Im. J Rodrorwn Oncology 61ol Printed in the U S.A. All nghts

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24. pp.

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??Clinical Original Contribution

FIG0 STAGE IIIA CARCINOMA OF THE UTERINE CERVIX VIVEK Division

S. KAVADI,

of Radiotherapy,

M.D. AND PATRICIA J. EIFEL, M.D.

The University

of Texas M. D. Anderson

Cancer Center,

Houston,

TX

Between 1955 and 1988,44 patients with FIG0 Stage IIIA carcinoma of the cervix were treated with radiotherapy at The University of Texas M. D. Anderson Cancer Center. This represents only 3% of the 1473 Stage III cervical carcinoma patients treated at M. D. Anderson during this time period. The 5- and IO-year actuarial survival rates of patients with Stage IIIA disease were 37% and 34%, respectively. The actuarial pelvic disease control rate was 72% at 5 and 10 years. Of the 23 patients who experienced a recurrence of their disease, 10 had a recurrence in the pelvis only, 11 had distant metastases only, and two had recurrences in the pelvis and distantly. Two factors, parametrlal disease extension and discontinuous involvement of the lower third of the vaglna were important predictors of prognosis. The 5-year survival rate of 27 patients with parametrlal involvement was 25% compared with 56% for the 17 patients without parametrial disease (p = 0.05). The 5-year survival rate of 13 patients with discontinuous (“skip”) lesions in the lower third of the vagina was 15% compared with 48% for 31 patients who presented with direct extension of disease to the lower vagina (p = 0.05). This was because of a high rate of distant disease recurrence in patients with skip lesions since pelvic control rates were similar for both groups. No patient who presented with both parametrial extension and discontinuous vaginal involvement survived 5 years. In contrast, patients with lesions that extended directly from the cervix to involve the lower vagina without involving the parametrlum had an excellent 5-year survival rate of 73%. Cervical cancer, Stage IIIA, Prognostic factors, Radiotherapy.

disease was staged at initial evaluation according to the following M. D. Anderson criteria: Stage IIIA: Fixation to one pelvic sidewall or involvement of the lower one third of the vagina. Stage IIIB: Fixation to both pelvic sidewalls or hydronephrosis. Seven hundred ninety-three patients had M. D. Anderson Stage IIIA disease and 680 had Stage IIIB disease. Of the 793 patients with M. D. Anderson Stage IIIA tumors, only 44 had involvement of the lower third of the vagina without pelvic wall fixation and could therefore be classified as having FIG0 Stage IIIA disease. These 44 patients, who represent 3% of all Stage III cervical carcinoma patients treated at M. D. Anderson during this period form the study group. All 44 patients were treated with radiotherapy (RT) at M. D. Anderson. Thirty-two patients (73%) were treated with a combination of external beam radiation and brachytherapy, nine were treated with external RT only, and three were treated with intracavitary therapy only. Three patients did not finish the planned course of treatment: one had a narrow vagina and intracavitary therapy could not be delivered as planned, the second had pro-

INTRODUCTION

In the International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical carcinoma, Stage IIIA denotes a group of patients with disease involvement of the lower third of the vagina without extension to the pelvic sidewall or hydronephrosis (1). This presentation of cervical cancer is extremely rare. Although only a small proportion of patients present with Stage IIIA disease, their extensive vaginal disease involvement presents a challenging clinical problem. Because this disease presentation is so unusual, patients with Stage IIIA disease are rarely analyzed separately. Few series in the literature include more than lo-20 Stage IIIA patients. We have reviewed our experience with 44 Stage IIIA patients to determine their survival and local-regional control rates, patterns of failure, and important predictors of prognosis. METHODS

AND MATERIALS

Between 1955 and 1988, 1473 patients received initial treatment for Stage III carcinoma of the cervix at the M. D. Anderson Cancer Center. In most patients, primary Presented at the 33rd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Washington, DC, November, 199 1. Reprint requests to: Patricia J. Eifel, M.D., Division of Ra-

diotherapy (Box 97), The University of Texas M. D. Anderson Cancer Center, 15 15 Holcombe Blvd., Houston, TX 77030. Accepted for publication 2 1 January 1992.

211

1. J. Radiation Oncology 0 Biology 0 Physics

212

gressive disease after external RT was completed, and the third patient died of coexistant medical problems during treatment and had carcinoma present at the time of death. External beam treatment was delivered with high energy (18-25 MV) photons with parallel-opposed AP/PA or four-field technique. The mean external dose was 48.4 Gy (range 20-70 Gy). Initial external radiotherapy was delivered using a 15 X 15 cm field. Shrinking fields were used when external doses to the pelvis exceeded 50 Gy. Intracavitary radium treatment was delivered using a Fletcher-Suit or Fletcher-Suit-Delclos applicator system. In most cases, brachytherapy treatment was delivered to the entire vagina using vaginal cylinders (5). In nine patients, interstitial implants were used to supplement the dose from external and intracavitary therapy to the vagina. One patient was felt to have residual disease after external RT and underwent anterior exenteration. The median follow-up of non-relapsing patients was 57 months (range 2-267 months). Four patients with less than 3 years follow-up died of intercurrent disease. The probabilities of pelvic disease control and survival were calculated from the start of treatment using the Berkson and Gage life-table method. Patients who died of causes other than cervical cancer were censored. Patients who died of unknown causes within 5 years of treatment were scored as treatment failures. Those who died of unknown causes after 5 years were scored as intercurrent deaths and were censored in an actuarial fashion. Major radiation complications were graded according to RTOG/EORTC criteria: Grade 3, bowel obstruction or bleeding requiring surgery; Grade 4, necrosis, perforation, or fistula formation; and Grade 5, deaths directly attributable to radiation effects. Symptoms were scored as complications unless the patient was known to have active pelvic disease at the time. Complication rates were calculated actuarially. Patients who died of disease without experiencing a major complication were also censored. All comparisons between groups were made using the log rank test.

Volume

24,

Number 2, 1992

30(2)

20,

para

lo0

0

,,,,,,,,,,,,,,,,,,,,,,,,~,,,,,,,,,,,,,,,, 1 2 3 4

5

6

7

8

+

9

10

Time (years) Fig. 1. Survival of patients with (para +) or without (para -) parametrial involvement. The numbers in parentheses indicate the number of patients surviving at 5 and 10 years (p = 0.05).

The 5- and IO-year actuarial survival rates of the 44 patients were 37% and 34%, respectively. The rates of pelvic disease control were 72% at 5 and 10 years. Twentythree patients experienced a recurrence of their disease. Of these, 10 had recurrent disease apparently confined to the pelvis, 11 developed distant metastases only, and two developed recurrent disease in both the pelvis and distant sites. The median time to recurrence was 14 months. The first sign of disease recurrence was noted within 2 years of treatment in 18 patients (78%), between 2 and 5 years in three patients, and after 120 and 233 months in two patients. Seventeen patients had no parametrial involvement, 12 had unilateral involvement, and 15 had bilateral involvement. The survival and pelvic disease control rates for the 17 patients without parametrial involvement and for the 27 patients with parametrial involvement are shown in Figures 1 and 2. Survival was significantly better for patients without parametrial involvement than it was for those with parametrial involvement (56% vs 25% at 5 years, p = 0.05). The pelvic disease control rate was also better for patients without parametrial involvement, but

RESULTS go-

Forty-two patients had squamous carcinoma and two patients had undifferentiated carcinoma. The median age at presentation was 59 years (range 37-91 years). The presenting symptoms are shown in Table 1.

80-

Para

-

Pam

+

70605040-

Table 1. Presenting Symptom

30-

symptoms Number

20-

of patients

1001

Menometrorrhagia Postcoital bleeding Postmenopausal bleeding Vaginal discharge Pain No symptoms

5 3 32 17 3 1

CI

1

2

3

4

5 6 Time bears)

7

8

9

f

10

Fig. 2. Pelvic disease control of patients with (para +) or without (para -) parametrial involvement. The numbers in parentheses indicate the number of patients surviving at 5 and 10 years (p = 0.16).

Stage IIIA

carcinoma of the

cervix 0 V. S. KAVADI AND P. J. EIFEL

the difference was not statistically significant (88% vs 6 1% at 5 years, p = 0.16). Thirty-one patients had direct, continuous extension of disease to the lower third of the vagina and 13 patients had discontinuous (“skip”) lesions. The survival and pelvic disease control rates for the 3 1 patients with continuous lesions and for the 13 patients with skip lesions are shown in Figures 3 and 4. The actuarial survival rate at 5 years was poorer for patients with skip lesions (15%) than for those with continuous lesions (48%) (p = 0.05). The pelvic disease control rates for the continuous and skip groups were comparable, 72% and 75%, respectively. Thus, the lower survival rate reflects a high rate of distant relapse in patients with discontinuous lesions in the lower third of the vagina. When the two variables, presence/absence of parametrial disease and type of lower third vaginal involvement, are analyzed concurrently, four patient groups are formed. Figure 5 shows the survival characteristics of these four groups. The overall comparison achieves statistical significance with a p value of 0.03. Patients with continuous vaginal extension and without parametrial involvement did extremely well, with 5- and lo-year survival rates of 73%. Patients with either skip lesions or parametrial involvement had an intermediate survival of 29-36%. Patients with both skip lesions and parametrial involvement did very poorly, with none surviving at 5 years. Seven patients experienced Grade 3-5 complications. The actuarial rate of major complications (Grade 3 or above) was 2 1%. Two patients died of treatment complications. One patient had a sigmoid perforation, developed overwhelming sepsis, and died. She had, however, no evidence of cancer at the time of death and for survival analysis was scored as an intercurrent death. The second patient died 13 months after treatment. She had vaginal necrosis, bowel obstruction leading to resection, severe wound infection, and fistula formation. No pelvic biopsies or autopsy were performed, and her pelvic disease status remained unclear. Therefore, she was considered to have

60 50 40 30 20

213

1

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1

2

1,111,

3

4 Time

5 6 (years)

r,r1,Tr,,,,,,,l 7

8

9

10

Fig. 4. Pelvic disease control of patients with continuous or skip involvement of the distal vagina. The numbers in parentheses indicate the number of patients surviving at 5 and 10 years.

had major complications and was also considered in survival analyses to have died from her cancer. Her case illustrates the difficulty in distinguishing recurrence from complications in this group of patients who are treated aggressively for extensive disease.

DISCUSSION

Patients with Stage IIIA carcinoma of the cervix belong to a very rare group. As a result, their survival rate, prognostic features, and patterns of failure are usually not analyzed separately from other patients with Stage III disease. The 44 Stage IIIA cases treated at M. D. Anderson between 1955 and 1988 represent only 3% of all Stage III patients treated during this time period. In most cases, these patients were treated aggressively with a combination of external beam radiation and brachytherapy. The treatment approach was relatively uniform through the years. We

100 90 80 70 F? ‘s 60 2

50

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40

s

30

0

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1

2

3



,,,,,,,,,,,,,,,,,,,,,,

4 Time

5 6 (years)

7

8

9

,,I

1

2

3

4 5 6 Time bears)

7

8

9

10

10

Fig. 3. Survival of patients with continuous or skip involvement of the distal vagina. The numbers in parentheses indicate the number of patients surviving at 5 and 10 years (p = 0.05).

Fig. 5. Survival of patients with tumors displaying one, both, or neither of the adverse prognostic features of parametrial involvement and discontinuous (skip) involvement of the distal vagina. The numbers in parentheses indicate the number of patients surviving at 5 and 10 years (p = 0.03).

1. J.

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Radiation Oncology 0 Biology0 Physics

currently treat the whole pelvis to doses of 40-45 Gy at 1.8-2.0 Gy per fraction with AP/PA fields of 18 MV photons, including the entire vagina and bilateral inguinal regions in the fields. This is followed by brachytherapy consisting of intrauterine tandem and vaginal cylinders to bring the paracentral dose to 80-90 Gy and the pelvic sidewall dose to 50 Gy while respecting bladder and rectal tolerance. If significant parametrial disease persists at the time of the intracavitary therapy, it is boosted with external RT to 60-65 Gy. Vaginal disease is also treated to a minimum dose of 70-80 Gy. Interstitial implants are used to achieve this dose if the disease is amenable to implantation. Hintz et al. have suggested vaginal tolerance limits of 140 Gy to the upper vaginal mucosa and 98 Gy to the lower vaginal mucosa (7). We have used somewhat more conservative limits of 120- 130 Gy to the upper vagina and 70 to the entire distal vaginal mucosa. Smaller areas of distal tumor involvement may be boosted with interstitial therapy to a total dose of 80 Gy. The 5-year survival and pelvic disease control rates in this series were 37% and 72%, respectively. We determined two variables to be important predictors of prognosis: parametrial involvement and the pattern of vaginal involvement. Patients with parametrial involvement had a significantly lower survival and a lower rate of pelvic disease control (although this did not reach statistical significance). The increased pelvic failure rate and accompanying decrement in survival may be explained by the greater tumor volume associated with parametrial involvement. In contrast, the decreased survival of patients with discontinuous vaginal involvement appears to result from a relatively increased rate of distant metastases. Patients with “skip” lesions have a significantly lower survival rate (15%) than those with continuous involvement but have comparable pelvic disease control rates. Patients with “skip” lesions and parametrial involvement were in

Volume 24, Number 2, 1992 the worst prognostic

group, with all patients

dead of dis-

ease by 5 years. Patients with continuous lesions who had no parametrial involvement were in the most favorable group, with a 5-year survival of 73%. Most authors report Stage III results without categorizing the patients as IIIA or IIIB. Table 2 lists several series that have reviewed this group of patients. The 5year survival rates for patients with FIG0 Stage IIIA disease range between 9% and 62%. The weighted average 5-year survival rate of 13 1 patients in the five series that state both the number and survival rate of FIG0 Stage IIIA patients is 34%. The 5-year survival rates for patients with Stage IIIB disease range between 33% and 50% in these same series. In the most recent Patterns of Care Study reported by Coia et al., the 5-year survival rate for all Stage III patients was 33%, and the authors state that patients with Stage IIIA and IIIB disease had the same survival rates (3). In a review of 3 1,543 patients treated at 114 institutions in 35 countries, the authors ofthe 1988 FIG0 Annual Report described a crude survival rate of 3 1% for all patients with Stage III disease (1). Thus, although some authors have suggested that patients with Stage IIIA disease have a somewhat more favorable outcome than other Stage III patients (2, 8), the general experience reviewed in Table 2 suggests that the survival rates are similar. The reports summarized in Table 2 illustrate how rare it is for patients with cervical cancer to have extensive vaginal involvement without pelvic wall fixation or hydronephrosis. In most series that report the number of patients with IIIA disease, this presentation has been observed in less than 5% of Stage III patients. Only Montana et al. have reported a significantly larger proportion of patients (24%) with Stage IIIA disease (10). The FIG0 classification states, “A (vaginal) growth that has extended to the portio and reached the area of the

Table 2. Summary of the liturature Survival %

Author

Year

Fletcher (4) Jampolis et al. (9) Hilesmaa et al. (6) Thar et al. (12) Montana et al. ( 10) Cardinale et al. (2) Perez et al. (11) Horiot et al. (8) FIG0 (1) Coia et al. (3) Kavadi and Eifel

1971 1975 1981 1982 1986 1986 1986 1988 1988 1990 Current

No. of FIG0 IIIA patients

11 48 17 11

5 44

Total Stage III patients 599 218 311 61 203 237 482 31,543 115 1473

FIG0 IIIA/ all Stage III %

3.5 24 4.6

4.3 3

* M. D. Anderson Cancer Center staging system (see Methods and Materials).

FIG0 Stage IIIA

9 26 58 45 62

BIB

M.D.A. Stage* IIIA

BIB

45 54

36 40

36

31

33 35 34 45 50

All Stage III

32 33

61

39 31 33

37

Stage IIIA carcinoma of the cervix 0 V. S.

external OSshould always be allotted to carcinoma of the cervix” (1). However, in some cases, Stage IIIA carcinoma of the cervix may be very difficult to differentiate from primary carcinoma of the vagina particularly when extensive vaginal disease prevents good visualization of the cervix. The clinical diagnosis of lower vaginal involvement is also somewhat subjective. There is no anatomical landmark identified with the start of the lower third of the vagina. The anterior and posterior vaginal walls are not of equal length, the normal vaginal length may be obscured by tumor, and the anterior distal vagina may be compressed by bulky endocervical tumor. Therefore, even though the FIG0 criteria for classification of IIIA disease

KAVADI AND

P. J.

EIFEL

215

are clear, the clinical implementation of these guidelines may be inconsistent. In summary, we have determined survival and pelvic disease control rates and prognostic features of 44 Stage IIIA patients treated with a fairly homogeneous treatment approach. Our 5-year survival rate of 37% is similar to the 5-year survival rate for all Stage III patients, including IIIB patients, as reported in the literature. Since this disease presentation is so rare, comprising only 3% of all Stage III patients at M. D. Anderson, and the survival is comparable to IIIB patients, the subclassification of Stage III according to FIG0 criteria is unrealistic and does not provide useful prognostic information.

REFERENCES 1. Carcinoma of the cervix uteri. In: Pettersson, F., ed. Annual

report on the results of treatment in gynecological cancer F.I.G.O. 1988. Stockholm, Sweden: Radiumhemmet; 1988: 29-34. 2. Cardinale, J.; Peschel, R.; Gutierrez, E.; Kapp, D.; Kohorn, E.; Schwartz, P. Stage IIIA carcinoma of the uterine cervix. Gynecol. Oncol. 23: 199-204;1986. 3. Coia, L.; Won, M.; Lanciano, R.; Martial, V.; Martz, K.; Hanks, G. The patterns of care outcome study for cancer of the uterine cervix. Results ofthe second national practice survey. Cancer 66:245 l-2456; 1990. 4. Fletcher, G. Cancer of the uterine cervix. Janeway lecture, 1970. Am. J. Roentgenol. 3:225-242;1971. 5. Fletcher, G.; Hamberger, A. Squamous cell carcinoma of the uterine cervix. Treatment technique according to size of the cervical lesion and extension. In: Fletcher, G., ed. Textbook of radiotherapy. Philadelphia, PA: Lea & Febiger; 1980:720-778. 6. Hilesmaa, V.; Vesterinen, E.; Nieminen, U.; Griihn, P. Carcinoma of the uterine cervix Stage III: a report of 3 11 cases. Gynecol. Oncol. 12:99- 106;198 1.

7. Hintz, B.; Kagan, A.; Chan, P.; Gilbert, H.; Nussbaum, H.; Rao, A.; Wollin, M. Radiation tolerance of the vaginal mucosa. 6:71 l-716;1980. 8. Horiot, J.; Pigneux, J.; Pourquier, H.; Schraub, S.; Achille, E.; Keiling, R.; Combes, P.; Rozan, R.; Vrouson, C.; Daly, N. Radiotherapy alone in carcinoma of the intact uterine cervix according to G. H. Fletcher guidelines: a French cooperative study of 1383 cases. Int. J. Radiat. Oncol. Biol. Phys. 14:605-611;1988. 9. Jampolis, S.; Andras, J.; Fletcher, G. Analysis of sites and causes of failures of irradiation in invasive squamous cell carcinoma of the intact uterine cervix. Radiology 15:68 l685; 1975. 10. Montana, G.; Fowler, W.; Varia, M.; Walton, L.; Mack, Y.; Shemanski, L. Carcinoma of the cervix, Stage III. Results of radiation therapy. Cancer 57: 148- 154; 1986. 11. Perez, C.; Camel, H.; Kuske, R.; Kao, M.; Galakatos, A.; Hederman, M.; Powers, W. Radiation therapy alone in the treatment of carcinoma of the uterine cervix: a 20-year experience. Gynecol. Oncol. 23: 127-140;1986. 12. Thar, T.; Million, R.; Daly, J. Radiation therapy of carcinoma of the cervix. Sem. Oncol. 9:299-3 11;1982.

FIGO stage IIIA carcinoma of the uterine cervix.

Between 1955 and 1988, 44 patients with FIGO Stage IIIA carcinoma of the cervix were treated with radiotherapy at The University of Texas M. D. Anders...
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