Unconvent ional Fractionation Studies and Tpo t Correlation Hassan K. Awwad

T his article gives a critical analysis of some unconventional fractionation studies conducted

mostly by Egyptian graduate medical students in partial fulfillment for academic degrees. Emphasis is laid on the clinical and radiobiological rationale of these studies with a summary of any available in- terim or long-term end-results. The linear-quadratic (LQ) model is used in assessing the relative efficacy of the various schedules ~-3 in terms of their "biologi- cally effective dose" (BED).~'3 For this, an a/13 ratio of 3 Gy is assumed for late and 10 Gy for early reactions and tumors. A time-factor formalism 4~ is combined in the LQ system in order to account for any loss in the BED due to concurrent tumor repopulation. The parameter c~ is then set at 0.3 Gy -~ and an appropri- ate value for the T~, (see article by Fowler in this issue for definition of terms) is used. A correction for incomplete repair is included in case of multiple fractions per day schedules with short interfraction intervals. 7

A c c e l e r a t e d H y p e r f r a c t i o n a t i o n (AHF) i n P o s t o p e r a t i v e I r r a d i a t i o n

Microscopic tumor cell residues after surgery of locally advanced solid tumors are likely to be fast growing in view of having a small cell number and a better microenvironment, leading to an increased growth fraction and a reduced cell loss. ~ An acceler- ated repopulation process may, therefore, prevail right from the outset without a time lag. The short treatment time in AHF may offset this proliferation process. Furthermore, the small fractions used may have a sparing effect on late-reacting tissues includ- ing those concerned with the healing processes.

From the Radiotherapy Department, National Cancer Institute, Fore El Khalig, Cairo, Egypt.

Address reprint requests to Professor Hassan K. Awwad, MD, Radiother- apy Department, National Cancer Institute, Kasr El Aini St, Fore El Khalig, Cairo, Egypt.

Copyright �9 1992 by W.B. Saunders Company 1053-4296/92/0201-0016505.00/0

AHF in the Postoperative Irradiation of Bladder Cancer

In a randomized study, 9 the efficacy of AHF postoper- ative irradiation in reducing the risk of local recur- rence after cystectomy in T 3 bladder cancer could be confirmed; the 5-year disease-free survival rate was 26% + 6% in the cystectomy alone and 51% +- 6% in the AHF-postoperative radiotherapy group. The AHF schedule involved the use of three fractions per day with a fraction size of 1.25 Gy, an interfraction interval of 3 hours, and a total dose of 37.5 Gy per 30 fractions in 11 days. A third conventional fraction- ation (CF) arm comprising 50 Cry per 25 fractions for 5 weeks was then added. ~~ Late complications were more frequent after CF, particularly dermal fibrosis (AHF: none; CF: 36%), late small bowel reactions including fistula (AHF: 10%; CF: 36%) and late rectal reactions including stenosis (AHF: 6%; CF: 23%). This is consistent with the relative BED values for late reactions; being 83.5 for CF and 53.1 Gy 3 for AHF after correction for incomplete repair during an interfraction interval of 3 hours. This emphasizes the advantage of a small fraction size in sparing late- reacting tissues. Assuming that an accelerated repop- ulation process prevails right from the outset without a time lag and a mean Tw, of 6.7 days, 8 the time- corrected BED ....... would be 42.2 for CF and 38.2 Gyl0 for AHF, ie, the difference between the two schedules regarding tumor response is much less remarkable than that concerning late reactions. This is in accor- dance with an observed overall long-term treatment failure rate of 40% after CF and 45% after AHF. The incidence and severity of acute reactions (mainly diarrhea) did not significantly differ in both groups.

AHF in the Postoperative Irradiation of l.~cally Advanced Head and Neck Cancer

Patients in stage III and IV squamous cell carcinoma of the head and neck who survived radical surgery received postoperative irradiation with randomiza- tion to either CF (50 Gy per 25 fractions for 5 weeks) or AHF (three fractions per day, 1.4 Gy per fraction, 4-hour interfraction interval, and a total dose of 42 Gy per 30 fractions for 11 days). Il The in vitro 3H-thymidine labeling index (TLI) was determined

6 2 Seminars in Radiation Oncology, Vol 2, No 1 (January), 1992:pp 62-66

Unconventional Fractionation Rationales and T~, 63

in representative tumor fragments. The overall 2-year disease-free survival rate amounted to 46% with some, but insignificant, superiority of AHF (54%) over CF (39%). However, if the results are compared according to the TLI, a significantly better survival incidence is noted after AHF in patients with actively proliferating tumors, with the most significant cut-off point at a TLI of I0.4% corresponding to a Tr~ , of 4.5 days (Table 1). Assuming that accelerated repopula- tion prevails throughout radiation treatment with no time lag, a tumor with a T~,o, of 4.5 days would have a time-corrected BED ...... of 42 for CF and 42.2 Gy~0 for AHF, with a tendency for AHF to become progres- sively more effective with further increases in the proliferation rate. This suggests that cell kinetic measurement in head and neck cancer may have the potential of predicting which patient will benefit from accelerated fractionation. ~ The peak of acute mucositis was observed towards the end of the second week of AHF and during the fourth week of CF, and was generally more severe and prolonged after AHF. This is consistent with the concept that the more rapid dose accumulation during AHF may interfere with the mucosal regenerative response.~3 Late tissue reactions were significantly milder after AHF (mainly edema, dermal fibrosis, late wound sloughing, steno- sis, fistula or trismus). This conforms with BED values of 83.5 and 65.9 G% for CF and AHF, respec- tively.

The postoperative irradiation head and neck can- cer trial is still in progress, but the T~,, is currently estimated on the basis of labeling the patient with iododeoxyuridine (IUdR) instead of the in vitro YLI. 12

U n c o n v e n t i o n a l F r a c t i o n a t i o n i n t h e R a d i c a l R a d i o t h e r a p y o f H e a d a n d N e c k C a n c e r

The choice of an optimum overall time depends on both the speed of tumor growth and the intrinsic radiosensitivityY ~'ts Tumors having a low sensitivity

with a fast growth might be better treated with accelerated fractionation. A long overall time might be more optimal in case of slow growth and high sensitivity, u Within the optimum treatment time, it is advantageous to use multiple daily fractions in order to reduce the fraction size and improve the tolerance of late-reacting tissues. ~ Determination of T,,, along with a suitable parameter of intrinsic radiosensitivity may, therefore, help in predicting which patient would benefit from either AHF or hyperfractionation (HF).

Prediction of the Response to AHF or HF According to Tpo t and Intrinsic Tumor Radiosensitivity

Patients with T2 to T4/N0 to N3 head and neck cancer are randomized ~7 to either CF (70 to 72 Gy for 35 to 36 fractions for 7 weeks), AHF (three fractions per day, interfraction interval of 6 hours, 1.6 Gy per fraction, first course 28.8 Gy per 18 fractions for 8 days followed by a gap of 12 to 14 days and a second course of 43.2 Gy per 27 fractions in 11 days) or HF (two fractions per day, 1.15 Gy per fraction, interfrac- tion interval of 6 hours, total dose 80.5 Gy per 70 fractions for 7 weeks). The gap serves to avoid irradiation during the development of the mucosal regenerative response. 18 The AHF and CF schedules are identical with those of the EORTC HF and AHF trials] ~ For late effects, the BED values of CF, HF, and AHF are near to each other; being respectively 116.7, 114, and 111 Gy~. Tro ~ is determined using IUdR labeling.J2 The intrinsic sensitivity is expressed in terms of the surviving fraction after 2 Gy (SF2) using the cell adhesive matrix (CAM) assay) 9 The possibility that knowledge of the two biological param- eters may be more predictive than a single one will be investigated. Subsets of patients with certain growth and sensitivity characteristics appropriate for either AHF or HF may eventually be identified. However, the predictive value of the CAM assay in individual tumors and the influence of cellular heterogeneity have also to be carefully analyzed. ~'2~

Table 1. The Two-Year Disease-Free Survival Incidence in the Conventional Fractionation (CF) and Accelerated Hyperfractionation (AHF) Groups According to the TLI (T~.,,)

Proportion of Disease-Free Survivors

Treatment TLI < 10.4% TLI > 10.4% Total (T~,, > 4.5 day) (Tpo , < 4.5 day)

CF 11/19 (58%) 0/9 (0%) 11/28 (39%) AHF 9/16 (56%) 4/8 (50%) 13/24 (54%) Total 20/35 (57%) 4/17 (24%) 24/52 (46%)

P = .0143 according to the exact Fisher's test (two-tail).

64 Hassan K. Awwad

Substituting a Two-Fraction Per Day AHF Regimen for the 'Strong' Standard CF Regimen in the Radical Radiotherapy of Head and Neck Cancer

The standard regimen comprises 70 Gy per 35 fractions in 7 weeks. 2~ The AHF regimen includes two fractions per day, 1.5 Gy per fraction, an interfrac- tion interval of 8 hours, and a total dose of 63 Gy per 42 fractions in 29 days. The standard regimen is expected to be "hotter" as regards late reactions with a BED of 116.7 Gy~ compared with 94.5 Gy 3 for AHF. Without a time correction, the BED, ...... of the standard and AHF regimens are 84 and 72.5 Gyl0, respectively. However, owing to the longer treatment time of the standard regimen, a greater proportion of the total dose might be wasted to offset repopula- tion. Since the mean T~,o, of head and neck cancer is about 5 days, the optimum treatment time is pre- dicted to be about 4 weeks. H Accordingly, the AHF regimen is expected to achieve about the same tumor control level as the standard regimen, but with a reduced late complication rate. The short treatment time has additional logistic advantages while the use of two fractions instead of three fractions per day is more practical and allows an interfraction interval long enough for the completion of repair. However, the rate of dose accumulation is 15 Gy per week instead of 10 Gy per week. This may account for the observed early appearance of more intense acute mucosal reactions in the AHF group. L3 The observed immediate complete remission rates were 50% and 67% in the AHF and CF groups, respectively. The long-term end-results are still pend- ing.

H y p o f r a c t i o n a t i o n

Hypofractionation has well-recognized clinical and radiobiological shortcomings, principally an in- creased risk of late complications due to large frac- tions] '22 Hypofractionation is, therefore, rarely used with curative intents, but may offer logistic advan- tages in palliation.

Sequential Single-Dose, Half-Body Irradiation (HBI) in Non-Hodgkin's Lymphoma (NHL)

This was applied '23 as a first-line treatment for pa- tients in stage III or IV NHL. A single dose of 6 to 8 Gy was given to the upper HB followed, 4 to 6 weeks later, by 8 Gy to the lower half. A booster dose of 14

to 16 Gy for 7 to 8 days was given 2 to 4 weeks later, to any residual disease or to sites of originally bulky nodes. Radiation-related lung damage was noted in 32% of patients and a dose-rate effect could be shown; an incidence of 12.5% for a dose-rate of 0.10 Gy or less per minute versus 36% for more than 0.10 Gy per minute. Furthermore, 27% of the patients developed biochemical evidence of reversible liver damage 3 to 12 months after therapy. In the light of this high incidence of late complications, the use of sequential HBI in a radical setting should be in the form of a muhifraction, rather than a single-dose, treatment.

Hypofractionation in the Palliation of Inoperable Colorectal Cancer

Patients with locally advanced colorectal cancer 2~ were randomized to either CF (50 Gy per 25 frac- tions for 5 weeks) or hypofractionation (30 Gy for 3 weeks with three doses of 10 Gy each). Ignoring the 1-week difference in the treatment time, both sched- ules would have the same BED (60 Gyl0 ) for acute reactions and tumor response. Eighty-three percent of patients tolerated the acute effects of hypofraction- ation compared with 73% in the CF arm. The remission rate and duration were also similar in both groups. However, the hypofractionation regimen is expected to be "hotter" as regards late effects, with a BED of 130 compared with 83.5 Gy 3 for CF. It may be argued, however, that the life expectancy of such patients is not long enough for the full development of late effects. Therefore, hypofractionation seems to be a more practical substitute for daily fractionation in the palliation of advanced colorectal cancer.

Sequential HBI as a Substitute for Systemic Chemotherapy in Small Cell Lung Cancer

Patients with limited small cell lung cancer, 25 are randomized to one of two arms: Arm/: upper HBI to a dose of 6 Gy (lung-uncorrected) followed after 1 week by locoregional irradiation, 32 Gy per 16 frac- tions for 3.5 weeks and a booster of 10 Gy per 5 fi~actions for 1 week to a reduced volume with spinal cord shielding. This is followed by 8 Gy to the lower HB. Arm I/: three cycles of cyclophosphamide/ adriamycin/vincristine (CAV) followed 3 weeks later by locoregional radiothera W of 36 Gy per 15 frac- tions for 3 weeks, 2.4 Gy per fraction, and three more CAV cycles after a 3-week gap. Four out of 7 patients of arm I developed serious lung damage, with 2 deaths and 2 instances ofcor pulmonale. The upper HBI dose had to be reduced to 5 Gy after correction

Unconventional Fractionation Rationales and Tpo , 6 5

for lung density. Two out of 5 pat ients having the

modified dose developed mild pneumonit is . In view of the high incidence of lung damage from HBI,

when combined with locoregional radiotherapy, it

does not seem to be an appropriate substi tute for

systemic chemotherapy in the m a n a g e m e n t of small cell lung cancer.

AHF After Neoadjuvant Chemotherapy of Carcinoma of the Nasopharynx

The results of neoadjuvant chemotherapy in locally

advanced head and neck cancer are generally not

satisfactory. On e in terpre ta t ion would be an induced

accelerated proliferation of stem-cells as a result of the chemotherapy-induced reduction in cell num- ber. ~ In this study, 27 patients with locally advanced

carcinoma of the nasopharynx are first given two cycles of a combinat ion of cisplatin and 5-FU. Pa-

t ients are then randomized to either CF (65 to 70 Gy

for 6.5 to 7 weeks) or .Ally (three fractions per day,

1.6 Gy per fraction, total dose of 72 Gy per 45

fractions for 5 weeks with a gap of 12 to 14 days after the first 8 days). Radiotherapy is s tarted 1 week after

chemotherapy in order to minimize any interaction.

The study aims at test ing whether a shortened t ime

can offset the influence of any accelerated repopula-

tion process induced by the neoadjuvant chemother- apy or developing dur ing a longer t r ea tmen t time.

Conclusions 1. AHF was shown to offer therapeutic advantages in

postoperative irradiation of bladder and head and

neck cancer where tumor cell residues are ex-

pected to be actively proliferating and where a

reduced fraction size may spare late-reacting tis-

sues concerned with healing.

2. The possibility that cell proliferation measure-

men t coupled with intrinsic radiosensitivity assay may help in predicting which pat ient would ben- efit from either accelerated or hyperfractionation is investigated (see Table I).

3. The use ofhypofract ionat ion is bet ter restricted to

palliative radiotherapy. The use of large radiat ion fractions can lead to serious late complications.

4. The possibility that accelerated fractionation can offset the possible acceleration of cell proliferation

after neoadjuvant chemotherapy is current ly be- ing investigated.

5. The LQ model provides a useful framework for

analyzing the relative merits of fractionation sched-

ules particularly when a t ime factor and correc- tion for incomplete repair are included.

Acknowledgment I would like to express my thanks to all graduate students and their super~4sors for their permission to include their studies in this re,Aew. They include Dr. Iman Foad (Supervisor: Prof. L. Fariss), Dr. Amr El Wishi (Supervisor: Prof. S. EI-Badav, y), Dr. Magdi Saad (Supervisor: Prof. S. El Haddad), Dr. Tarik Shouman (Supervisor: Prof. H. Awwad). My thanks are also due to Dr. M.S. Zaghloul, Prof. S. EI-Haddad, Dr. H. Nayal and Dr. E. EI- Ghoneimi for permission to quote their unpublished data or work in progress.

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66 Hassan K. Awwad

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