Int. _I. Radiation Oncology Biol. Phys.., Vol. 5, pp. 2053-2057 0 Pergamon Press Ltd., 1979. Printed m the U.S.A.

??Brief Communication

0360-3016179/112053-05$02.0010

MANAGEMENT OF LATE SECOND OR LATE RECURRENT SQUAMOUS CELL CARCINOMA OF THE CERVIX UTERI AFTER SUCCESSFUL

INITIAL RADIATION TREATMENT

THONGBLIEW PREMPREE, M.D., Ph.D.,? TAE KWON, M.D.,+ UMBERTO VILLASANTA, M.D., F.A.C.0.G.Z and RALPH .M. SCOTT, M.D.?

University of Maryland Hospital, School of Medicine, Baltimore, Maryland 21201

Late second or late recurrent squamous cell carcinoma of the cervix uteri after successful initial radiation treatment is a very rare disease. Surgery is generally accepted as the treatment of choice for late second or recurrent invasive cervical cancer. We have re-irradiated six of eight patients with very late invasive cervical cancer; three survived more than 5 years with no evidence of disease (NED); two achieved guod palliative results without major complications. The treatment of choice for second in situ cervical cancer is surgery with excellent results.

It is felt that there is a definite need for continued follow-up over many years, especially in the young age group to obtain early diagnosis and effective treatment.

Late second ca. of the cervix, Late recurrent ca. of the cervix, Ca. cervix, Squamous cell ca. cervix.

INTRODUCTION

The terms persistence or recurrence often are used to describe the clinical status of treated tumors. Persistence refers to the continued presence of tumor after treatment and recurrence to complete disappearance followed by a re-manifestation of the tumor after the treatment. In the majority of cases of cancer of the cervix, recurrences are manifest within two years (SO-85%) and rarely after 5 years (l-2%) following the treatment. l5 Several factors have been cited as cause of persistence or early recurrence (1-2 yrs.), but inadequate dosage to the tumor appears to be responsible for most failures.s*12

Late recurrence (5-10 years), on the other hand, is an entity far more difficult to assess.1*51s In addi- tion to dosage to the tumor, several other factors including host susceptibility and resistance, and our inability to recognize early stages of recurrence have all been cited as possibly being responsible.s3 Recur- rences after ten years of apparent disease-free survi- val are even more surprising and inter- esting. ~AWJ~J~~~O-~~ These lesions present an intrigu- ing problem to determine if they are true recur- rences or new cancers. This is a study of 13 such

cases. Eight appeared as very late recurrent or late second invasive squamous cell carcinoma of the cervix and five occurred as very late recurrent or late second carcinoma in situ after what appeared to be successful irradiation treatment.

METHODS AND MATERIALS Between 1957 and 1977, 1733 patients with proven

invasive carcinoma of the cervix were treated at the University of Maryland Hospital, Department of Radiation Therapy. During the same time, 8 patients with late second invasive cervical cancer and five patients with late second in situ cancer of the cervix were diagnosed and treated.

This incidence of late second invasive cervical cancer (8/1733=0.46%) is compatible with the 0.5% incidence reported by McIlhaney and Kaplan.15 If late second invasive and in situ cancers of the cervic were all included, the incidence would be (13/1733) 0.75%.

Table 1 summarizes the pertinent data relating to eight patients with invasive cervical cancer and Table 2 summarizes data of 5 patients with in situ cervical cancer.

tDepartment of Radiation Therapy. 22 S. Greene Street, Baltimore, MD 21201. *Department of Obstetrics and Gynecology. Accepted for publication 21 August 1979. Reprint requests to: Thongbliew Prempree, M.D., Ph.D., Acknowledgement-Debbie Kahn provided secretarial

Department of Radiation Therapy, Martha V. Filbert Ra- assistance. diation Center, University of Maryland Hospital,

20.53

2054 Radiation Oncology 0 Biology 0 Physics November-December 1979, Vol. 5, No. 11 and No. 12

Table 1. Patient data: Invasive cervical cancer

First cancer Second cancer

Interval to FIGOt second

Patient Age stag- Treatment cancer Pap smear Findings Treatment Outcome no. (year) ing (years)

1 (123)

2 (lZ9)

3 (Z2)

4 (lZ8)

5 (120)

6 (Z7)

7 (1%)

8 34

I

IB

IB

IB

IIB

IIB

IIB

I

TP 3500 t-ad/ 312 weeks + Ra. 5400 mg. hrs.

2 Radium (total 6000 mg. hr.) TP 4000 radl4 weeks

TP 2000 radl2 weeks TV cone 3500 radl7 treat- ments

4500 mg. hrs. +2000 R in air TP

TP 4000 radl 4 weeks PWs 4600/4/2 weeks +Ra. 5200 mg. hrs.

TP 2000 radl 2 weeks+lst Ra. 5040 mg. hrs. (72 hrs.) PWs 2000 radi2 weeks 2nd Ra. 3360 mg. hrs. (48 hours)

TP 4000 radl4 weeks + Ra. 6120 mg. hrs. (72 hrs.) + hysterectomy 2 months later

TP 4000 radl4 (1965) (Post weeks PWs 5000

TAH & rad/5 weeks + BSO) Ra. 2 ovoids

2160 mg. hrs. (72 hrs.)

32 Not done Invasive squamous Ileal loop conduit, NED 8+ ceil ca. cervix with VV fistula Stage IVA

electron-35MeV years TP 6000 rad/6 weeks RPW 7000 radl7 weeks LPW 6000 rad/6 weeks

13 Not done Stage I cervix TP 2000 radl2 weeks NED 11+ squamous cell TV cone years ca. (IB) 4000 radl3 weeks

11 Positive Squamous cell ca. cervix, vagina (IB)

TV cone 6000 radl4 weeks

NED 7+ years (Died of other ca. in 1970)

16 Positive Squamous ca. vaginal vault

Radium needles 5500 Recur in rad/6 + days 2 years

Total pelvic exentera- tion NED 1 1 + years

13

10

20

12

Positive Squamous cell ca. Refused surgical Disease cervic Stage III treatment present

when last seen Oct. 1974

Not done Mass in pelvis Total pelvic NED IO+ Stage III sq. ca. exenteration years cervic, invasive

Not done Invasive sq. ca. TP 2000 rad/2 weeks Residual cervix with VV + rotational therapy disease fistula 2000 rad/2 weeks show but (Stage IVA) good response. Refused acheived

to have ra. therapy palliation

Not done Invasive sq. ca. TP 2000 radl2 weeks Residual cervix rotation 220012112 disease (Stage IIIB) weeks + ovoid and but

radium needles in achieved left parametrium palliation 3000 rad

tIntI. Federation of Gynecologists and 0bstetricians.14 TP=total pelvis irradiation. Pap smear=Papanicolaou. TV=transvaginal therapy.

PW =pelvic wall irradiation. RPW=right pelvic wall irradiation. LPW =left pelvic wall irradiation.

NED=no evidence of disease (cancer). VV=vesico-vaginal. TAH&BSO=total abdominal hysterectomy & bilateral salpingo-oophorectomy.

Uterine squamous cell carcinoma management 0 T. PREMPREE et al.

Table 2. Patient data: In Situ cervical cancer

2055

First cancer Second cancer

Interval to FIG0 second

Patient Age Stag- Treatment cancer Pap smear Findings Treatment Outcome no. (year) ing (years)

1 (lz4)

2 (lGZ7)

3 (I&)

4 (l&)

5 (&I)

IA

IB

IB

IIIB

IB asso- ciated with preg- nancy

TP 2000 rad/ 2 weeks+Ra. 5400 mg. hrs. (72 hr.)+Ra. 2640 mg. hrs. (48 hrs.)

Radium 5760 mg. hrs. (72 hrs.) +PWs 2000 radl2 weeks radium 5760 mg. hrs. (72 hrs.)

TP 2000 radR weeks PWs 3500 rad/3/2 weeks Radium 5400 mg. hrs. (72 hrs.) Radium 3 120 mg. hrs. (48 hrs.)

TP 4000 rad/ 4 weeks LPW 5500 rad/5/2 weeks RPW 5000 rad/S weeks+Ra. 5760 mg. hrs. (72 hrs.)

TP 2000 rad/ 2 weeks PWs 4000 radM weeks+Ra. 7680 mg. hrs. (% hrs.)

13

12

14

12

11

Positive In situ ca. in cervix and upper vagina

Positive In situ ca. Total pelvic NED 7t upper vagina exenteration years

Positive 1n situ ca. upper vagina

Positive In situ ca. upper vagina

Positive In situ ca. upper vagina

TAH&BSO

Partial NED less vaginectomy than 1 1978 year

Partial vaginectomy 1978

TAH&BSO and partial vaginectomy

NED 1/2 years

NED less than 1 yr.

NED 3 yrs.

TP=total pelvis irradiation. Pap smear = Papanicolaou . TV = transvaginal therapy. NED=no evidence of disease (cancer). VV=vesico-vaginal. TAH&BSO=totaI abdominal hysterectomy & bilateral sapingo-oophorectomy. PW =pelvic wall irradiation. RPW=right pelvic wall irradiation. LPW=left pelvic waII irradiation.

Interesting features Age-Most of these patients were relatively young

at the time of their initial diagnosis and treatment by irradiation. One was in the late twenties, four in the thirties, six in the early forties and two in the early fifties.

Histology-In all patients, both the first and sec- ond cancers were squamous cell carcinoma.

Staging-At the time of the second diagnosis five of the eight patients with invasive cervical cancer presented with a more advanced stage than when they were first diagnosed. It is important to note here that International Federation of Gynecologists and Obstetricians (FIGO) classification is applicable only to the first cancer not the second one.14 We use it in the second cancer only to describe the exten- sion of the disease.

2056 Radiation Oncology 0 Biology 0 Physics November-December 1979, Vol. 5, No. 11 and No. 12

Papanicolaou smear Late second invasive cervical ca. (Table l)-

Papanicolaou test, performed as part of the follow-up in three patients provided information for early diag- nosis. No pap smear was performed in the other five patients.

Late second in situ cervical ca. (Table 2)-Early diagnosis was made in all five patients apparently as a result of positive routine pap smear. Biopsy was obtained and proper treatment ensued with excellent results.

TREATMENT

Treatment for the first cancer As Tables 1 and 2 show, all patients received a

combination of external irradiation and radium; cur- rently accepted treatment schedules were used, stage by stage. Whole pelvis irradiation was carried out by using joCobalt teletherapy, four-field technique with 15x15 cm. AP and PA ports and 15x 10 cm. lateral ports. The radium therapy was given two weeks after completion of external irradiation. The amount of shown in Tables 1 and 2. The only difference is that before 1957 orthovoltage X-ray was used for external irradiation.

Treatment for second cancer (A) Invasive ca. (Table 1). In one patient, total

pelvic exenteration was performed, with good re- sults. Six patients received radiation alone ranging from whole pelvis irradiation, transvaginal therapy, radium needles implant or combination.

As Table 1 shows, the treatment was modified and individualized according to the extent of the disease as well as the amount and type of radiation previously used. If a full course of whole pelvis irradiation was given for the first cancer by four-field technique, we usually used short course of four-field or rotational therapy technique with a smaller field for the second cancer to achieve whole pelvis and/or pelvic wall irradiation.

(B) In situ ca. (Table 2). The treatment for in situ ca. ranged from partial vaginectomy to total abdominal hysterectomy with bilateral salpingo- oophorectomy. Total pelvic exenteration was per- formed in one patient because of questionable inva- sive ca. of the vagina but the final pathological re- port confirmed in situ ca.

RESULTS

(A) Invasive ca. (Table 1) Of six patients treated by radiation for their sec-

ond cancer, three patients survived with no evidence of disease (NED) more than 5 years (3/6=5&G); two

patients had short term symptom-free survival after completion of irradiation; one patient failed after re- irradiation but was successfully salvaged by total pelvic exenteration.

In one patient, total pelvic exenteration was per- formed, with no evidence of disease (NED) for more than 10 years.

One patient refused to have surgical treatment and was transferred to another location with no further follow-up.

Based on the eight patients who were treated, five had long term survivals NED (5/8=62.5%).

(B) In situ ca. (Table 2) Of five patients treated by surgical therapy, all

patients showed excellent results at the time of this writing with no evidence of recurrence of their dis- eases ranging from one to seven years.

DISCUSSION

Late recurrence vs. late second cancer Available data give rather conflicting evidence re-

garding late recurrence vs. second cancer. Several reports suggest, but not conclusively, that there is a low, but definite number of late recurrences among several cancer patients who were treated previously with irradiation alone1~3~5~s~10~1*~1s~*H and one who re- ceived surgical treatment a1one.20 Still it is clear from every report that this is an equivocal diagnosis and that a second cancer is not excluded.4,7*11,16 The term, late recurrence, can be used only to describe the reappearance of cervical cancer after a long ap- parent disease-free survival following treatment either by surgery or irradiation. 1,2,7~1fi

Treatment of choice The question of whether these tumors represent

new or recurrent cancers is largely academic; the major problem is the choice of the best treatment when they do occur. Previous reports and our own experience suggest that treatment depends upon the extent of the disease, the type of treatment pre- viously administered, and the time interval between the initial treatment and the second appearance of cancer. *M*~J*J~J~J~ In the literature, radical surgery is suggested most often as the treatment of choice.,3,fi,12,13*17 In a few patients retreatment with irradiation has been possible after careful consid- eration.12* Obviously, this experience is limited.

In patients with both early recurrence (l-5 years) and late recurrence (5-10 years), re-irradiation gen- erally is not considered because of low normal tissue tolerance. We have re-irradiated six of eight patients with very late recurrent cervical ca. (or late second ca. more than 10 years) with 50% success NED (one

Uterine squamous cell carcinoma management 0 T. PREMPREE et nl. 2057

patient with Stage IV and two with Stage IB dis- ease); two patients achieved a palliative result. Re- treatment by irradiation after 10 or more years fol- lowing the first irradiation may be feasible in selected patients where the normal tissue state has good tolerance. Further studies are needed to eluci- date this point.

Early detection Table 2 shows that all five cases of in situ ca.

were diagnosed early by Papanicolaou smear. Treatment at that time is relatively easy with excel- lent success. It appears then that early detection is the key to success, thus emphasizing the need for continued surveillance long after the initial treat- ment.

CONCLUSION (1) Late second invasive cancer of the cervix is

described in eight patients 10 to 32 years after ap-

parent successful treatment of an initial cervical cancer by irradiation.

(2) Late second in situ cancer of the cervix is also described in five patients 11 to 14 years after suc- cessful treatment by radiation.

(3) The second invasive cervical cancer generally is detected in a more advanced stage than the first.

(4) Treatment of choice for second invasive cervi- cal cancer depends on stage of disease, previous treatment and the time lapse between the first and second cancers. Surgery is generally accepted as the treatment of choice. We have re-irradiated six patients; three survived NED more than five years; two achieved a good palliative result without serious complications.

(5) Treatment of choice for second in situ cervical cancer is surgery with excellent results.

(6) In our series, five of eight cases of very late invasive cervical cancer have been salvaged (62.5%).

(7) This presentation emphasizes the need for continued follow-up over many years, especially in the younger age groups.

REFERENCES 1. Barrie, J.R., Brunschwig, A.: Late second cancers of

the cervix after apparently successful initial radiation therapy. Am. J. Roentgenol. Radium Ther. Nucl. Med. 108(l): 109-112, 1970.

2. Bonte, J., Ide, P.: Prognostic value of persistent cancer cells in vaginal smears of patients with cervical carcinoma treated by radiotherapy. .I. Reprod. Med. 6(5): 226228, 1971.

3. Calame, R.J.: Recurrent carcinoma of the cervix. Am. J. Obstet. Gynecol. lOS(3): 380-385, Oct. 1969.

4. Calame, R.J., Perticucci, S., de Fazio, L.: Multiple primary carcinoma of the uterus: A review. Obstet. Gynecol. Surv. 25(3): 191-206, March 1970.

5. Colpitts, R.V., Rogers, R.E.: Recurrent carcinoma of the cervix at the University of Texas M.D. Anderson Hospital and Tumor Institute at Houston Jan. 1948 - August 1963. Cancer of the Uterus and Ovary. Chicago Year Book Medical Publishers, Inc., 1969, pp. 269 282.

6. Concourde, F., Maestro, A.: The management of re- currences of malignant tumors of the uterine cervix by 42 MeV betatron. Radiol. Clin. Biol. 39(5): 407-418, 1970.

7. Cook, G.B.: A comparison of single and multiple pri- mary cancers. Cancer 19: 959-%6, 1966.

8. Covington, E.E.: Recurrence of carcinoma of the cer- vix after 15 years. Am. J. Obstet. Gynecol. 87: 471- 477, 1%3.

9. Evans, S.R., Hilaris, B.S., Barber, H.R.K.: External interstitial irradiation in unresectable recurrent

iihcer of the cervix. Cancer 28: 1284-1288, 1971. 10. Geisler, H.E.: Carcinoma of the cervix or vagina, 10 or

more years after therapy: Recurrence or new primary? J. Ind. State Med. Assoc. 67: 711-712, 1974.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

Hutchinson, G.B.: Late neoplastic changes following medical irradiation. Cancer 37: 1102-l 107, 1976. Jones, T.K., Jr., Levitt, S.H., King, E.R.: Retreat- ment of persistent and recurrent carcinoma of the cer- vix with irradiation. Radiology 95( 1): 167-174, 1970. Keettel, W.C., Van Voorhis, L.W., Latourette, H.B.: Management of recurrent carcinoma of the cervix. Am. J. Obstet. Gynecol. 102(5): 671-679, 1968. Kottmeier, H.L.: Classification and staging of malig- nant tumors in the female pelvis. J. Int. Fed. Gynecol. Obstet. 9: 172-179, 1971. McIlhaney, J.R., Jr., Kaplan, A.L.: Recurrences of carcinoma of the cervix after ten years. South Med. J. 62(9): 1119-l 122, 1969. Morton, R.F., VillaSanta, U.: New cancers arising in 1563 patients with carcinoma of the cervix treated by irradiation. Am. .I. Obstet. Gynecol. 115(4): 462-466, 1973. Nowakowski, W.: Recurrences of cervical carcinoma treated with Co60. Radiobiol. Radiother. 9(5): 609-614, 1968. Prasasvinichai, S., Glassburn, J.R., Brady, L.H.: Treatment of recurrent carcinoma of the cervix. Znt. J. Radiation Oncology Biol. Phys. 4: 957-961, 1978. Pride, G.L., Buchler, D.A.: Carcinoma of vagina 10 or more years following pelvis irradiation therapy. Am. J. Obstet. Gynecol. 127: 513-517, 1977. Sheldon, R.S., Decker, D.G., Lee, R.A.: Recurrence of carcinoma of the cervix 25 years after primary sur- gical treatment: Report of a case. Am. J. Obstet. Gynecol. llO(8): 1140-1141, 1971. Van Herik, M., Decker, D.G., Lee, R.A., Symmonds, R.E.: Late recurrence in carcinoma of the cervix. Am. J. Obstet. Gynecol. 108: 1183-1186, 1970.