. on Monday and one fraction on Tuesday.

Option 2

Daily fractions from Monday to Saturday in week 8 and week 9, no treatment on Sundays, then 3 fr. in week 10 from Monday to Wednesday.

Option 3

Daily fractions from Monday to Friday in weeks 8, 9, and 10, no treatment on Saturdays and Sundays.

Option 4

Keep tumor BED₁₀ equal, change fraction size, treat on weeks 8 and 9 from Monday to Friday, no treatment on Saturdays and Sundays.

Option 5

Use an intermediate fraction size as compared to Option 4 to balance between an increase in normal tissue BED₃ and a decrease in tumor BED₁₀, treat on weeks 8 and 9 from Monday to Friday, no treatment on Saturdays and Sundays.

As is evident in [Table 1], a plan to give bi-daily fractions from Monday to Saturday or daily fraction over Monday to Saturday leads to a decrease in the effective tumor BED₁₀. To compensate, one may consider changing the fraction size to keep the effective tumor BED₁₀ to that originally intended. To do this, we may use a modified equation:

Solving the quadratic equation for d yields a value of d = 3.58 Gy. Plugging the value of d in yields a normal tissue BED₃ of 145 Gy, which is about 25% higher than the planned initial BED₃. To consider the equivalent in terms of 2-Gy fraction size,

which gives a total 2-Gy equivalent dose of 86 Gy in 43 fr. and would invariably lead to increased normal tissue complications. An intermediate dose per fraction of d = 2.75 Gy yields a normal tissue BED₃ of

which is nearly similar to planned initial BED₃. However, the effective tumor BED₁₀, in this case, would be

a 20% reduction to the planned initial tumor BED₁₀. Thus, given the circumstances, the most efficient method to compensate would be to give two daily fractions of 2 Gy from Monday to Saturday, since this translates to the lowest decrease in tumor BED₁₀ among the different compensations, with a similar normal tissue BED₃. This ensures that the therapeutic ratio, although affected adversely, is less reduced as compared to the other options. However, one must be wary that twice-daily fractions from Monday to Saturday leave very little time for normal tissue repair and care should be taken to ensure adequate spacing between daily fractions. Sublethal damage repair requires at least a 6-h interfraction gap, while the spinal cord typically has a slower recovery and requires a minimum of eight hours.^[12],[14] In clinical practice, bi-daily fractions are not recommended daily or on consecutive days due to an increased risk of incurring toxicities for late reacting normal tissues like the spinal cord. They should be well spaced out over the remaining or available treatment time. The best compensation balances a decrease in tumor BED₁₀ and an increase of the risk of normal tissue toxicities.

Outcome

This gentleman is on regular follow-up without any sign of disease.

Patient 2

Patient 2 was a 32-year-old gentleman who had a pT3N1 carcinoma of the right buccal mucosa postsurgery and had been planned for a tumor dose of 60 Gy in 30 fr. over 39 days with a tumor BED₁₀ of

and a normal tissue BED₃ of

The patient defaulted in the last week of treatment after having received 50 Gy in 25 fr. over 32 days, only to report 3 weeks later.

Option 1

Do not restart radiotherapy further and keep the patient on follow-up.

Option 2

Daily fractions from Monday to Friday in week 9.

Planning to restart radiotherapy in this patient and completing the remaining fractions over 1 week leads to an effective tumor BED₁₀ that is nearly two-thirds of the planned original [Table 1].

However, if it is assumed that the patient will receive no further radiotherapy, then as per the dose already received,

This translates to a 9% lower effective tumor dose with a reduced normal tissue dose.

Thus, in this situation, comparing BED₁₀ after 60 days (by restarting treatment) with BED₁₀ after 32 days (withholding further radiotherapy) clearly shows that the latter option represents the best compensation.

Outcome

This gentleman is on regular follow-up without any sign of disease.

Patient 3

Patient 3 was a 53-year-old gentleman with carcinoma of the left lower alveolus (pT2N1) who had been operated and planned for a dose of 60 Gy in 30 fr. over 39 days and an effective tumor BED₁₀ of

After receiving 15 fr. of radiotherapy, the patient had defaulted for 1 week.

Option 1

Daily fractions from Monday to Saturday in week 5, no treatment on Sunday, then daily fractions from Monday to Friday in week 6, give an additional well-spaced fraction (bi-daily fraction) on four out of these days after treatment restart (e.g., Monday and Thursday of weeks 5 and 6).

Option 2

Daily fractions from Monday to Friday in weeks 5, 6, and 7, no treatment on Saturdays and Sundays.

Option 3

Twice daily fractions with hyperfractionation from Monday to Friday in weeks 5 and 6, no treatment on Saturdays and Sundays.

In this patient, the actual time remaining on our hands to complete treatment in order to maintain the overall treatment time is around 2 weeks. In order to deliver 15 fr. in that time span, the best compensation is to treat the patient for 6 days including Saturday for the first week and till Friday on the last week (11 fr.), giving bi-daily fractions for four of these days (4 fr.). This ensures a maintained effective tumor BED₁₀ without an adverse increase in normal tissue BED₃.

For the sake of a theoretical discussion, it is worthwhile to consider two more scenarios. If we were to give the remaining 15 fr. in terms of daily fractions (5 days a week), the overall treatment time is prolonged by 5 days, and the effective tumor BED₁₀ becomes

a reduction of 7% in the planned initial BED₁₀. The other option is hyperfractionation with bi-daily fractions. Assuming a fraction size of 1.5 Gy given twice daily maintaining the original planned treatment time and using , where N is now the required number of fractions of hyperfractionated radiotherapy,

Solving for N gives us a value of N = 21. Approximating this to 20 fr. for the sake of convenience of giving twice-daily doses from Monday to Friday to keep the overall treatment time intact yields a tumor BED₁₀ of

and a normal tissue BED₃ of

Considering that the spinal cord is an organ at risk, hyperfractionation may reflect a judicious choice. This spares late reacting normal tissues (like the spinal cord) which are dependent on the prescribed dose per fraction rather than the total dose. To illustrate this and to calculate the BED₂ of the spinal cord, the expected normal BED₂ of the cord derived from by substituting an α/β value of 2 gives us

For the option of hyperfractionation, 15 fr. of radiotherapy had already been given at 2 Gy per fraction and a remaining 20 fr. planned at a fraction size of 1.5 Gy would result in a spinal cord BED₂ of

a reduction in the BED₂ that may be particularly important because of bi-daily fractions and the fact that the spinal cord recovery takes a minimum of 8 h. Therefore, like in example 1, whenever twice-daily fractions are chosen, they should be well spaced.

Outcome

This gentleman was treated on weekends and including bi-daily fractions is on regular follow-up without any sign of disease.

Patient 4

Patient 4, a 40-year-old gentleman, had a cT2N1 tumor of the supraglottic larynx and had been planned for concurrent chemoradiotherapy to a dose of 70 Gy in 35 fr. After receiving the first fraction of radiotherapy, the patient had informed of his inability to continue treatment at this time due to logistical reasons.

Option

Induction chemotherapy

Considering the evidence of induction chemotherapy,^[15],[16] he was started on chemotherapy with the aim of 2–3 cycles followed by reassessment and replanning with definitive intent to the same dose.

Outcome

This gentleman underwent two cycles of induction chemotherapy with a carboplatin–paclitaxel doublet given every 3 weeks, followed by radiotherapy to a dose of 70 Gy in 35 fr. over 7 weeks.

Patient 5

Patient 5 was a 65-year-old frail gentleman with a cT4aN3b tumor of the dorsum of the tongue and had been planned for palliative radiotherapy to a dose of 20 Gy in 5 fr. He defaulted after receiving 2 fr. of treatment.

Option

Palliative chemotherapy or best supportive care

It was decided to stop his treatment and consider him for palliative chemotherapy or best supportive care keeping in mind his performance status.

Outcome

This gentleman was started on weekly injection of methotrexate. He progressed after 4 months and succumbed to his disease after 8 months.

Discussion

Employing these examples, we have revisited the concept of the BED and how little tweaks in its calculation hold the key to deal with the delays that may be brought about by a global emergency. Definitive curative treatments for HNSCC represent a high priority based on the magnitude of clinical benefit of treatment, and there are definite risks posed by delays and waiting in the form of unscheduled gaps.^{[17],[18],[19],[20]} The loss of local control can be as high as 1.4% per day^[21] owing to accelerated repopulation, which is reflected by the daily BED equivalent of radiation (K). While the value of K taken as 0.9 in this report^[2],[13] is somewhat higher than the value reported elsewhere which are in the range of 0.6–0.7 Gy,^[21] this only means that the possible deficits in BED in our report are aggressive estimates and the situation in practice will be similar or better. The methods of compensation should always aim to preserve the overall treatment time, by way of treating on weekends, increasing dose per fraction, or treating with bi-daily fractions with enough gap to allow repair of normal tissues [Figure 1].

Figure 1: Methods of compensation for treatment breaks, adapted from Ref.^[2]

Click here to view

Adaptive replanning for treatment delays can help to attain better dosimetric results and improve the therapeutic ratio.^[22],[23] Judicious planning of radiotherapy and cooperation of departmental colleagues including clinicians, physicists, and technicians with regular surveillance can aid in radiobiologically and clinically significant improvements in outcomes.^[24] We cannot reiterate it enough that bi-daily fractions are not recommended on consecutive days due to an increased risk to late reacting normal tissues like the spinal cord, and whenever possible, should be well-spaced out during the remaining treatment days. In conclusion, the best method for gap compensation for unscheduled treatment breaks is not straightforward and will often aim to strike a balance between a reduced tumor BED and an increased risk of late toxicities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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