29 Adjuvant chemotherapy after radical hysterectomy for cervical cancer M. LAHOUSEN H. PICKEL J. H A A S
Invasive cervical cancer in Stages Ib to IIb can be treated by surgery or radiotherapy, or both. The guidelines found in the literature for the treatment of the individual stages of cervical cancer differ. At many centres, Stage IIb cancer is treated by primary radiotherapy (DiSaia and Creasmen, 1981; Piver et al, 1985) while in other centres radical surgery is preferred (Ober, 1978; Zander et al, 1980; Burghardt et al, 1987). The question is further complicated by the possibility of radiotherapy before surgery (Burch and Chalfant, 1970; Fletcher and Rutledge, 1972; Stallworthy, 1981). At our hospital we treat the majority of Stage I and II cancers by surgery (Chapter 24). Until 1978 all patients routinely received postoperative radiotherapy (total dose: 60-70 Gy) directed at the middle of the true pelvis. WHY
POSTOPERATIVE
RADIOTHERAPY.9
Postoperative radiotherapy was meant to eradicate microscopic tumour residuals missed by surgery. The effect of radiotherapy on tumour deposits in pelvic lymph nodes is undisputed, but it requires an even distribution of the dose in the true pelvis, and an adequate tumour-kill dose at the target. A total dose of 70-80 Gy in the mid-pelvis almost completely ensures the eradication of tumour residuals. However, the rectum and bladder tolerate only 60 Gy. Higher doses increase the early and delayed effects of radiotherapy--such as Vesicovaginal fistula and ureteral stenosis. I,arger tumour volumes require higher doses which entail a higher complication rate. Radiotherapy of the para-aortic field causes especially severe side effects in the upper abdomen. The complications, even deaths, reported by Piver (1987) and Wharton et al (1976) after application of tumoricidal doses of radiation to the para-aortic field make this procedure questionable. Adjuvant radiation therapy may not enhance five-year survival. This applies equally to patients with and without node metastasis (Table 1), and is confirmed by our experience. There was no difference in the survival rate of patients who had or had not received postoperative radiotherapy in Bailli~re's Clinical Obstetrics and Gynaecology--Vol. 2, No. 4, December 1988
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M. LAHOUSEN ET AL
Table 1. Five-year survival rate of patients with metastases to the pelvic lymph nodes after radical abdominal hysterectomy and pelvic lymphadenectomy for Stage Ib cervical cancer. Piver and Chung (1975) Hsu et al (1972) R a m p o n e et al (1973) Masubuchi et al (1969) Burch and Chalfont (I970) Kelso and Funnel (1973) Morrow (1980) Martimbeau et al (1982)
81 14 14 30 120
62.9 57.1 57.1 60.0 53.0
39 32 23 144 -
55.2 40.6 56.0 59.0 -
Total
259
58.0
238
52.7
Stages Ib, IIa or IIb cervical cancer (Figure 1), even in patients with positive nodes (Figure 2).
LYMPH NODE INVOLVEMENT Node involvement indicates tumour propagation and systemic spread. Histologically visible invasion of blood vessels raises the possibility of distant metastasization (Figure 3). Both factors influence treatment results. If 100
90 80
"-'•-" ....
78.4% 76.5%
70
g
60
40 30 20 10 0
o Survival
(years)
Figure 1. Survival of patients who have (- - -, n = 170) or have not had ( - •, n = 184) postoperative radiotherapy in Stage Ib or lib cervical cancer.
ADJUVANT CHEMOTHERAPY
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100" 90 80 7062.2%
60-
55.4%
v
50403020-
10 0 Survival (years)
Figure 2. Survival of patients with positive nodes who have (- - -, n = 59) or have not had ( - - n = 77) postoperative radiotherapy.
nodes are positive, the five-year survival rate of patients after truly radical surgery is about 60%. There was no statistically significant difference between patients who had or had not had postoperative radiotherapy. The unfavourable results associated with node involvement are very probably the results of disease spread. Tumour deposits lie not only in the nodes, almost all of which can be removed by thorough surgery, but also in the lymph channels between the nodes. The surgeon cannot be sure of having removed these completely. These cell nests, and perhaps small remaining nodes, are probably sources of tumour recurrence. Postoperative radiotherapy was not able to eliminate such tumour residuals in the true pelvis. This raised the issue of whether systemic chemotherapy would improve survival. CHEMOTHERAPY
Stage IIIb cervical cancers are inoperable. The patients are referred to primary radiotherapy. Montana et al (1986) reported a five-year survival rate of 30% in such patients. The patients died of local persisting tumour, of recurrence, or of distant metastasis. The development of antineoplastic agents effective against squamous cell cancer suggested an alternative treatment for patients with advanced cervical cancer. Cis-platinum, cyclo-
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M. L A H O U S E N ET A L 100-
9083.2% 80.....
70-
72.0%
60v
~ t/3
5040 30 20 10 0
o
i Survival (years)
F i g u r e 3. Survival of p a t i e n t s w i t h (- - -, n = 199) or w i t h o u t (
, n = 155) v a s c u l a r i n v a s i o n .
phosphamide, adriamycin, methotrexate, vincristine, bleomycin, and mitomycin C were used in a variety of combinations. As in other cancers, cisplatin was the most effective drug. The most effective schedule to date has been that proposed by Alberts et al (1981) containing bleomycin, mitomycin C, vincristine, and cisplatin. Between 1981 and June 1985 we treated 39 patients according to Alberts' schedule. Eight of these patients had Stage IIIb or IVb cancer, and nine had distant metastasis after radical abdominal surgery for Stage Ib or IIb disease. Twenty-two patients had recurring or persisting tumour after radical surgery and postoperative complete radiotherapy (n = 10) or after primary radiotherapy (n = 12). All 39 patients had squamous cell carcinoma for which curative surgery or radiotherapy was no longer possible. A prerequisite for chemotherapy was intact renal function and no urinary tract obstruction, for which four women received a nephrostomy. Table 2 shows the chemotherapy schedule. On day 1 the patients received vincristine (0.5 mg/m2), cisplatin (50 mg/m 2) and bleomycin (30 mg) intravenously. Fluid (2000 ml) was given ahead of cisplatin. On day 2, 10 mg/m 2 of mitomycin C were administered. After a pause on day 3, the patients received the day 1 schedule without the cisplatin. On the 22nd day cisplatin was administered (50 mg/m 2) after hyperhydration. The combination was repeated four times at three-week intervals (Lahousen et al, 1987).
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Table 2. Chemotherapy regimen.
vincristine bleomycin cis-platinum mitomycin-C Day 2 Day 4 vincristine bleomycin Day 22 cis-platinum
Day 1
0.5 30.0 50.0 10.0 0.5 30.0 50.0
mg/m 2 mg mg/m 2 mg/m 2 mg/m2 mg mg/m 2
i,v, i,v. i.v. i.v. i.v. i.v. i.v.
RESULTS
Table 3 gives the criteria used to gauge the response to chemotherapy. Remission was achieved in 58.8% of the patients without previous radiotherapy (Table 4). In three of these patients the remission was complete and still persists over five years later. The results were less favourable among the patients who had previously had radiotherapy. Of the 22 patients in this group, 45.4% had objective remission (Table 5), and three had complete remission for almost two years. The average survival of the 20 patients who responded favourably to chemotherapy was 20.7 months (Table 6). Survival averaged 62 months in patients with complete remission, but only 7 months in patients with incomplete remission. Overall, 51.3% of the patients had complete or partial remission for at least six months (Table 7). Table 3. Criteria used to gauge the response to chemotherapy. Complete Partial No change
Disappearance of all clinical evidence of turnout for at least six months, Decrease of 50% or more in the sum of the product of the diameters of measured lesions for a minimum of six months. No evidence of tumour reduction, increase of 5(1% in the size of the tumour, or appearance of a new lesion. Table 4. Chemotherapy of cervical cancer with n o prior radiation: objective response. Response
Number
Complete Partial No change Total
3 7 7 t7
% 17,6 t 41.2 , 58.8 41.2 100,0
Table 5. Chemotherapy of cervical cancer with prior radiation: objective response. Response
Number
Complete Partial No change Total
3 7 12 22
% 13.6 / 31.8 j 45.4 54.6 I00.0
M. LAHOUSENET AL
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Table 6. Duration of survival after chemotherapy. Survival (months) Number range mean Non-irradiated patients
Complete response and partial response No change
10/17 (3*) 7/17
7-62 2-14
24.7 6.3
7-48 2-17
16.7 6.3
Patients subjected to primary or postoperative irradiation
Complete response and partial response No change *Still alive.
10/22 12/22
Table 7. Chemotherapy of cervicalcancer all cases: objective response. Response Number % Complete 6 15.4 / Partial 14 35.9 ~ 51.3 No change 19 48.7 Total 39 100.0
Side-effects Apart from temporary alopecia and nausea, we saw no serious side-effects. There were no neurological deficits, signs of ototoxicity, or severe myelosuppression. Serum creatinine and urea levels stayed normal. Four women had increased skin pigmentation similar to that seen in dialysis patients. This effect can be ascribed especially to bleomycin.
Adjuvant polychemotherapy These results led us to consider adjuvant chemotherapy for selected patients who had undergone primary surgery for invasive Stage Ib, IIa or IIb cervical cancer. The question was whether adjuvant chemotherapy could improve the relatively poor survival of patients with positive nodes or demonstrated vessel invasion. A decision about chemotherapy was made on the basis of the histological evaluation of the surgical specimen. Polychemotherapy was given to patients with positive pelvic or parametrial nodes or in cases where the tumour had invaded the vascular space (Table 8). We wanted to determine whether systemic therapy was better suited than radiotherapy for the elimination of tumour residuals.
Table8. Indicationsfor adjuvant chemotherapy after radical abdominal hysterectomy. Positive pelvic lymph nodes Positive parametriat lymph nodes Tumour invasion of the vascular space
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ADJUVANT CHEMOTHERAPY
Results of adjuvant chemotherapy We separated our patients into three groups according to treatment. All patients underwent standardized radical abdominal hysterectomy. In 166 patients this was the only treatment. A total of 170 patients underwent postoperative radiotherapy with cobalt-60. Twenty-nine patients received postoperative chemotherapy according to the schedule mentioned above. Each of the three groups of patients was burdened with certain risk factors: tumour size, pelvic or parametrial node involvement, and vascular invasion. Figure 4 shows that the patients who received chemotherapy were, by far, at the highest risk. The tumour size was larger, and the frequency of node involvement and vascular invasion more common than in the other two groups. Nonetheless, after a three-year follow up the chemotherapy patients had fewer recurrences and fewer deaths (Figure 5).
100-
80-
60.
g g. 40 .
/
. . .
/
,
,/ r
20-
j
"""
\ \ \ J / t
o
''~
/
lal
(b)
(c)
Figure 4. Distribution of (a) turnout size, (b) positive pelvic lymph nodes, (c) positive parametrial lymph nodes and (d) vascular invasion in patients after surgery. [ ] radical abdominal hysterectomy + radiotherapy (n = 170); [ ] radical abdominal hysterectomy only (n = 166); [ ] radical abdominal hysterectomy + chemotherapy (n = 29).
The small number of patients and the three-year follow up preclude the drawing of statistically significant conclusions about differences in survival among the three groups. But this preliminary investigation supports the use of a combination of antineoplastic agents in patients with certain risk factors. We consider postoperative chemotherapy to be promising in patients with systemic disease.
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M. LAHOUSEN ET AL 100-
80-
6o-
0- 40-
o
1 Recurrence
Death
Figure 5. Three-year survival rate of patients after surgery. [ ] radical abdominal hysterectomy + radiotherapy (n = 170); [ ] radical abdominal hysterectomy only (n = 166); radical abdominal hysterectomy + che'motherapy (n = 29).
SUMMARY
Invasive cervical cancer can be treated by surgery, radiotherapy, and cytostatic chemotherapy. For decades, surgery alone or in combination with radiotherapy was the treatment of choice. At our hospital, primary radiotherapy was reserved for patients with advanced disease. Antineoplastic agents, especially combinations which included cisplatin, achieved good results in patients with advanced disease---or after other therapeutic modalities had been exhausted. This led us to use postoperative chemotherapy for high-risk patients with positive pelvic or parametrial nodes or vascular invasion. Radiotherapy had not improved the survival of such patients. A combination of bleomycin, vincristine, mitomycin C and cisplatin was used. The results were compared with those of patients who had received radical abdominal surgery only (n = 166) or surgery and postoperative radiotherapy (n = 170). The 29 patients who underwent surgery and chemotherapy had a statistically higher incidence of all risk factors. Nonetheless, after a threeyear follow-up they had fewer recurrences and fewer deaths than did the other patients. We believe that systemic antineoplastic treatment can reduce recurrences and death in patients with invaswe systemic cervical cancer. REFERENCES Alberts DS, Martimbeau PW, Survit EA & Oishi N (1981) Mitomycin-C, bleomycin, vincrisfine, and cis-platinum in the treatment of advanced, recurrent squamous cell carcinoma of the cervix. Cancer Clinical Trials 4: 313-316.
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Burch JC & Chalfant RL (1970) Preoperative radium, irradiation and radical hysterectomy in the treatment of cancer of the cervix. American Journal of Obstetrics and Gynecology 106: 1054-1064. Burghardt E, Pickel H, Haas J & Lahousen M (1987) Prognostic factors and operative treatment of Stages Ib to IIb cervical cancer. American Journal of Obstetrics and Gynecology 156: 988-996. DiSaia PJ & Creasman WT (1981) Clinical Gynecologic Oncology, 64 pp. St Louis: CV Mosby. Fletcher GH & Rutledge FN (1972) Extended field techniques in the management of cancer of the cervix. American Journal of Roentgenotogy 114:116-122. Hsu CT, Cheng YS & Su SC (1972) Prognosis of uterine cervical cancer with extensive lymph node metastasis. American Journal of Obstetrics and Gynecology 114: 954-962. Kelso JW & Funnel JD (1973) Combined surgical radiation treatment of invasive carcinoma of the cervix. American Journal of Obstetrics and Gynecology 116: 205-213. Lahousen M, Pickel H & Tamussino K (1987) Chemotherapy for advanced and/or recurrent cervical cancer. Archives c~fGynecology and Obstetrics 240: 247-252. Martimbeau PW, Kjorstad KE & Iversen T (1982) Stage Ib carcinoma of the cervix. The Norwegian Radium Hospital: II. Results when pelvic nodes are involved. Obstetrics and Gynecology 60: 215-218. Masubuchi K, Tenjin Y, Kubo H & Kimura M (1969) Five-year cure rate for carcinoma of the cervix uteri. American Journal of Obstetrics and Gynecology 103: 566-573. Montana GS, Fowler WC, Varia MA et al (1986) Carcinoma of the cervix, Stage III. Results of radiation therapy. Cancer 57: 148-154. Morrow CP (1980) Panel report: is pelvic radiation beneficial in the postoperative management of Stage Ib squamous cell carcinoma of the cervix with pelvic node metastasis treated by radical hysterectomy and pelvic lymphadenectomy? Gynecologic Oncology 10: 105110. Ober KG (1978) Die abgestufte operative Therapie des Zervixkarzinoms. Geburtshilfe und Frauenheilkunde 38: 671-682. Piver MS (1987) Current management of lymph node metastasis in early and locally advanced cervical cancer. In Rutledge FN, Freedman RS & Gershenson DM (eds) Gynecologic Cancer. Diagnosis and Treatment Strategies, pp 251-264. Austin: University of Texas. Piver MS & Chung WS (1975) Prognostic significance of cervical lesion size and pelvic node metastasis in cervical carcinoma. Obstetrics and Gynecology 46: 507-510. Piver MS, Krishnamsetty RM & Emrich LJ (1985) Survival of non-surgically staged patients with negative lymphangiograms who had Stage IIb carcinoma of the cervix treated by pelvic radiation plus hydroxyurea. American Journal of Obstetrics and Gynecology 151: 1006-1008. Rampone JF, Klem V & Kolstad P (1973) Combined treatment of Stage Ib carcinoma of the cervix. Obstetrics and Gynecology 41: 163-167. Stallworthy J (1981) Clinical invasive carcinoma of cervix: combined radiotherapy and radical hysterectomy as primary treatment. In Coppleson M (ed.) Gynecologic Oncology. Fundamental Principles and Clinical Practice, pp 508-516. Edinburgh, London, Melbourne and New York: Churchill Livingstone. Wharton JT, Jones III HW, Day TG et al (1976) Pre-irradiation celiotomy and extended field irradiation for invasive carcinoma of the cervix. Obstetrics and Gynecology 49: 333-338. Zander J, Baltzer J, Lohe KJ et al (1980) Carcinoma of the cervix: an attempt to individualize. American Journal of Obstetrics and Gynecology 139: 752-759.