Int. J. Radiation Oncology Biol. Phys.. Vol. 32. No. 5, pp. 1275 1288. 199s Copyright 0 199.5 Elrevier Science Ltd Printed in the USA. All rights reserved

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l Clinical Original Contribution

CARCINOMA OF THE UTERINE CERVIX. I. IMPACT OF PROLONGATION OF OVERALL TREATMENT TIME AND TIMING OF BRACHYTHERAPY ON

OUTCOME OF RADIATION THERAPY

CARLOS A. PEREZ, M.D., PERRY W. GRIGSBY, M.D., HERNAN CASTRO-VITA, M.D. AND MARY ANN Loam-r, M.B.A.

Radiation Oncology Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO

Purpose: Some studies have described decreased pelvic tumor control and survival rates in invasive carci- noma of uterine cervix when the overall thue in a course of definitive irradiation is prolonged. We attempt to confirm or deny these observations and evaluate the impact of timing of brachytherapy on outcome. We also explore the hypothesis that more extensive tumors technically require prolongation of the course of irradiation; thus, decreased tumor control and survival in these patients may not necessarily be the result of time/dose factor. Methods and Materials: Records of 1224 patients (Stage IB to III) treated with definitive irradiation (combination of external beam and two intracavitary insertions to deliver doses of 70 to 90 Gy to point A) were reviewed. Follow-up was obtained in 97% of the patients (median, 12 years; minimum, 3 years; maximum, 28 years). The relationship between outcome and overall treatment time and time of intracavi- tat-y insertions was analyzed in each stage and according to tumor size/extent. Results: There was strong correlation between overall treatment time (OTT) and tumor stage ( 17 weeks: 81% for Stage IB; 74% for Stage IIA; 52% for Stage IIB; and 47% for Stage III). Interruptions of therapy accounting for prolongation of treatment time occurred in 25-30% of patients, most frequently because of holidays and weekends and side effects of therapy. Overall treatment time had a major impact on pelvic tumor control in Stages IR, IIA, and IIB; in Stage IB lo-year actuarial pelvic failure rates were 7% with O’IT 17 weeks, 22% with 7.1 to 9 weeks, and 36% with >9 weeks (p s 0.01). For Stage IIA the correspond- ing values were 14%, 27%, and 36% (p = O-OS), and in Stage IIR pelvic failure rates were 20%, 28%, and 34%, respectively @ = 0.09). In Stage III, pelvic failure was 30%, 40%, and 50%, respectively @ = 0.08). There was aiso a strong correlation between OTT and lo-year cause-specific survival (CSS) ; in Stage IB rates were 86% with OTT of 57 weeks, 78% for 7.1 to 9 weeks, and 55% for ~9 weeks @ < 0.01). The corresponding rates in Stage IL4 were 73%, 41%, and 48% (p 5 0.01). For patients with Stage IIR, CSS rates were 72% for OTT 57 weeks, 60% for 7.1 to 9 weeks, and 70% for >9 weeks (p = 0.01). Patients with Stage III disease had 45% IO-year CSS when treatment was delivered in 9 weeks or less and 36% for longer overall times (p = 0.16). In multivariate analysis of patients with Stage IB and IIA, OTT and clinical stage were the most important prognostic factors for pelvic tumor control, disease-free survival, and CSS. Tumor size was a prognostic factor for CSS. In Stages IIR and III, OTT, clinical stage, unilateral or bilateral parametriai invasion, and dose to point A were siguilicant prognostic factors for pelvic tumor control, disease-free survival, and CSS. Prolongation of time had a significant impact on pelvic tumor control and CSS regardless of tumor size, except in Stage IR tumors s3 cm. Regression analysis confirms previous reports that prolongation of OTT results in decreased pelvic tumor control rate of 0.85% per day for all patients, 037% per day in Stages IR and IIA, O&3% per day in Stage IIB, and 0.54% for Stage III patients treated with 285 Gy to point A. Performance of ail intracavitary insertions within 4.5 weeks from initiation of irradiation yielded decreased pelvic failure rates in some groups of patients (8.8 vs. 18% in Stage II? and IIA tumors 54 cm and 12.3 vs. 35% in Stage IIR) (p 5 0.01). Conclusions: Prolongation of treatment time in patients with Stage II!, IIA, IIR, and III carcinoma of the uterine cervix has a significant impact on pelvic tumor control and CSS. The effect of OTT was present regardless of tumor size except in Stage IR tumors 53 cm. This may be related to biologic factors such as

Presented at the 36th Annual Meeting of the American Soci- Acknowledgement-The authors are deeply indebted to John ety for Therapeutic Radiology and Oncology, 2-6 October, 1994, San Francisco, CA.

F. Fowler, Ph.D., D.Sc., for his incisive and contructive critique of this manuscript.

Reprint requests to: Carlos A. Perez, M.D., Radiation Oncol- ogy Center, Suite 200,45 11 Forest Park, St. Louis, MO 63108. E-mail: perez@roc.wustl.edu.

Accepted for publication 8 May 1995.

1275

1276 1. J. Radiation Oncology 0 Biology 0 Physics Volume 32, Number 5, 1995

cell repopulation and increased proliferation resulting from treatment interruptions, in addition to initial clonogenic cell burden. Irradiation for patients with invasive carcinoma of the cervix should be delivered in the shortest possible overall time.

Carcinoma of uterine cervix, Radiation therapy, Tumor control, Survival, Outcome.

INTRODUCTION

Definitive radiation therapy alone has been established as effective treatment in patients with carcinoma of the uter- ine cervix. Tumor control and survival in Stages I and IIA are comparable when patients are adequately treated with either definitive irradiation or radical surgery ( 10, 16). Several authors have described worse outcome with prolongation of overall treatment time in patients treated with radiation therapy (14, 15, 18, 20). We further ex- plore this relationship and, in addition, correlate impact of treatment time with size of tumor and timing of intra- cavitary insertions.

METHODS AND MATERIALS

The records of 1224 patients with histologically proven Stage IB, IIA, IIB, and III carcinoma of the uterine cervix treated with definitive irradiation alone at the Mallinck- rodt Institute of Radiology, Barnes Hospital, Washington University School of Medicine, between January 1959 and December 1989, were reviewed, and preexisting com- puter files were updated. More than 90% of the tumors were epidermoid carcinoma, approximately 7% were ade- nocarcinoma, 2% were adenosquamous carcinoma, and less than 1% were other histologic types. Excluded from the analysis was a group of 45 patients with Stage III disease treated before 1965 in fewer than 28 days with lower doses, sometimes for palliation. Patients with carci- noma of the cervical stump were also excluded. Fifty-one patients with Stage IIB disease, on whom an extraperito- neal pelvic lymphadenectomy was performed before 1967 in a study assessing the effect of irradiation on the pelvic lymph nodes, were included in this study. Patients with involved periaortic lymph nodes were assigned to the respective clinical stage disregarding periaortic lymph node metastases and were treated in a manner similar to the others, except for irradiation to the periaortic lymph nodes (approximately 50 Gy tumor dose, 1.8 Gy daily, in 5 to 6 weeks).

Patients were initially evaluated with physical and pel- vic examinations, routine blood count, chemistry profile, chest radiograph, and intravenous pyelogram. Lymphan- giograms were performed in patients with bulky Stage IB and IIA disease and in most patients with Stage IIB dis- ease until 1984, when computed tomography was increas- ingly used. Barium enema was routinely performed in patients with Stage IIB and III disease and in those with Stage IB and IIA disease who had lower intestinal symp- toms. Multiple punch biopsies of the cervix were obtained for all patients, and dilatation and curettage was fre- quently performed at the time of first implant. Patients

were jointly staged by the radiation oncology and gyneco- logic oncology staffs according to the International Feder- ation of Gynecology and Obstetrics (FIGO) classification ( 19) with modifications (3). When there was a disagree- ment, the patient was assigned to the less-advanced stage.

Cases were followed up periodically by the radiation and gynecologic oncology staffs for at least 3 years or until death. Median follow-up in surviving patients was 12 years (minimum, 3 years; maximum, 28 years). Infor- mation was available for 97% of patients from institu- tional records, from letter or telephone contact with refer- ring physicians, and occasionally through direct commu- nication with the patient or relatives. Cases lost to follow- up were censored at that time from the risk groups and considered dead with tumor.

Overall treatment time (in days and weeks) was di- vided into three specific periods: 7 weeks or less (the time in which the usual course of therapy is administered, including external beam and two intracavitary insertions); 7.1 to 9 weeks; and longer than 9 weeks were arbitrarily chosen.

Pelvic recurrences were detected by pelvic examination (evidence of cervix/vaginal recurrence or persistent or progressive parametrial induration) and, whenever possi- ble, punch or needle biopsies. The presence of posttreat- ment hydronephrosis, leg edema, or sciatic pain was the basis for clinical classification of a pelvic recurrence.

Recurrences were classified as cervical (local), mar- ginal (in the vagina), or parametrial; all three were cate- gorized as pelvic failures. Distant metastases were those occurring outside the pelvis.

Irradiation techniques and doses Although general treatment policies were followed,

therapy was individualized depending on tumor stage and configuration, geometry of the pelvic organs, age of the patient (5 to 10% reduction for those older than 65 years of age), previous history of pelvic inflammatory disease or pelvic surgical procedures (5 to 10% dose reduction), and judgment of the physician.

As previously described (27,28), patients were treated with high-energy photons, initially 22 MV (betatron) and later 18 to 25 MV from linear accelerators ( 10 to 40 Gy to whole pelvis plus an additional dose to parametria with midline step wedge or rectangular blocks to complete 50 Gy for Stages IB and IIA, and 60 Gy for patients with Stage IIB and III tumors). Fractionation was 1.8 to 2 Gy tumor dose daily, five fractions per week. External irradiation was administered through anteroposterior (AP) and posteroanterior (PA) 15 X 15 cm portals (at patient surface) in Stage IB and IIA disease or 15 X 18

Carcinoma of the uterine cervix l C. A. PEREZ et al. 1277

CA Uterine Cervix

MIR RADIATION THERAPY TECHNIQUES

WEEKS

EXTERNAL AT 0 1 2 3 4 5 6 7 6

Whole Pelvis m-0

Parametria 0- (midline block)

INTRACAVITARY #l #2

INSERTION I I

Parsmetrial Boost D

Fig. 1. Schema of radiation therapy techniques for carcinoma of the cervix used at Mallinckrodt Institute of Radiology. Pa- tients are treated with external beam doses ranging from 10 to 40 Gy, with additional parametrial doses (using midline shielding) to complete 50 to 60 Gy to parametria (depending on tumor volume), in daily fractions of 1.8 Gy. Two or occa- sionally three brachytherapy insertions are performed, interca- lated with the external irradiation. Specific tumor doses to point A are prescribed based on stage and volume, adding dose distri- bution from whole pelvis external irradiation and brachytherapy insertions. Usual overall treatment time is 7 to 8 weeks.

cm portals in patients with Stage IIB to include the com- mon iliac lymph nodes.

Until 1965, the Ter-Pogossian applicator’ or original Fletcher applicator was used. Since then, Fletcher-Suit afterloading applicators have been routinely used. Radium sources were replaced with 6oCo in 1960 and with ‘?‘Cs in 1971. Regardless of the isotope, all doses were pre- scribed in RaEqmg-h, and doses to point A and pelvic nodes were calculated. The dose rate at point A was ap- proximately 0.6 to 0.7 Gy/h.

Usually two intracavitary insertions were carried out. In patients with Stage I-IIA tumors, the first intmcavitary in- sertion was done initially or after administration of 10 to 20 Gy to the pelvis. In some patients with bulky or more advanced stage tumors the whole pelvis dose was 30 to 40 Gy, and the first insertion was performed in the third or fourth week. A second insertion was performed 1 to 2 weeks later, depending on tumor regression, with the patient contin- uing external irradiation during this time to complete 50- 60 Gy to the parametria with a midline step-wedge or rectan- gular block. When necessary, a third insertion was carried out at the completion of external therapy. When them were no unforeseen schedule interruptions, the prescribed therapy was completed in 42 to 48 days including weekends (less than 7 weeks) (Fig. 1).

The prescription for brachytherapy doses varied from 6500 to 7500 mgRaEq-h for Stage IB (60 to 70 Gy to point A) to 8000 to 8500 mgRaEq-h (72 to 75 Gy to point A) for Stages IIB and III; with large tumors it was sometimes necessary to administer 40 Gy to the whole pelvis, in which case the total intracavitary dose was re-

duced to 5000 mgRaEq-h (45 Gy to point A). Total doses to point A from external beam irradiation and brachyther- apy were 70 to 85 Gy for Stage IB and 85 to 90 Gy for more extensive tumors. The dose to the pelvic lymph nodes ranged from 50 to 70 Gy.

Data analysis The data were analyzed in several ways to correlate the

overall length of radiation therapy with various outcome parameters: (a) cause-specific survival was correlated with clinical tumor stage; (b) incidence of pelvic recur- rences (central or parametrial ) was correlated with tumor stage and size of lesion; (c) logistic regression analysis was used to determine variations in pelvic tumor control according to tumor stage and dose to point A (in some subgroups) ; and (d) multivariate analysis was performed for variables with potential impact on pelvic tumor control or cause-specific survival.

Analysis of clinical data was done using a computer’ statistical software package.’ All survival curves and sur- vival functions used the actuarial life table as applied by Cutler and Ederer (8). Survival time was calculated from the date of therapy initiation.

Actuarial pelvic tumor control at 5 years as a function of overall treatment time was plotted on scattergrams for all patients and for the subsets of the various clinical stages. A linear regression analysis was applied to the data points, and the impact of overall treatment time on pelvic tumor was expressed as a percent decrease in such control for each day of prolongation beyond 30 days. Patients were clustered into various similar treatment times, and the numbers are indicated on the graphs.

Test statistics were canied out using generalized Wil- coxon (Breslow) log-rank test and generalized Savage (Mantel-Cox) test (22). Survival analysis with covariates was based on the Cox form of the proportional hazards regression model (6). The Pearson product-moment cor- relation was computed from all pairs of acceptable values for the scatterplots (26).

RESULTS

The overall treatment time was 7 weeks or less in 338 of 4 15 patients ( 8 1% ) with Stage IB tumors, 7.1 to 8 weeks in 38 patients (9%), 8.1 to 9 weeks in 20 patients (5% ) , and more than 9 weeks in 19 patients (5% ) . The corresponding numbers for 137 Stage IIA patients were 102 (74%), 17 (12%), 8 (6%), and 10 (7%). Patients with Stage IIB and III disease had a greater proportion of longer treatment times, as most of these patients re- ceived an additional 10 Gy to the involved parametrium. In 391 Stage IIB patients, 205 (52%) were treated in 7 weeks or less, 99 (25%) in 7.1 to 8 weeks, 57 ( 15%) in

’ Washington University, St. Louis, MO. * VAX 8600, Digital Equipment Corp., Maynard, MA.

’ BMDP Statistical Software, University of California Press, Los Angeles, CA.

1278 I. J. Radiation Oncology l Biology l Physics Volume 32, Number 5, 1995

Table 1. Carcinoma of the uterine cervix (1959-1989): cause of treatment interruption correlated with stage

Stage

Cause of interruption IB IIA IIB III

n = 415 n = 137 n = 391 n = 281

Holidays and extended weekends 30 (23%) 12 (22%) 84 (33%) 61 (23%) Intercurrent disease 2 (2%) 1 (2%) 5 (2%) 5 (2%) Radiation therapy side effects 8 (6%) 5 (8%) 25 (10%) 27 (10%) Disease side effects 0 1 (2%) 5 (2%) 0 Unspecified 83 (65%) 39 (65%) 131 (52%) 164 (63%) Other 5 (3%) 1 (2%) 3 (1%) 3 (1%) Total 128 60 253 260

8.1 to 9 weeks, and 30 (8%) in more than 9 weeks. The corresponding numbers for 281 Stage III patients were 109 (39%), 64 (22%), 54 (19%), and 54 (19%).

The recorded causes of treatment interruption in the various tumor stage groups are shown in Table 1. The most frequent cause of treatment interruption was unspec- ified. Analysis of this subset showed that 80% of the interruptions were 3 days or fewer, 18% were 4 to 7 days, and only 2% were 8 days or longer. For the purpose of this analysis we believe that this is not critical information because we are analyzing only overall treatment time and not specific reasons for time gaps. Weekends and holidays (longer than a 2-day interruption) accounted for 23% to 33% of interruptions, and side effects of therapy for 6% to 10% of the unplanned therapy delays.

Cause-speci$c survival In Stage IB the lo-year cause-specific survival (CSS )

was 86% in 338 patients treated in 7 weeks or less, and 78% in 58 patients treated between 7.1 and 9 weeks, which is significantly higher than the 55% observed in 19 patients with prolongation of treatment time over 9 weeks (p I 0.01) (Fig. 2a). In patients with Stage IIA tumors treated in 7 weeks or less, the lo-year CSS was 73%, in contrast to only 41 to 43% for 35 patients with longer overall treatment times (p < 0.01) (Fig. 2b). In those with Stage IIB disease, the lo-year CSS was 72% in 205 patients treated within 7 weeks, 60% in 156 patients treated in 7.1 and 9 weeks, and 70% for 30 patients treated in over 9 weeks (p = 0.01) (Table 2). In Stage III pa- tients, there was no significant variation in CSS when correlated with overall treatment time (39 to 42%) (p = 0.5 1) ; however, in a subset of patients who received doses of 85 Gy or higher to point A, we also observed lower lo-year survival rates when overall treatment time was longer than 9 weeks (38% vs. 46% for shorter times) (p = 0.08).

Patterns of failure The overall pelvic recurrence rates are summarized in

Table 3. In patients with Stage IB disease, the rate was 8% (26 of 338) when overall treatment time was 7 weeks or less, in contrast to 22% (17 of 77) with longer periods

CA Uterine Cervix: 1959 - 1989 CAUSE-SPECIFIC SURVIVAL CORRELATED WITH

OVERALL TREATMENT TIME

B a 40- - 5 7 weeks (n = 338) - 7.1 - 9 weeks (n = 59) A >9weeks(n=19)

20 - p 2 .Ol

0 0 1 2 3 4 5 6 7 6 9 10

YEARS AFTER THERAPY

(4

CA Uterine Cervix: 1959 - 1989 CAUSE-SPECIFIC SURVIVAL CORRELATED WITH

OVERALL TREATMENT TIME

20 -

- 5 7 weeks (n = 102) --+- 7.1 - 9 weeks (n = 25) - >9wwks(n=lO)

p 2 .Ol

0 0 1 2 3 4 5 6 7 6 9 10

YEARS AFTER THERAPY

03

Fig. 2. Cause-specific survival correlated with overall treatment time for Stages IB (a) and IIA (b).

Carcinoma of the uterine cervix 0 C. A. PEREZ et al. 1279

Table 2. Carcinoma of the uterine cervix (1959-1989): Ten-year actuarial cause-specific survival correlated

with overall treatment time

Treatment time (weeks)

Clinical stage 5 7 7.1-9 >9 p-value

IB 338 (86%) 58 (78%) 19 (55%) 0.01 IIA 102 (73%) 25 (41%) 10 (48%) 0.01 IIB 205 (72%) 156 (60%) 30 (70%) 0.01 III 114 (42%) 118 (42%) 54 (39%) 0.43 III (Point A

2 80 Gy) 70 (46%) 85 (44%) 39 (37%) 0.16

of time (p 5 0.01) (Fig. 3a). Distant metastases were observed in 15% of patients treated in less than 7 weeks (51 of 338) compared with 23% (18 of 77) in those treated in longer times (p = 0. I 1) . In Stage IIA the pelvic failure rate was 14% (14 of 102) for patients treated in 7 weeks or less and 25.7% for those treated for longer periods of time (p = 0.08) (Fig. 3b). The corresponding incidence of distant metastases was 28.5 and 43%, respec- tively. In patients with Stage IIB disease the total pelvic failure rate was 19% (38 of 205) with overall treatment time of 7 weeks or less and 27% (50 of 186) in patients treated for longer periods of time (p = 0.09). The distant metastases rates were 22.4 and 31.7% (59 of 186), re- spectively. In Stage III the lo-year pelvic failure rate ranged from 42 to 50% with various treatment times (p = 0.42) and the distant metastases rate, from 44 to 5 I%, without correlation with overall treatment time. In the subgroup receiving 285 Gy, the lo-year pelvic failure rate was 39% when treated in 9 weeks or less vs. 46% with longer treatment times (p = 0.22).

Pelvic failures and overall treatment time Because we have previously reported a significant im-

pact of tumor size on pelvic tumor control and survival in these patients (29), we correlated pelvic tumor control and overall treatment time with tumor stage and lesion size. In Stage IB there was no correlation in lesions less than 3 cm in diameter; in lesions 3.1 to 4.9 cm, it was present but not statistically significant; in lesions 5 cm in diameter or larger it was statistically significant (10%

Table 3. Carcinoma of the uterine cervix (1959- 1989): Ten-year actuarial pelvic recurrence correlated

with overall treatment time

Treatment time (weeks)

Clinical stage 5 7 7.1-9 >9 p-value

IB 338 (7%) 58 (22%) 19 (36%) 5 0.01 IIA 102 (14%) 25 (27%) 10 (36%) 0.08 IIB 205 (20%) 156 (28%) 30 (34%) 0.09 III 114 (38%) 118 (44%) 54 (49%) 0.18 III (Point A

2 80 Gy) 70 (32%) 85 (40%) 39 (51%) 0.08

CA Uterine Cervix: 1959 - 1989 PELVIC TUMOR RECURRENCE

CORRELATED WlTH LlFlGe:“B OF TREATMENT a

100

80 - 5 7 weeks (n = 338)

- 7.1 - 9 weeks (n = 58)

5 60

8

El P 40 I

A > 9 weeks (n = 19) p 5 .Ol

YEARS AFTER THERAPY

(4

CA Uterine Cervix: 1959 - 1989 PELVlC TUMOR RECURRENCE

CORRELATED WITH k;Nz-r;OF TREATMENT aa

100

- ~7weeks(n=102)

-m- 7.1 - 9 weeks (n = 25)

ii GO- -a- >9weeks(n=lO)

8

p = .08

z n 40-

l---‘L---C-A-

2ol* f---l 2 3 4 5 6 7 8 9 10

YEARS AFTER THERAPY

(b)

Fig. 3. Pelvic tumor recurrence correlated with length of treat- ment for Stages IB (a) and IIA (b).

pelvic failure rate with overall treatment time of less than 7 weeks compared with 50 to 60% with longer times) (p 5 0.01) (Fig. 4a). In Stage IIA disease, overall treatment time correlated with pelvic recurrence rate in tumors less than 3 cm and 3.1 to 4.9 cm (p = 0.06 and 0.01, respec- tively ) . However, no correlation was observed in lesions 5 cm or larger (Fig. 4b).

In Stage IIB disease there was a significant correlation between overall treatment time and pelvic failure rate (p = 0.04) in patients with unilateral parametrial involve- ment, but this was not noted in the group with bilateral parametrial disease (Fig. 5a). In Stage III disease there was no correlation between overall treatment time and pelvic recurrence in patients with unilateral or bilateral parametrial invasion (Fig. 5b) _

To exclude the possibility that patients with metastatic pelvic or periaortic lymph nodes were more prevalent in

1280 I. J. Radiation Oncology l Biology 0 Physics Volume 32, Number 5, 1995

CA Uterine Cervix: 1959 - 1989 PELVIC TUMOR RECURRENCE CORRELATED

WITH LENGH OF TREATMENT

Stage IB 70

60 cm 13

p = .67

- 57weeks - 7.1 -0weeks - .Gmks

YEARS AFTER THERAPY

YEARS AFTER THERAPY

70 25cm 60

c 56 f f---+--.., r-

1 2 3 4 5 6 7 6 9 10

YEARS AFTER THERAPY

(4

CA Uterine Cervix: 1959 - 1989 PELVIC TUMOR RECURRENCE CORRELATED

WITH LENGH OF TREATMENT

Staae IIA

<3 - cm

p=.o6 - <7weeks - - 7.1 >Gweeks -9weeks

10

‘0 1 2 3 4 5 6 7 6 9 10

YEARS AFTER THERAPY

70

60 3.1 - 4.9 cm

10

0

YEARS AFTER THERAPY

60 25cm

p=.96

10

‘0 1 2 3 4 5 6 7 6 9 10

YEARS AFTER THERAPY

(b) Fig. 4. Pelvic tumor recurrence correlated with length of treatment and tumor size for Stages IB (a) and IIA (b)

the groups with prolongation of overall treatment time or delay in performance of intracavitary insertions, the pel- vic failure rate was analyzed as a function of the status of the lymph nodes on lymphangiogram reports. There was no significant correlation in the distribution of pa- tients with positive/suspicious or negative lymphangio- grams in the various treatment time groups. A trend was observed toward a higher number of failures in patients with positive/suspicious lymphangiograms (p-values ranging between 0.6 and 0.9). Furthermore, to rule out the possible association of a greater incidence of pelvic recurrences with interruptions of therapy secondary to tumor-related causes, the data were analyzed. There were no significant differences in failure rates in patients with tumor- or therapy-related interruptions and the other groups (p-values ranged from 0.2 to 0.9).

A correlative analysis similar to that reported by Fyles e? al. (14) was carried out to determine the loss of pelvic tumor control as a function of prolongation of overall treat- ment time. The 5-year actuarial pelvic tumor control in all 1224 patients receiving 85 Gy or higher doses to point A demonstrated a loss of about 0.85% in pelvic tumor control per day of treatment (p 5 0.01) (Fig. 6). In patients with Stage IB and IL4 tumors, loss of pelvic tumor control was 0.37% per day (Fig. 7a) and in Stage IIB, 0.68% per day (Fig. 7b). In Stage III disease, when all patients were con- sidered, there was a weaker correlation between loss of pelvic tumor control and overall treatment time (Fig. 8a) ; however, there was 0.54% decrease in tumor control per day when the analysis was limited to patients receiving 85 Gy or greater doses to point A (Fig. 8b).

To decrease or eliminate the possibility that patients who

Carcinoma of the uterine cervix 0 C. A. PEREZ et al. 1281

CA Uterine Cervix: 1959 - 1989 PELVIC TUMOR RECURRENCE CORRELATED

WITH LENGH OF TREATMENT

CA Uterine Cervix: 1959 - 1989 PELVIC TUMOR RECURRENCE CORRELATED

70

60

50

Stage IIB

Unilateral

- <7weeks - 7.1 - 9 weeks - r9wwks

WITH LENGH OF TREATMENT

Stage III

2 3 4 5 6 7 6 9 10

YEARS AFTER THERAPY

Bilateral

1 2 3 4 5 6 7 8 9 10

YEARS AFTER THERAPY

(4

Unilateral

- <7waeks - 7.1 - 9 weeks - >9weeks

YEARS AFTER THERAPY

Bilateral

p = .61

0 1 2 3 4 5 6 7 6 9 IO

YEARS AFTER THERAPY

03

Fig. 5. Pelvic tumor recurrence correlated with length of treatment and unilateral or bilateral parametrial invasion for Stages IIB (a) and III (b).

received a parametrial boost were more likely to have larger tumors, we analyzed the incidence of pelvic failures in 6 patients with Stage IB and 25 with Stage IIB and III disease who received a parametrial boost. The pelvic recurrence rates were 16%, 14%, and 26%, respectively (p = 0.58), similar to those of patients receiving no parametrial boost. The incidence of pelvic recurrences was 22% in patients treated in 9 weeks or less and 30% for longer treatment times (p = 0.69). Thus, administration of a paramehial boost did not have an impact on the results.

Multivariate analysis Several prognostic variables correlated with outcome

(Table 4). In Stage IB and IIA, elapsed days of irradiation (overall treatment time) and clinical stage showed a strong correlation with pelvic tumor control and cause- specific survival regardless of tumor size. Tumor size was a statistically significant factor in cause-specific survival but not in pelvic tumor control. Dose to point A was not related to either outcome parameter.

In Stages IIB and III, there also was a strong correlation between elapsed days of irradiation and clinical stage and both pelvic tumor control and cause-specific survival; the

same is true of the dose to point A. Parametrial invasion (whether unilateral or bilateral) was statistically signifi- cant for pelvic tumor control but not for cause-specific survival.

Impact of timing of intracavitary insertions on pelvic tumor control

At our institution, therapy is planned so that the two intracavitary insertions are carried out within 4 to 5 weeks from the initiation of radiation therapy. Review of patient progress notes showed that in only 4% of patients was a technical difficulty recorded as the reason for delaying performance of the intracavitary insertions (large tumor, inability to identify cervical OS, poor tumor regression, etc.). In patients with Stage IB or IIA disease, the pelvic failure rate was 6.5% if the two insertions were carried out within this period of time, in contrast to 16% when the second insertion was delayed for more than 4.5 weeks (p = 0.02). No significant difference in tumor control was noted in larger lesions (Fig. 9a). To rule out the possibility that technical difficulties related to larger tu- mors were the cause for prolongation of treatment time and worse results, the data were reanalyzed for patients

1282 I. J. Radiation Oncology 0 Biology 0 Physics Volume 32. Number 5, 1995

CA Uterine Cervix: 1959 - 1989 CYEAR ACTUARIAL PELVIC TUMOR CONTROL

AND OVERALL TIME OF IRRADIATION DOSE TO POINT A t 8500

All Patients

100

ii

6

E 2 -

8 60 g

8

3 70-

: 5

iii P 60 - c t $

I

$ ‘; p 5 .Ol \ slope: -.65649 R = -.737

40

r ’ ’ ’ ’ ’ ’ ’ ’

pT-zq

26 35 42 49 56 63 70 77 64

OVERALL TREATMENT TIME (days)

Fig. 6. Five-year actuarial pelvic tumor control and overall time of irradiation for all patients treated with 85 Gy or greater to point A.

with Stage IB and IIA lesions less than 3 cm in diameter. The pelvic failure rate was still 5% (8 of 155) when the insertions were carried out within 4.5 weeks from initia- tion of external irradiation in contrast with 11% (6 of 54) when performed at later times. The difference is not statistically significant (p = 0.23), but because of the small sample size, a few patients in either group would have made the difference statistically significant. Patients with tumors larger than 3 cm undergoing intracavitary insertions within 4.5 weeks had a pelvic failure rate of 16% (18 of 114) vs. 25% (20 of 81) for patients im- planted at later times (p = 0.17).

In Stage IIB disease, the pelvic failure rate was 12.3% when both intracavitary insertions were performed within 4.5 weeks and 34% with longer times (p I 0.01). To exclude the possible association of a greater number of pelvic failures in patients to whom an additional 10 Gy boost was delivered to the parametrium, analysis of these patients was performed. Of the 15 patients in this group, two exhibited pelvic recurrences ( 13%). In Stage III le- sions, no significant correlation was noted between timing of brachytherapy and pelvic failure rate (Fig. 9b).

Three intracavitary insertions were performed in 37 patients: in 9 for inadequate first or second intracavitary implant, in 13 for residual tumor at the completion of standard therapy, and in 15 for unspecified reasons. The &year pelvic failure rate was 18% in the first two groups

and 32% in the last group, results similar to those of patients treated with one or two intracavitary insertions (p = 0.4). Thus, the number of brachytherapy procedures did not significantly affect the results.

DISCUSSION

Empirically, radiation oncologists have suspected for many years that prolongation of treatment time could have an adverse effect on radiation therapy outcome. However, it was not until Denekamp (9) demonstrated compensa- tory proliferation in the epithelium of the skin of mucosa, which accelerates at 2 or 3 weeks after initiation of irradi- ation, and Withers et al. (38) described experimental ob- servations documenting acceleration of repopulation of tumor cells after fractionated radiation therapy, that we had a better biologic understanding of these events. Fowler ( 11) emphasized the importance of rapid prolifer- ation of malignant cells as a factor influencing tumor control probability.

Baumann et al. (2) reported in a series of experiments in nude mice bearing a human squamous cell carcinoma a progressional increase in TCDSo (dose giving tumor control rates of 50%) with longer periods of time ranging from 2 to 10 weeks, with radiation doses from 43 to 102 Gy; the loss of tumor control dose was 1 Gy per day of prolongation time. Repopulation of clonogenic tumor cells was thought to be an important factor; other mecha- nisms such as an increasing fraction of hypoxic tumor cells associated with prolongation of time could not be ruled out.

Recently, several publications have documented de- creasing control of irradiated tumors with prolongation of treatment time in human tumors ( 1, 13- 15, 18, 20, 35, 38). On the other hand, Parsons et ~2. (25) noted, in 107 patients with large-volume Stage IB or IIA and Stage IIB, III, or IVA carcinoma of the cervix treated with irradiation alone, no significant difference in local tumor control or survival when patients were treated with contin- uous or split-course technique. Marcia1 er al. (21) also reported no significant difference in outcome in patients with Stage IIB, IIIA, and IIIB carcinoma of the cervix treated with split-course or continuous irradiation.

It is noteworthy that Tpo, (potential doubling time) data (37 ) preceeded clinical reports of loss of pelvic tumor control by several years. Keane et al. ( 18) were the first to report such an effect in carcinoma of the cervix (for Stages I and II 0.7% per day and for Stages III and IV < 1.2% per day decreased pelvic tumor control). Fyles et al. ( 14) demonstrated the adverse effect of increased treatment duration on pelvic tumor control in 830 patients with cervical carcinoma treated with irradiation alone. Loss of tumor control approximated 1% per day of treat- ment prolongation beyond 30 days. In contrast to our report, this effect was predominately observed in Stages III and IV compared with Stages I and II. Measurements of T,,, using halogenated pyrimidines in head and neck

Carcinoma of the uterine cervix 0 C. A. PEREZ et al. 1283

CA Uterine Cervix: 1959 - 1989 5-YEAR ACTUARIAL PELVIC TUMOR CONTROL

AND OVERALL TIME OF IRRADIATION

24 0 64 h If 21

0

4

A F

CA Uterine Cervlx: 1959 - 1989 5-YEAR ACTUARIAL PELVIC TUMOR CONTROL

AND OVERALL TIME OF IRRADIATION

30 35 40 45 50 55 60 65 70 30 35 40 45 50 55 60 65 70

OVERALL TREATMENT TIME (days) OVERALL TREATMENT TIME (days)

(4 @I

Fig. 7. Five-year actuarial pelvic tumor control and overall time of irradiation for Stages IB and IIA (a) and Stage IIB (b).

and cervix cancers demonstrated median values of 5 days, which is significantly shorter than the volume doubling times described and consistent with accelerated prolifera- tion (37). Lanciano et al. (20), in an analysis of 837 patients from the Patterns of Care Study treated with doses of 65.99 Gy or greater for squamous cell carcinoma of the uterine cervix, also reported a highly significant decrease in pelvic tumor control and survival with prolon- gation of treatment times. They described a 4-year actuar- ial infield recurrence rise from 6 to 20% when total treat- ment time increased from 6 weeks or less to 10 weeks (p = 0.0001); this translated into significantly decreased survival. The clinical stage of the tumor and overall treat- ment time were significant prognostic factors for infield recurrence. Their observations are in agreement with ours.

In general, more extensive tumors, which have a higher local failure rate, require longer overall treatment times. Our analysis shows that in patients with Stage IB tumors less than 3 cm in diameter or in patients with extensive parametrial involvement (Stage IIB bilateral or Stage III), prolongation of treatment time did not correlate with pel- vic tumor control. This is further evidence of the impor- tance of overall treatment time of irradiation when spe- cific total tumor doses are delivered. In small tumors most doses are effective, whereas in large tumors higher doses

are required to be effective. Prolongation of treatment is relevant only when there is an increasing probability of controlling the tumor within a range of irradiation doses.

Regression analysis of our patients confirms the report by Fyles et al. ( 14) of the loss of pelvic tumor control as a function of prolongation of time (from 0.6 to 0.86% per day of prolongation of time). The lack of correlation of treatment time and pelvic tumor control in all of our patients with Stage III is superseded by a positive correla- tion in the subset of patients receiving doses higher than 85 Gy as described by Fyles et al. (14). In our analysis age was not a significant prognostic factor, contrary to their experience. Sugawara et al. (34) also noted a sig- nificant increase in pelvic recurrences (40 to 41%) in 97 patients with Stage III-IV disease receiving doses of 93 Gy or greater to point A when overall treatment time was longer than 42 days compared with patients treated in shorter times ( 10 to 18%).

Girinsky et al. ( 15), in 386 patients with Stage IIB- III carcinoma of the cervix treated with irradiation (45 to 50 Gy whole pelvis and 10 Gy intracavitary curiether- apy to a mean volume of 3 11 ? 127 cm3 ) , also observed a loss of tumor control and overall survival when the treatment time exceeded 52 days. Time interval between external and intracavitary irradiation, overall treatment

I284 I. J. Radiation Oncology 0 Biology 0 Physics Volume 32, Number 5, 1995

CA Uterine Cervix: 1959 - 1989 5-YEAR ACTUARIAL PELVIC TUMOR CONTROL

AND OVERALL TIME OF IRRADIATION Stage Ill

75 l 25

72

25 30 35 40 45 50 55 60 66 70 75 60 66 OVERALL TREATMENT TIME (days)

(a)

35 40 45 50 55 60 65 70 OVERALL TREATMENT TIME (days)

03

Fig. 8. Five-year actuarial pelvic tumor control and overall time of irradiation for all Stage III patients (a) and a subset of patients treated with 85 Gy or greater to point A (b).

CA Uterine Cervix: 1959 - 1989 B-YEAR ACTUARIAL PELVIC TUMOR CONTROL AND OVERALL TIME OF IRRADIATION DOSE TO

POINT A 2 8500 90 Stage Ill

p < .Ol slope: -.53955 R = -.704

45 18

I I I I I I I

time, and hemoglobin levels/blood transfusions were the most highly significant prognostic factors on multivariate analysis. The lo-year local recurrence-free survival rate decreased rapidly when overall treatment time exceeded 52 days, and relative risk of local recurrence increased by a factor of 2.4 when overall treatment time was ex- tended from 52 to more than 62 days. A 1.1% loss of

pelvic tumor control per day was observed in their regres- sion analysis, findings similar to ours. They noted that the external radiation dose (including boost to pelvic wall) was not significant on univariate analysis and was not used in multivariate analysis. Our conclusion is that, if adequate doses of irradiation are administered in smaller lesions as in Stage IB tumors less than 3 cm in diameter,

Table 4. Carcinoma of the uterine cervix (1959- 1989): Multivariate analysis of prognostic factors

Prognostic variable

Pelvic tumor control Cause-Specific survival

p-Value of Final Model p-Value of Final Model variables regression Exponent of variables regression Exponent of entered coefficient regression entered coefficient regression

into model (2 SE) coefficient into model (2 SE) coefficient

Stage IB and IIA Elapsed days of irradiation Clinical stage Tumor size Dose to point A

Stages IIB and III Dose to point A Elapsed days of irradiation Clinical stage Parametrial extension

0.001 0.0309 + 0.0081 1.0314 0.018 0.5936 + 0.2650 0.9977 0.394 -0.0024 2 0.0029 -0.8195 0.534 o.oooo t 0.0001 0.6040

0.001 -0.0003 + 0.0001 0.001 0.0175 k 0.0051 0.001 0.3362 + 0.0622 0.049 0.3079 t 0.1582

0.9997 0.001 -0.0002 + o.oooo 0.9998 1.0176 0.018 0.0160 2 0.0046 1.0161 1.3996 0.001 0.3229 + 0.0526 1.3811 1.3605 0.111 0.2123 2 0.1340 1.2366

0.001 0.0272 + 0.0065 1.0276 0.001 0.7590 + 0.2019 2.1361 0.001 -0.0076 + 0.0024 0.9924 0.998 o.oooo + o.oooo 1.0000

Carcinoma of the uterine cervix 0 C. A. PEREZ et al. 1285

CA Uterine Cervix: 1959 - 1989 INCIDENCE OF PELVIC FAILURES CORRELATED

WITH TIME OF IMPLANT AND SIZE OF TUMOR Stage IB-IIA

54cm 40 r

D 5 2 30

I

p = 0.02 2

>4cm

p= 1.0

0 0 Within 4.5 Later than 4.5 Within 4.5 Later than 4.5

TIME BOTH IMPLANTS PERFORMED (weeks)

(4

CA Uterine Cervix: 1959 - 1989 INCIDENCE OF PELVIC FAILURES CORRELATED

WITH TIME OF IMPLANT AND SIZE OF TUMOR

Staae IIB Staae 111 u140 E 3 3 30

v 520

i! !- 5 10 0

E 0

Within -than 4.5

TIME BOTH IMPLANTS PERFORMED (weeks)

@I

Fig. 9. Incidence of pelvic failures correlated with time of implant and size of tumor for Stages IB and IIA (a) and Stages IIB and III (b ) ,

it is more difficult to demonstrate a dose response, and the impact of overall treatment time may be less or not significant.

In the reports by Fyles et al. ( 14)) Girinsky et al. ( 15)) and Lanciano et al. (20) there was a strong correlation between overall treatment time and loss of pelvic tumor control in patients with Stage IIB and III disease, whereas in our analysis this correlation was more striking in Stage III tumors when doses higher than 85 Gy were delivered to point A. The reason for the apparent discrepancy in the results is unclear at this time; it is possible that only higher doses of irradiation will be effective in compensat- ing for the clonogenic tumor repopulation that may take

place with interruptions of treatment, as suggested by our observation of a positive correlation between prolonga- tion of treatment time and loss of tumor control of 0.54% per day in patients with Stage III receiving doses of 85 Gy or higher.

With regard to the timing of intracavitary insertions, we demonstrated that some patients (Stage IB-IIA less than 4 cm and Stage IIB ) had a lower pelvic tumor control rate when there was a delay over 4.5 weeks in performing these procedures. Bosch and Mar&l (5)) in 297 patients treated with one or two intracavitary insertions after com- pletion of 4000 R (doses not expressed in Gy) adminis- tered in 6 weeks, observed no significant difference in 5-

1286 I. J. Radiation Oncology l Biology l Physics Volume 32, Number 5, 1995

year survival in patients with Stage I, II, and III disease when intracavitary brachytherapy was carried out within 13 days after completion of external irradiation. However, a lower survival rate was noted with delays of 14 days or more, particularly in patients with Stage III disease (38 vs. 18% 5-year survival rate). As in our experience, Girinsky et al. ( 15) reported that the time interval be- tween external treatment and intracavitary curietherapy was an important prognostic factor.

For many years radiation oncologists paid no special attention to overall treatment time, but as noted by Fowler and Lindstrom ( 12)) based on in vitro studies on potential doubling time using flow cytometry (4, 3 1, 36, 37 ) , it is now apparent that we should be more concerned with keeping overall treatment times as short as possible. In an analysis of 12 reports of radiation therapy of head and neck cancer, Fowler and Lindstrom ( 12) noted that the effect of total dose on tumor control was significant in some series, while in others it was undetectable. However, in 10 of 12 analyzed data sets, overall time was a signifi- cant factor in determining local tumor control (p < 0.05 ) . The median value for all 12 series was 14% loss of local control per week of extra overall time. The authors em- phasized that, whether observed losses of local tumor control are a reflection of proliferation of the tumor cells or some element of physician selection (less-favorable tumors being treated in longer overall times), it is difficult to determine from retrospective studies whether the pro- longation of time is due to split-course or fractionation schedules. In their analysis prolongation of treatment time for whatever reason correlated with worse local tumor control, even when analyzed with tumor size. Our analy- sis, which separates patients according to stage and tumor size, diminished the impact of tumor selection, yet within effective dose ranges, the impact of prolongation of treat- ment time on tumor control was evident in most patients.

Unfortunately, with available methods there is no prac- tical and accurate way to determine cell kinetics charac- teristics of tumors such as doubling time of clonogenic cells and repair time, although in vitro methods have been reported to assess radiosensitivity (30). Wilson et al. (37) described median 7’,,,, values for uterine cervix (21 tu- mors) of 4.5 days using bromodeoxyuridine ( BUdR) and flow cytometry. Using PC10 antigen, Oka et d. (23) observed a transient increase in the Ki-67 index with doses below 9 Gy in 18 patients with squamous cell carci- noma of the cervix treated with irradiation; it reached a peak value at 9 Gy and decreased at doses of 1.8 Gy and 2.7 Gy. The mean PC10 index showed a plateau from pretreatment to 9 Gy, after which it decreased. The mean mitotic index was less than 1% before irradiation and decreased to lower levels with subsequent doses of irradi- ation. The authors concluded that radiation doses of 5.4 to 9 Gy increase the number of cycling squamous tumor cells in Gl or G2 phase and that this transient increase was attributable to the combined effects of recruitment and Gl or G2 block. Thus, the significance of Ki-67 and

effective doubling time (T,rr) is not clearly understood, although as noted by Fowler and Lindstrom ( 12)) the similarity of Tp, and T,,.,- values (not necessarily their identity) is striking.

Cell loss is another important factor in tumor regres- sion, and how soon after treatment spontaneous cell loss falls to zero is not clear. According to Fowler and Lind- Strom ( 12), strong biologic considerations suggest that it occurs either when three or four fractions of 2 Gy have been delivered or when the tumor has shrunk appreciably, whichever is later ( 1 or 2 weeks from start of irradiation for head and neck and other carcinomas). The data from Withers et al. (38) suggest 3 to 4 weeks ( 12,32). Roberts and Hendry (32) reanalyzed the data presented by With- ers et al. (38) for head and neck tumors and concluded that there was confirmation of a significant lag before the onset of repopulation. The inclusion of a lag time tended to increase the mean value of the time factor from 0.55 Gy per day to 0.66 Gy per day. These authors concluded that accelerated repopulation may begin by 2 weeks into treatment.

Skladowski et al. (33) confirmed this concept in an analysis of 971 patients with squamous cell carcinoma of the supraglottic larynx. They observed that if a gap in treatment time began before Day 19 after start of radiation therapy, local tumor control was considerably lower than that of patients who did have a gap in treatment. Oddly, there was no impact on tumor control when the gap began at Days 20 through 29, but a detrimental effect on tumor control was again noted when the gap occurred toward the end of treatment.

In an analysis of RTOG studies 79- 13 (hyperfraction- ated irradiation) and 79- 15 (misonidazole and irradiation) of patients with moderately and advanced squamous cell carcinoma of the head and neck, Pajak et al. (24) reported that multivariate analysis of effects of major and unac- ceptable variations in protocol found prolongation of overall time to be a significant detrimental factor (3-year local control fell from 27 to 13% for patients with treat- ment prolongation of 14 days or more) (p = 0.01). Cox et al. (7) described similar observations in patients irradi- ated with higher doses (269.6 Gy) for unresectable non- small cell lung cancer. Obviously, future reports of ther- apy results and design of clinical trials should describe and carefully control for variations in overall time of administration of radiation therapy.

On a sobering note, Keane ( 17) warned of interpreta- tion of retrospective clinical data as presented here be- cause of possible physician bias in treatment allocation and dose prescription and the heterogeneity of patient characteristics, tumor type, stage, and dose of irradiation. Roberts and Henley (32) underscored the difficulties in analysis of retrospective data, which may contain many potential sources of bias, and that conclusions concerning repopulation effects (in patients) must be considered ten- tative until better data are available.

The high incidence of unspecified causes of interrup-

Carcinoma of the uterine cervix 0 C. A. PEREZ et al. 1287

tion in our analysis (52 to 65%) points out a lack of interest of the treating radiation oncologist in recording the reasons for such interruptions. However, because the main focus of our analysis was the overall treatment time and not the specific reasons for treatment interruptions, it is unlikely that there may be a bias. This and other reports should be an incentive in the future to radiation oncologists to strive to decrease treatment interruptions and to carefully record these events for a more accurate analysis of this parameter.

Regardless of the intricacies of biologic methodology

and considerations, a practical conclusion is that, in the treatment of patients with radiation therapy, we should minimize treatment time and avoid any planned or un- planned interruptions or delays, including timely integra- tion of external beam and intracavitary irradiation in pa- tients with carcinoma of the uterine cervix.

We agree with Girinsky et al. ( 15) that the results of retrospective studies such as this one must be validated in a prospective randomized protocol to test the impact of overall irradiation treatment time on outcome.

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