hypofractionation reduces the therapeutic ratio in early glottic carcinoma

$: Hypofractionation reduces the therapeutic ratio in early glottic carcinoma$
hr. J. Radiarion Oncology Ho/. Phys.. Vol. 15, pp. 365-372 Printed in the U.S.A. All rights reserved.

0360-3016/88 $3.00 + .OO Copyright 0 1988 Pergamon Press plc

??Original Contribution

HYPOFRACTIONATION REDUCES THE THERAPEUTIC RATIO IN EARLY GLOTTIC CARCINOMA

DIANA HARRISON, MRCP, FRCR,* ELIZABETH CRENNAN, FKACR,? DEBORAH CRUICKSHANK, B.A. (HoNs),$ PETER HUGHES, FRCS, FRCR, FRACRt

AND DAVID BALL, FRACRT

Peter MacCallum Cancer Institute, 48 1 Little Lo&ale St., Melbourne, Victoria, 3000, Australia

From 1969-1985 two types of fractionation schedules with similar time, dose, and fractionation factor (TDF) values were used to treat 197 patients with Tis, Tl, and T2 squamous cell curcinoma of the vocal cord. One hundred and thirty-one patients were treated with conventional daily 2.0 Gy fractions, and 66 patients were treated once per week with large (5.5-6.6 Gy) fractions (hypofractionated group); both groups were treated over a period of approximately 6 weeks. The local failure and complication rates for patients completing treatment in the two groups were compared; a patient was regarded as having suffered a serious complication of treatment if laryngectomy or tracheostomy had to be performed in the absence of active disease, or if antibiotics and/or corticosteroids had to be prescribed for laryngeal oedema and/or necrosis. In patients with Tis and Tl disease, the failure rate was worse in the hypofractionated group than in the conventionally treated group (p = 0.06). In the smaller group of T2 patients, no significant difference was found in the failure rates between the hypo- and conventionally fractionated groups. Complication rates were similar in Tis/Tl and T2 patients, but significantly higher in the hypofractionated group (p < 0.001). Neither stage nor fractionation schedule had an effect on survival, but huyn- gectomy/tracheostomy free survival was significantly worse in Tis/Tl patients receiving hypofractionated treatment, (p = 0.008) although not in T2 patients. These results indicate that in Tis/Tl glottic cancer, hypofractionation of radiotherapy produces a reduction in the therapeutic ratio.

Carcinoma of larynx, Hypofractionation.

INTRODUCI’ION

Fractionation of radiotherapy is well established as a means of improving the therapeutic ratio since it reduces the risk of complications involving late reacting tissues while maintaining acceptable levels of local tumor control. Maximization of the therapeutic ratio becomes crit- ical where the treatment is high dose with curative intent. Unfortunately, protracted fractionation schedules place demands both on patients and on the workload of a busy radiotherapy department. There is, therefore a tempta- tion to reduce the total number of fractions per course of treatment, at the same time increasing the size of dose per fraction. However, in a recent review of the subject, Cox has concluded that, based on the available clinical evidence, hypofractionation is associated with reduced rates of local control and increased rates of delayed morbidity. ’

The radiotherapeutic treatment of early squamous cell

carcinoma (SCC) of the vocal cord is consistently associated with high levels of tumor control and a low incidence of late morbidity.3 Hence early glottic cancer provides an excellent opportunity to assess the efficacy of differing radiotherapeutic techniques and schedules.

At Peter MacCallum Cancer Institute (PMCI) a large number of patients with early (Tis, T 1, T2) glottic cancer have been treated with once a week fractionation, parallel with a group of patients with the same disease who were treated with conventional daily fractionation. We report here an analysis of the results of treatment in the two groups of patients with particular reference to differences in local control and late radiation morbidity between the two groups.

METHODS AND MATERIALS

The records of all patients with carcinoma of the larynx who were referred to the PMCI between 1969 and

* Fellow in Radiation Oncology. t Section of Radiation Oncology. $ Statistician. Reprint requests to: Dr. D. Ball.

Acknowledgements-We would like to thank the Department

365

of Medical Photography, Peter MacCallum Cancer Institute for preparing the illustrations, and Mrs Jenienne Lake for typing the manuscript.

Accepted for publication 2 March 1988.

366 I. J. Radiation Oncology 0 Biology 0 Physics August 1988, Volume 15, Number 2

1985 were reviewed. Patients with biopsy-proven SCC of the vocal cords were restaged according to the laryngo- scopic findings recorded in the patients’ records because the staging of glottic cancer changed during the study period. Only those tumors whose descriptions matched the Tis, T 1 NO and T2NO categories of the UICC staging clas- sification* have been included in the analysis. The study population consisted of a total of 197 patients, 10 (5%) of whom were women: four patients were staged as Tis, 147 as T 1 and 46 as T2. Because of their small numbers, the patients with Tis disease have been grouped with the patients with T 1 disease.

rent use from the commencement of the study period until 1980, only conventional fractionation has been em- ployed since 1980.

Two patients who died of causes unrelated to their cancer before completing the prescribed course of treatment have been excluded from the time to failure, laryngectomy/tracheostomy free survival (LTFS) and morbidity analyses, but have been included in the analysis of survival from commencement of treatment.

All patients were treated supine using a 4 or 6 Mv linac. All patients had simulator films taken and most patients were treated in an immobilization cast. Three of the Tl patients treated once per week and three Tl patients treated 5 days per week were treated through a single lateral field. The remaining patients were treated with either two lateral parallel opposed fields or a pair of ante- rior oblique wedged fields depending on the patient’s anatomy. All fields were treated daily.

Two types of fractionation schedule were used. The majority of patients were treated with daily 2.0 Gy fractions, 5 days per week. A smaller number of patients were treated with large fractions once a week to a total dose with a time dose fractionation (TDF) factor value similar to that of the conventional regime. Table 1 lists the fractionation schedules used and their corresponding TDF values, obtained from the tables of Orton & Ellis.4 During the study period, a number of radiotherapists prescribed treatment for laryngeal cancer. Some pre- ferred to prescribe one fraction per week, and others, five fractions per week. Prescribing practices were not con- sciously influenced by patient factors. Although the weekly and daily fractionation regimens were in concur-

All patients were followed regularly after treatment at PMCI or the referring hospital and the complications of treatment and episodes of recurrence documented. A patient was regarded as having suffered a serious complication of treatment ifi ( 1) antibiotics and/or corticosteroids had to be prescribed for laryngeal oedema and/or necrosis in the absence of recurrent or active disease; and/or (2) surgery (laryngectomy or tracheostomy) had to be performed because of oedema and/or necrosis in the absence of recurrent or active disease. Treatment failure was said to have occurred if the patient developed histo- logically proven recurrence involving the vocal cord or if there was incomplete resolution of disease in spite of treatment.

Some patients appeared to have clinical or histological features of radionecrosis in addition to evidence of recurrent disease. Because it can be difficult to be certain in the presence of recurrent disease whether laryngeal oedema/ necrosis is disease related or treatment related, all of these patients have been regarded as suffering recurrence rather than treatment complications, even though the features suggesting radionecrosis may have preceded his- tologic evidence of recurrence by many months.

Table I. Dose fractionation schedules used in relation to T-Stage

Schedule Number (no of fractions

X dose per fraction) TDF value Tis/Tl T2

Patients treated one day per week 2 x 6.0 Gy 1* - 7 x 5.5 Gy ss 7 x 6.0 Gy 98 3:+ 13 7 x 6.6 Gy 110 12 -

53 13

Patients treated five days per week 21 x 2.0Gy 30 x 2.0 Gy 33 x 2.0 Gy

99 98$ 3dl 108 - 2

98 33

Patient survival and time to failure were calculated from the time of commencement of treatment using the product limit method. Because most patients with recurrent disease or serious morbidity are salvaged by surgery, laryngectomy/tracheostomy-free survival is a more use- ful measure of therapeutic success. LTFS curves were plotted using the product limit method, treating deaths without laryngectomy or tracheostomy as censored. The effect of the two fractionation schedules on the incidence of serious morbidity was also compared using product limit survival analysis, using the dates of commencement of steroids or antibiotics for morbidity or the date of laryngectomy as appropriate, and treating deaths as censored. Differences in survival, LTFS, time to failure and morbidity rates between the different stage and treatment groups were tested using the logrank test.* Mann- Whitney tests’ were used to compare age and field size between groups. Cox regression analysis’ was used to assess the effect of multiple factors on time to failure, LTFS and complication rates.

* Both patients died from non-cancer related causes before completing prescribed course of treatment.

t Includes one patient with Tis disease. $ Includes three patients with Tis disease.

RESULTS

Comparisons were made for all study outcomes between patients treated 5 days per week (conventional

Hypofractionation 0 D. HARRISON et al. 361

fractionation) or 1 day per week (hypofractionation). Analyses of treatment failure rates and LTFS were performed separately for Tl & T2 patients because of the different behaviour of the two groups. Apart from T stage and fractionation regimen, it was anticipated that age and field size may have influenced treatment outcome and multivariate analyses were also performed to take account of these effects. Figures 1 and 2 show the age and field size distributions grouped according to T stage and treatment schedule. Tl patients treated with conventional fractionation (median 63.4 yrs) were significantly younger than the hypofractionated group (median 67.2 yrs) (p = 0.02) and field sizes were significantly larger (p < 0.0001). Although similar differences were seen in patients with T2 disease (median 62.8 and 65.2 yrs re- spectively), they were not statistically significant. Figure 3 shows the survival of the four different stage and treatment groups. There was no significant difference between the groups (p = 0.17).

Figure 4 shows the treatment failure rates according to treatment schedule for Tl and T2 patients who com- pleted the prescribed course of treatment. All treatment failures were clinically diagnosed and had biopsy proven

local recurrence except for one incidental clinically silent local recurrence found at autopsy, and one patient whose disease responded incompletely to treatment. In patients with Tis/T 1 disease, the failure rate in the hypofractionated group was higher than the rate seen in the conventionally treated group (p = 0.06). This difference is some- what masked by an unexpected negative relationship between field size and failure rates. Examination of the effect of age, field size, and fractionation schedule on failure rates was undertaken using Cox regression, which showed that larger field size (24000 mm2) was associated with shorter time to failure (p = 0.06 for change in deviance) and that patients treated with conventional fractionation had significantly longer recurrence-free survival (p = 0.03 for change in deviance, after adjusting for the effect of large field size). Variation in field sizes below 4000 mm2 and age had no significant effect on treatment failure rates.

Two patients who were treated with a lower TDF value (7 X 5.5 Gy, TDF = 85) both developed local recurrence. If only those patients treated with regimes with almost identical TDF values (60 Gy/30 fractions, TDF = 99 vs 42 Gy/7 fractions, TDF = 98) are compared, the differ-

!I I WEEK 98 patimtl

lzl 1 + WEEK 53 patient8

30-39 40-49 50-59 60-69 70-79 60-09 90-99

AGE IN YEARS

50

45

40

35

t- 5

30

- B

25

= 20

15

10

5

0 30-39 40-49 SO-59 60-69 70-79 60-69 90-99

AGE IN YEARS

Fig. I. Age distribution of (a) T 1 patients and (b) T2 patients.

368 I. J. Radiation Oncology 0 Biology ??Physics August 1988, Volume 15, Number 2

1500- woo- 2WO- 3000- 3500- 4w0- 1999 2499 2999 3499 3999 % 4999

FIELD SIZE IN MM2

5 I WEEK 33 patimta

IlEEK 13 petlarks

l50& ?'I mxl yox& 3500- 4o'log 7‘0 5ow+ 3999

FIELD SIZE IN MM2

Fig. 2. Field size (in square millimetres) distribution of (a) T 1 patients and (b) T2 patients.

ence in treatment failure rates still favors the conventionally fractionated group (p = 0.05 for change in deviance in Cox regression, after adjusting for the effect of large field size). Two of the three patients treated weekly with a single lateral field developed recurrence, however, none of the three patients treated daily with the same tech- nique recurred.

In patients with T2 disease, there was no significant difference in local control rates between the daily and weekly fractionation groups, although again larger field sizes were associated with shorter time to failure.

Table 2 lists the serious complications according to stage and treatment group, and includes patients requiring laryngectomy or tracheostomy for necrosis or oe-

-.- Tl 5CwK

- Tl l#wK

T2 SINK

_____-m-T2 i#H

1 p = 0.17 1

o! 1 II I I I I I u II II 11 0 2 4 6 6 10 12 14 YEARS FOLLOWING COMMENCEMENT OF TREATMENT

Fig. 3. Survival of patients from commencement of treatment.

Hypofractionation 0 D. HARRISON et al.

L____..__. E

‘_____,

2 60- !.___________________

2 - 51WEEK 3 98 PATIENTS 2 40-

sl ________ i#"EE,(

52 PATIENTS

g20- 2 ( p = 0.06 I

0 111111111111111 0 2 4 6 6 10 12 14 YEARS FOLLOWING COMMENCEMENT OF TREATMENT

3 40- _--_____

1MEK 13 PATIENTS

iii Y - 5lWEEK B 20- 32 PATIENTS

a ( p = 0.28 1

or I I‘, 1‘,,,,,,,,, 0 2 4 6 6 10 12 14 YEARS FOLLOWING COMMENCEMENT OF TREATMENT

Fig. 4. Failure-free survival of (a) T 1 patients and (b) T2 patients.

369

dema (no evidence of tumor in biopsy or laryngectomy specimen), as well as patients requiring antibiotics and/ or corticosteroids for the same complications. Figure 5 compares the complication-free survival in the two treatment groups for Tl & T2 patients. Complication rates did not differ according to stage, but there was a significantly higher complication rate in the patients treated with weekly fractionation (p < 0.000 1).

It might be reasonably expected that higher TDF val-

Table 2. Complications of treatment

Tl T2

Daily Weekly Daily Weekly Treatment fractions fractions fractions fractions

Steroids/ antibiotics 2 7* 1

Tracheostomy 1 0 :, 0 Laryngectomy 0 3 0 4

Total 3 10 1 5

* Includes one patient scheduled for laryngectomy but who died before surgery.

ues would be associated with a higher likelihood of complications and indeed 3 patients treated weekly with the 7 X 6.6 Gy suffered serious complications (two patients requiring laryngectomy, and the third scheduled for laryngectomy, but dying before surgery).

If only those patients with equivalent TDF are compared, the difference between complication rates is still highly in favor of the conventionally fractionated group (p = .OOOS). Cox regression analysis indicates that the only other factor affecting complication rates is age, with younger patients having a higher likelihood of complications.

Figure 6 compares the LTFS of the patients with T 1 disease treated daily and those treated weekly; there is a significant advantage for those treated daily (p = .008). If only those patients treated with regimes with almost identical TDF values are compared, the LTFS of the conventionally fractionated group is still better (p = .048). Cox regression analysis indicates that larger field sizes were associated with lower rates of LTFS but neither age nor variation in dose above or below 60 Gy (conventionally fractionated group) or 42 Gy (hypofractionated group) dose had a significant effect, after adjustment for treatment schedule and field size.

Figure 7 compares the LTFS of patients with T2 dis-


s g 60-

G - 51nK 8

40- ____---- I#M

S 2 B

( = 0.004 1 p 20-

E E

0 I, I I I‘ I I I I I , I I,, 0 2 4 6 6 10 12 14 16 YEARS FOLLOWING COMMENCEMENT OF TREATMENT

- S#WK ____---- I#wK

( p = 0.002 I

o! I I 1 1 1 I I I

0 2 4 6 6'Ib 1

112 ,

14 YEARS FOLLOWING COMMENCEMENT OF TREATMENT

Fig. 5. Complication-free survival of (a) Tl patients and (b) T2 patients.

ease treated with the two different schedules. There is no significant difference between the groups (p = 0.41), nor were any of the other prognostic factors tested shown to have a significant effect.

DISCUSSION

This retrospective analysis has demonstrated that the use of large weekly fractions in Tis and Tl SCC of the

8 2 40 - 5tHK z s

1

____---- l#nK

i+! 20 ( p = 0.008 1

01 0 2 4 6 6 10 12 14 YEARS FOLLOWING COMMENCEMENT OF TREATMENT

Fig. 6. LTFS of T 1 patients.

Hypofractionation 0 D. HARRISON et al. 371

- 51WK ________ l#nK

l p = 0.41 1

01, I I I I I I I II 11 I I1 0 2 4 6 6 10 12 14 YEARS FOLLOWING COMMENCEMENT OF TREATMENT

Fig. 7. LTFS of T2 patients.

vocal cord is associated with both an increased recurrence rate and an increased complication rate when compared with a similarly staged group of patients treated by conventional daily fractionation, thus supporting Cox’s contention that hypofraction reduces the therapeutic ratio.’ The LTFS of only 69% at 5 years in the hypofractionated group is significantly worse than the 5-year figure of 90% for the conventionally treated group, which in turn is comparable with other published results of the treatment of T 1 glottic cancer.3 The increased incidence of serious complications in patients who received weekly treatment, although this schedule had the same TDF value as the daily regimen, provides further evidence in- validating the general applicability of TDF values as a means of comparing different fractionation schedules in terms of the equivalence or otherwise of their biological effectiveness especially in relation to delayed treatment- related morbidity. Singh has already shown that in the treatment of patients with Stage III carcinoma of the cervix, hypofractionation was associated with a marked in- crease in the incidence of serious delayed morbidity when compared with conventional fractionation, even though the two regimens had identical TDF values.6 In that study, tumor response rates and the incidence of acute reactions appeared however to be similar for both groups of patients. In our patients with Tis/T 1 disease, it was our impression that those treated with hypofractionation suffered less severe acute mucosal reactions than those patients treated daily, but this was difficult to docu- ment quantitatively from a review of the patients’ records. It appeared that there was a dissociation between the acute and late reactions in the hypofractionated group, as predicted by Thames et al.’

We have almost certainly underestimated the true incidence of serious late radiation morbidity because in a number of patients there were features suggesting the co- existence of radiation injury and recurrent disease, and in some instances the evidence of radiation injury preceded the biopsy proof of recurrence by many months.

Because we could not be certain that in these cases un- derlying recurrent disease was not the cause of the oedema and necrosis, all of these patients were classified as treatment failures, and not as instances of treatment morbidity.

The increased treatment failure rate in patients treated weekly was entirely caused by number of late recur- rences, between 2 and 5 years after irradiation. Why hypofractionation predisposed to an increased rate of late recurrence is unclear.

In our analysis, we examined the effect of field size on treatment failure rates because patients with T 1 disease treated daily were treated with significantly larger fields than were used for patients in the hypofractionated group. It was possible that the lower failure rate in the conventionally treated groups might therefore have been a result of more adequate treatment volumes (and corre- spondingly reduced risk of geographic miss), and not a result of treatment schedule. However, we were surprised to find that larger field sizes were associated with an increased rate of recurrence, an observation we are unable to explain by association with known prognostic factors. This relationship between field size and treatment failure in T 1 patients means that after allowance has been made for field size, the association between hypofractionation and increased failure rate is even more marked than if the effect of field size had been ignored altogether.

We also considered the older age of the hypofractionated group as a possible explanation of their poorer outcome. However our analysis showed that age itself had no significant effect on LTFS or treatment failure rates. The inverse relationship between age and complication rates certainly does not explain the poorer outcome of the older hypofractionated group.

In our patients with T2 disease, there were no significant differences in the local control rates between the patients treated daily and those treated weekly, but there was a significantly higher incidence of late complications in the hypofractionated group. It is possible that small


patient numbers may be responsible for the inability to detect differences in failure rates and LTFS. With the given number of patients, the power of detecting a two- fold difference in the medians (or hazard rates) is in the order of only 20%.

years. At PMCI T2 lesions are now treated with generally higher doses than would be used for T 1 disease.

Nevertheless the conventionally fractionated T2 group had a particularly poor local control rate and a LTFS of only 48% (s.e. = 11%) at 5 years, which does not compare favorably with the local control rates of approximately 70% reported from a number of centers.3 This difference may be due to chance, but may be related to the relatively low doses used at PMCI during the study period, and the possibility that the staging of T2 glottic cancer has not been consistently uniform over the last 30

During the period that hypofractionation was in use at PMCI, the convenience to patients, the reduced machine workload, and the lack of severe acute mucositis were all attractive features of weekly treatment, however when it became apparent that long term results of treatment were significantly inferior to those obtainable with conventional fractionation, its use was abandoned. As a result of our experience, we would counsel against the use of hypofractionation not only in the radical treatment of head and neck cancer, but also in the treatment of other sites where there are prospects of cure and long term survival.

REFERENCES

Cox, J.D.: Large dose fractionation. Cancer 55: 2105- 2111,198s.

5.

Dixon, W.J. (Ed): BMDP Statistical Software. Berkeley, University of California Press, 1985.

Hendrickson, F.R.: Radiation therapy treatment of larynx cancers. Cancer 55: 2058-206 1, 1985.

Orton, C.G., Ellis, F.: A simplication of the use of the NSD concept in practical radiotherapy. Brit. J. Radiol. 46: 529- 537,1973.

Siegel, S.: Non Parametric Statistics for the Behavioural Sciences. Tokyo, McGraw Hill, 1956. Singh, K.: Two regimes with the same TDF but differing morbidity used in the treatment of stage III carcinoma of the cervix. Brit. J. Radiol. 51: 357-362, 1978. Thames, H.D., Withers, H.R., Peters, L.J., Fletcher, G.H.: Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relation- ships. Int. J. Radiat. Oncol. Biol. Phys. 8: 2 19-226, 1982. U.I.C.C.: TNM Classijication of Malignant Turnours, 3rd edition. Geneva, U.I.C.C., 1978.

hypofractionation reduces the therapeutic ratio in early glottic carcinoma

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