EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC

CANCERS
Joshua Barrus
RADSCI 4670
December 2, 2020

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EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

Hyperfractionated Accelerated Radiotherapy for T1,2 Glottic Carcinoma

Sakata, K., Someya, M., Hori, M., Nakata, K., Takagi, M. and Hareyama, M., 2008.
Hyperfractionated Accelerated Radiotherapy for T1,2 Glottic Carcinoma. Strahlentherapie und
Onkologie, 184(7), pp.364-369.

Summary

Hyperfractionated Accelerated Radiotherapy for T1,2 Glottic Carcinoma is a quasi-

randomized controlled clinical trial conducted at Sapporo Medical University Hospital

comparing the local control and overall survival rates of conventionally fractionated and

hyperfractionated accelerated radiotherapy for localized, T1 and T2 squamous cell carcinoma of

the glottis. 196 patients were selected between 1984 and 2005 for participation in the study, of

which 131 were diagnosed with T1 N0 M0 squamous cell carcinoma of the glottis and 65 were

diagnosed with T2 N0 M0 squamous cell carcinoma of the glottis based on the UICC staging

system of 1987. Patients selected had an age range of 42 to 91 years with an average of 66 years.

Surviving patients participated in a follow-up at a minimum 12 months and maximum 145

months after the conclusion of treatment, with a median time of 63 months.

All patients in the study received external beam radiation therapy alone with curative

intent using either 60Co γ-rays or 4 MV X-rays. The group receiving conventionally fractionated

radiotherapy consisted of 56 patients treated between 1984 and 1989. These patients were treated

with 5 fractions of 2 Gy per week, delivered once daily to a total dose between 64 and 68 Gy.

Elapsed days for the conventionally fractionated group ranged from 44 to 57 days, of which only

those with elapsed days less than or equal to 53 days were included in the statistical analyses.

The group receiving a hyperfractionated accelerated radiotherapy course consisted of 140

patients treated between 1990 and 2005. This group received twice daily treatment of 1.72 Gy to

a total dose of 55 or 58.5 Gy. The elapsed days for the hyperfractionated accelerated treatment

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EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

group ranged from 22 to 27 days, of which only those patients whose elapsed days were less than

or equal to 24 days were included in the statistical analyses.

The treatment technique for all patients utilized parallel opposed lateral fields with a field

size between 6 × 6 cm and 7 × 7 cm. The dose was normalized at the isocenter and wedge filters

of 30º or 45º were used to achieve a dose inhomogeneity of less than 5% within the PTV for all

patients.

The endpoints used for analysis in this study were local control and overall survival.

Local control was considered only for patients in which local control was achieved through

radiation alone, rather than with additional surgery after treatment. It was found that both local

control and overall survival were significantly improved for T1 glottic tumors receiving

hyperfractionated accelerated radiotherapy compared to those receiving conventionally

fractionated radiotherapy. For T1 tumors treated with a hyperfractionated accelerated course,

local control rates were 94 ± 5.4% for 58.5 Gy and 87 ± 4.3% for 55 Gy total dose. The

conventionally fractionated treatments showed local control rates of 80 ± 7.3%, indicating

significant improvement for the higher dose hyperfractionated accelerated treatment schedule

compared with conventional fractionation. No significant difference was found in local control

of T2 tumors for different fractionation schemes. There was a significant increase in overall

survival for T1 tumors treated with hyperfractionated accelerated fractionation at both higher and

lower total doses compared with conventional fractionation. Patients receiving hyperfractionated

accelerated fractionation showed overall survival rates of 94 ± 5.4% for 58.5 Gy and 68 ± 9.3%

for 55 Gy total dose. Patients receiving conventional fractionation showed overall survival of 80

± 10%, indicating a significant increase in overall survival when using hyperfractionated

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EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

accelerated fractionation. No significant difference in overall survival was found between any of

the three fractionation schemes in patients with T2 tumors.

Assessment

This study is strong due to several measures that contribute to the reliability and validity

of the data, including the use of appropriate, consistent selection and randomization criteria

while reducing outliers that may alter the conclusions of the study. Randomized controlled trials

offer one of the highest levels of evidence in research; however, the study is imperfect in that

there were some practical measures taken that may affect the validity of the results.

One of the strong points of this study is its consistency in both selection criteria and

treatment technique, contributing to the internal validity and reliability of the study. The

participants were limited to patients diagnosed with the same site, TNM stage, and histology,

including only those patients with localized squamous cell carcinoma and with no tumor

involvement outside of the true glottis. Additionally, the staging for most participants was

performed by the same physician, which is another measure to ensure consistency of patient

selection. Despite participants being treated over a long period of time, using the same physician

and the same edition of the UICC staging system throughout the study minimized the effect of

changes in staging procedures and technology may have on the selection and assignment of

patients for the trial. The treatment techniques used were well-defined and largely consistent for

all participants. Every patient was treated with radiotherapy alone using parallel opposed beams,

with some variability in field size and the use of wedges to accommodate for individual patient

anatomy. The prescription point and dose inhomogeneity in the PTV was also standardized for

all treatment plans. This heavy standardization across all participant groups contributes to the

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test-retest reliability and internal consistency for this study. All these factors increase the internal

validity and reliability of the study, strengthening the data and giving legitimacy to the results.

Despite being a generally robust study, there were some factors that were not ideal for the

study that may have had an impact on the results. The study mentioned that patients were treated

using either 60Co γ-rays or 4 MV X-rays but did not specify which patients were treated with

each type of beam. While the prescription dose and dose inhomogeneity standards remain the

same throughout the trial, the energy difference between 60Co γ-rays (1.25 MeV) and 4 MV X-

rays may have an effect on dose distribution outside the PTV and incidence or severity of side

effects. Additionally, the randomization of patients into conventional and accelerated

fractionation groups was determined simply by the time period during which they were treated.

Because participants receiving the accelerated fractionation course were treated as far as 15 years

after the last of the participants who received the conventionally fractionated treatment,

improvements in technology, immobilization, imaging, etc. over those 15 years may lead to

some difference in results between groups.

In radiation therapy, especially when treating the head and neck, it is important to take

into consideration the effects of the treatments we are delivering and how different fractionation

schedules may cause varying problems for patients. While patients may experience side effects

differently depending on their daily dose, they may also experience logistical issues with

receiving twice-daily treatment for approximately 4 weeks. Because the treatments must be

spaced at least 6 hours apart, patients may be unable to come into work during the day or have

issues arranging transportation for both treatments. As healthcare workers who interact with

patients daily, it is important to keep in mind the impact that different treatments may have on

both clinical outcomes and our patients’ personal lives and wellness.

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EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

Results of a multi-institutional, randomized, non-inferiority, phase III trial of accelerated

fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer

Kodaira, T., Kagami, Y., Shibata, T., Shikama, N., Nishimura, Y., Ishikura, S., Nakamura, K.,
Saito, Y., Matsumoto, Y., Teshima, T., Ito, Y., Akimoto, T., Nakata, K., Toshiyasu, T.,
Nakagawa, K., Nagata, Y., Nishimura, T., Uno, T., Kataoka, M., Yorozu, A. and Hiraoka, M.,
2018. Results of a multi-institutional, randomized, non-inferiority, phase III trial of accelerated
fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer:
Japan Clinical Oncology Group Study (JCOG0701). Annals of Oncology, 29(4), pp.992-997.

Summary

Results of a multi-institutional, randomized, non-inferiority, phase III trial of accelerated

fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer is

a randomized, phase III clinical trial assessing the effects of accelerated fractionation (AF) on 3-

year progression-free survival (PFS) in patients with localized T1 and T2 squamous cell

carcinoma of the glottis. 370 patients were treated between 2007 and 2013, of which 184 were

assigned to the SF group and 186 were assigned to the AF group using a biased-coin assignment

to more evenly distribute patients based on T-stage and institution of treatment. Follow-ups with

patients were completed every 6 weeks up to 6 months after the conclusion of treatment,

followed by additional follow-ups every 3 months afterward, to assess for disease recurrence.

The median follow-up period for all participants was 4.8 years.

All patients were treated with photons between 3 and 6 MV using a linear accelerator.

The dose and fractionation were determined by using the biologically effective dose (BED) and

was standardized for each tumor stage and fractionation scheme. Patients in the SF group

received 66 Gy or 70 Gy for T1 and T2 tumors at 2 Gy per fraction, while patients in the AF

group received 60 Gy or 64.8 Gy for T1 and T2 tumors at 2.4 Gy per fraction, respectively. The

CTV’s and PTV expansions were standardized for both T1 and T2 tumors; the CTV for all T1

tumors included the true vocal cords with a 1 cm margin added for T2 tumors. PTV’s included

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EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

the CTV with an additional 0.5 to 1 cm margin. Patients included in the statistical analysis

included those who completed their course of treatment within 51 or 53 (T1/T2) days for the SF

group and within 39 or 43 (T1/T2) days for the AF group.

The primary endpoint examined in this study is the 3-year progression-free survival, for

which this study looked to confirm the non-inferiority of accelerated fractionation compared with

standard fractionation. Secondary endpoints that were considered included overall survival, local

progression-free survival, disease-free survival, survival with preserved voice function, complete

response rate, and acute adverse events. Although the study was not able to establish a

statistically significant difference between standard fractionation and accelerated fractionation

for most of these endpoints, Kodaira et al. did conclude that accelerated fractionation did offer

some clinical advantages without significantly impacting patient outcomes or acute adverse

events. The study was not able to establish a statistically significant difference in 3-year

progression-free survival, overall survival, local progression-free survival, disease-free survival,

survival with preserved voice function, complete response rate, or acute adverse events;

however, the local control rate for the SF and AF groups were 83% and 89.5% at 3 years after

randomization, indicating a significant improvement in local control rate for accelerated

fractionation.

The study referenced several other clinical trials and indicated that for some of the

endpoints in which this study found no significant difference, other studies have found

significant improvements in the use of accelerated fractionation. The study also noted that, while

it was not able to confirm the non-inferiority of accelerated fractionation, AF results in fewer

patient visits, a lower medical staff workload, and decreased medical costs. Based on these

results, it was suggested that accelerated fractionation schedules for early stage glottic tumors

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EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

may be a more practical treatment option with little effect on patient outcomes or acute adverse

effects.

Assessment

This study offers a randomized controlled clinical trial which has several strong

characteristics and some weaknesses that could have been improved. Randomized controlled

trials offer one of the highest levels of evidence in research, and the design of this study

generally improved the reliability and validity of the results.

The randomization process for this study is of particular interest, in that it did not create

an entirely random sample. The method used was a ‘biased-coin’ system, which allows

researchers to intervene in the random assignment of participants to more evenly distribute

participants based on tumor stage and institution at which they were treated. While this may

impact the randomness of the sample, this method is appropriate to ensure that the data for each

group better reflects results based on fractionation scheme rather than tumor stage or treatment

institution. Different institutions may have different equipment, immobilization, personnel, etc.,

so it is appropriate to purposefully redistribute patients to minimize the potential bias that could

be introduced by these factors.

The standardization of patient selection and treatment technique strengthened both the

internal validity and reliability of this study. Only patients with localized squamous cell

carcinoma of the glottis were selected and all patients in each group based on tumor stage and

fractionation schedule were given the same prescribed dose and fractionation schedule. A

relatively large sample size of 370 patients was also used, increasing the power of the sample

and contributing to the internal and external validity of the study. The strict standardization used

in the treatment of each patient also contributes to the external validity and reliability of the

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EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

study, making the study more reproduceable and keeping as many variables consistent between

groups as possible. Because overall treatment time has a significant impact on biological effect

and some patients are subject to missed treatments and extra elapsed days, outliers in overall

treatment time were excluded from the statistical analysis to ensure that the results reflected the

effects of the fractionation scheme under ‘normal’ conditions and bias was not introduced from

unplanned delays in treatment. The exclusion of this data was appropriate because it maintains

the focus of the study on the effects of different fractionation schedules and reduces unwanted

time effects that may influence the data.

One of the main weaknesses of this study is that outcomes and late toxicities were

evaluated a 3-years post-treatment. This is a relatively short period of time for any potential late

toxicities to arise in patients, which may have had an impact on the data. Many of the endpoints

evaluated in this study found no significant differences, and some even found worse results for

accelerated fractionation. The study referenced two other randomized controlled trials for

comparison and noted that the largely inconclusive results of this study did not necessarily agree

with the other studies. Each of these studies used 5-year local control rate, further suggesting that

the shortened follow-up period in this study did not allow enough time for the long-term

endpoints to develop. Outside of clinical outcomes and study design, the readability of the paper

and presentation of data was somewhat poor. Data, both in the text and visual aids, was difficult

to follow at times and a very large number of abbreviations in the text made it a challenge to find

and interpret the relevant data points.

The discussion section in this study acknowledged the largely inconclusive results but did

suggest that there were advantages to using accelerated fractionation for medical facilities and

staff. Lowering medical costs and decreasing patient visits both help improve patients’ lives

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EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

outside of their clinical outcomes. In clinical practice, it is important to consider atypical results

from a study with caution and to further research the short- and long-term effects of treatment

regimens that we deliver to patients. Some of the inconsistencies in the results of this study

compared with other similar studies brings to light the importance of reading critically and

establishing a broad understanding of the effects of different fractionation schemes before

accepting them as the standard of care.

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EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

Conventional fractionation should not be the standard of care for T2 glottic cancer

Dixon, L., Douglas, C., Shaukat, S., Garcez, K., Lee, L., Sykes, A., Thomson, D. and Slevin, N.,
2017. Conventional fractionation should not be the standard of care for T2 glottic
cancer. Radiation Oncology, 12(1).

Summary

Conventional fractionation should not be the standard of care for T2 glottic cancer is an

uncontrolled clinical trial to assess the survival outcomes and local control rates in patients

receiving a hypofractionated accelerated course of radiotherapy for T2 squamous cell carcinomas

of the glottis. 112 patients were treated between 1999 and 2005, of which all were diagnosed

with T2 N0 squamous cell carcinoma of the glottis and treated using the hypofractionated

accelerated fractionation schedule. The participants were further divided into groups of T2a and

T2b cancers for statistical analysis, but all participants received the same total dose and

fractionation. Follow-up with all patients was conducted at a minimum 3 years after treatment,

with a median time of 5.8 years.

All patients in the study were prescribed a total dose of 52.5 Gy in 16 fractions, to be

delivered once daily at 3.28 Gy per fraction. Patients were treated with either anterior oblique

fields or parallel opposed lateral fields for smaller volume and larger volume tumors,

respectively. All patients were treated using comparable field sizes and there was no intentional

treatment of regional lymph nodes. The outcomes for this fractionation schedule were compared

with those of four previous studies establishing the efficacy of the conventional fractionation of

70 Gy in 2 Gy per fraction.

The main endpoints examined were 5-year overall survival, 5-year local control, and 5-

year disease-specific survival. Severe morbidity was also considered as a secondary endpoint

used for comparison. This study found the average 5-year local control rate for the

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hypofractionated treatment schedule to be 82%, which agrees with the results of previous

hypofractionated treatments. Separated by tumor stage, T2a tumors had a 5-year local control

rate of 88.8%, while T2b tumors showed a much lower local control rate of 70.8%. Prior studies

utilizing conventional fractionation reported 5-year local control rates to be between 68% and

75%, indicating an increase in local tumor control for hypofractionated treatments in patients

with stage T2a glottic tumors, but no difference for stage T2b. The 5-year overall survival for the

hypofractionated course was 67% and 5-year disease-specific survival was 90%. This study also

notes that there is no significant difference in late toxicities between the hypofractionated

accelerated treatment and those using conventional fractionation. The rate of severe late effects

for hypofractionated treatments was between 1.1% and 1.8%, while conventionally fractionated

treatments had severe late effect rates between 1.3% and 2.6%. Despite these results, it is

emphasized in the analysis that the toxicity data collected for this study is limited and further

research may be needed to establish a more comprehensive picture of late toxicities in this

fractionation scheme.

The study concluded that, due to the increase in local control rates and little effect on late

toxicities, hypofractionated accelerated treatments should be the standard of care for stage T2

glottic tumors.

Assessment

This is an uncontrolled clinical trial in which a selected group of patients all received the

same dose and fractionation for the same stage and histology of glottic cancer. An uncontrolled

clinical trial offers a lower level of evidence than a randomized controlled trial, but the results

were compared with previous studies that used a conventionally fractionated treatment schedule

as a substitute for the control group.

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EFFECTS OF DOSE AND FRACTIONATION ON EARLY STAGE LOCALIZED GLOTTIC CANCERS

Due to the study design and methods of analysis, the results of this study are somewhat

less robust than a randomized controlled trial. However, many elements of the selection and

study design are valid and still offer a sound foundation for the conclusions of the study. The

sample size of 112 patients is relatively large, especially having only included patients with

localized T2 glottic tumors. This study compensated for its lack of a control group by referencing

the results of four different trials which used conventional fractionation for the treatment of

similar diagnoses. Using the results from multiple ‘substitute control’ groups increases the

accuracy of the data for the conventionally fractionated treatments. Comparing the results of the

hypofractionated treatment scheme with this combined data contributes to the internal validity of

the study. The selection criteria and treatment technique for all patients is specific and narrow,

making it easily reproducible and more reliable.

Despite many strong characteristics, this study also has weaknesses that are worthy of

discussion. One of the larger weaknesses in the data collection is that late toxicities were

evaluated and recorded in a very limited manner. The only late toxicities considered in the

analysis were those that were severe and required surgical intervention. This means that other

late toxicities that occurred below this high severity threshold were excluded. The study made

the conclusion that there was no significant increase in late toxicities for the hypofractionated

treatment schedule, but this result must be taken with caution. While this weakness was

acknowledged in the text, the validity of this specific data point does not seem sufficient to

establish a definitive standard of care. The study did, however reference multiple other clinical

trials which supported their conclusions.

This trial attempted to take steps toward establishing a very high daily dose as the

standard of care for stage T2 glottic cancers. When working to incorporate a fractionation

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schedule like this into clinical practice, it is especially important to communicate with patients

on a daily basis and monitor them for how they are tolerating treatment. Head and neck radiation

treatment often results in severe side effects which must be considered throughout the course of

treatment. In a clinical setting, radiation therapists play a critical role in ensuring that patients

can safely complete their course of treatment.

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References

1. Sakata, K., Someya, M., Hori, M., Nakata, K., Takagi, M. and Hareyama, M., 2008.
Hyperfractionated Accelerated Radiotherapy for T1,2 Glottic
Carcinoma. Strahlentherapie und Onkologie, 184(7), pp.364-369.

2. Kodaira, T., Kagami, Y., Shibata, T., Shikama, N., Nishimura, Y., Ishikura, S.,
Nakamura, K., Saito, Y., Matsumoto, Y., Teshima, T., Ito, Y., Akimoto, T., Nakata, K.,
Toshiyasu, T., Nakagawa, K., Nagata, Y., Nishimura, T., Uno, T., Kataoka, M., Yorozu,
A. and Hiraoka, M., 2018. Results of a multi-institutional, randomized, non-inferiority,
phase III trial of accelerated fractionation versus standard fractionation in radiation
therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group Study
(JCOG0701). Annals of Oncology, 29(4), pp.992-997.

3. Dixon, L., Douglas, C., Shaukat, S., Garcez, K., Lee, L., Sykes, A., Thomson, D. and
Slevin, N., 2017. Conventional fractionation should not be the standard of care for T2
glottic cancer. Radiation Oncology, 12(1).

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Links to References

Study 1: https://pubmed-ncbi-nlm-nih-gov.proxy.lib.ohio-state.edu/19016035/

Study 2: https://pubmed-ncbi-nlm-nih-gov.proxy.lib.ohio-state.edu/29401241/

Study 3: https://pubmed-ncbi-nlm-nih-gov.proxy.lib.ohio-state.edu/29137654/

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