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Concurrent chemo- and radiotherapy in patients with locally advanced carcinoma of the cervix
Annals of Oncology 7: 511-516, 1996. O 1996 Kluwer Academic Publishers. Tainted in the Netherlands.
Original article Concurrent chemo- and radiotherapy in patients with locally advanced carcinoma of the cervix E. Pras,1 P. H. B. Willemse,2 H. Boonstra,4 H. Hollema,3 M. A. A. M. Heesters,1 B. G. Szabo,1 H. W. A. de Bruijn,4 J. G. Aalders4 & E. G. E. de Vries2 Departments of * Radiotherapy, Netherlands
2
Medical Oncology,
3
Pathology and * Gynecological Oncology, University Hospital Groningen, The
68+) and in group II 23 months (14-90+ months). The 5-year overall survival, progression-free survival and local reBackground: The feasibility of concurrent chemotherapy and currence free survival for group I and II are, respectively, radiotherapy for advanced primary carcinoma of the cervix 69% versus 38% (P < 0.003), 67% versus 38% (P < 0.005) was evaluated and the results were compared to historical and 84% versus 43% (P< 0.0001). Two patients in each group developed posttreatment enteritis. controls. Patients and methods: In a single institution study, patients Conclusions: Radiotherapy with concurrent carboplatin (n — 74) with primary cervical carcinoma received 3 cycles and 5-fluorouracil resulted in a better overall survival, discarboplatin/5-fluorouracil concurrent with radiotherapy, fol- ease free survival and local disease free survival compared to lowed by salvage hysterectomy (group I). Treatment results historical controls. The toxicity of this schedule did not exwere compared with those of a historical control group ceed that of radiation alone in historical controls. (n - 39) (group n), treated similarly but without chemotherapy. Key words: carboplatin, cervical cancer, chemotherapy, Results: In group I median follow-up is 28 months (12- 5-fluorouracil, radiotherapy Summary
Although cisplatin is the most active drug in cervical cancer, its analog carboplatin will achieve 15%-25% Although the overall mortality of carcinoma of the response when used as a single agent and 26%-60% uterine cervix has been markedly reduced by the wide- combined with other drugs [6-18]. spread availability of effective cytologic screening proFor the (neo-)adjuvant setting, there is no agreement grams, survival by stage has not changed significantly on the optimal drug or drug combination, the timing or over the past 15 years [1, 2]. Forty to fifty percent of the sequence of chemotherapy and irradiation. The patients treated for invasive cervical cancer eventually most marked effects are found when chemotherapy relapse and the prognosis of these patients is extremely given simultaneously with radiotherapy. Cisplatin is a poor with only 6% of patients surviving more than 3 well-known radio-sensitizer [18]. Carboplatin shares years [3]. the radio-sensitizing potential with cisplatin in experiThe results of surgery in the early stages of invasive mental systems [19]. 5-Fluorouracil also has radiation cervical cancer have hardly changed [4]. Modern radio- enhancer capacities in vitro and clinically [20]. therapy techniques have achieved better local control Based on these data, a study was initiated combining than in older series [1, 5]. However, depending on simultaneous radio- and chemotherapy, its main aim tumor stage and size, radiotherapy may fail in 10%- being the improvement of local control. A combination 50%. This has stimulated the design of studies combin- of carboplatin and 5-FU was expected to induce less ing radiotherapy and chemotherapy. Combination with gastrointestinal and renal toxicity with moderate chemotherapy might improve local control and en- myelotoxicity than the reported side effects of cisplatin hance radiation effects, simultaneously affecting sub- in this setting. The use of this combination has not been clinical metastases [6]. reported earlier for patients with cervical carcinoma. A The value of chemotherapy has been most exten- group of patients which was treated previously in the sively studied in patients with metastatic disease. Single same institution with the same radiotherapeutic schedagents will result in remissions in 10%—25% of pa- ule without chemotherapy served as a control group. In tients, but the duration of most responses is limited and both groups, an additive hysterectomy was considered this will have only a modest effect upon survival [6]. after completion of combined treatment. Introduction
512 Patients and methods Patients with FIGO bulky stage IB and HA disease (>4 cm), and tumors stage I B , III and FVA were eligible for this single institution study. Entry criteria comprised a histopathologic proven diagnosis of primary carcinoma of the uterine cervix; age younger than 70 years with no past history of malignancy, no prior surgery, radiotherapy or chemotherapy. Patients with a WHO performance status 3 and 4 were excluded, as were patients with a leukocyte count <3.0 x 109/l and/or platelet counts < 125 x 109/l, serum creatinine >120 u.mol/1 and/or creatinine clearance <60 ml/min and patients with severe cardiac or infectious diseases. The staging of all patients was performed by a gynecologic oncologist together with a radiation oncologist under general anaesthesia. Pretreatment assessment included complete blood counts and blood chemistry, creatinine clearance, chest X-ray, abdominal and pelvic CT-scan, intravenous pyelography and on indication cystoscopy. Assessment of rumor response was performed 6 weeks after completion of radiotherapy, clinically according to the WHO/UICC criteria and histologically by biopsy or hysterectomy. For the evaluation of toxicity, the WHO criteria were adopted. Blood counts were performed weekly, and serum creatinine and liver functions monthly during treatment. Follow-up consisted of general and gynecologic examinations with cytology, blood counts and SCC-ag every 3 months during the first 2 years and every 6 months thereafter. Chest X-ray and CT abdomen were performed every year. The study was approved by the local Medical Ethical Committee and all patients gave informed consent before entry. The characteristics and treatment results of the patients receiving combined treatment (group I) are compared with a control group, comprising all consecutive patients who were treated with the same radiotherapy schedule as the sole modality over the preceding period (group n). The criteria for performing surgery in these patients were the same as for the patients in group I.
after 1 week the leukocyte counts had not recovered, the carboplatin dose was 25% reduced. Cycle 3 was given together with the external boost or in sequence to the second application of 137Cesium brachytherapy. Surgery
The feasibility of surgery was evaluated by a gynecologic examination under general anesthesia. If the gynecologist considered a radical resection possible and biopsies proved to be positive for tumor, a hysterectomy was performed about 6 weeks after completion of radiation. It comprised an extrafascial hysterectomy and removal of enlarged lymph nodes. In patients in whom a radical hysterectomy was not deemed feasible, or if multiple biopsies proved to be negative, a CT-scan was performed to evaluate the response. Statistical analysis
Local tumor control, recurrence-free and overall survival probability were determined from the first day of treatment until death or last follow-up by a log-rank analysis according to Kaplan and Meier [27]. The characteristics and log-rank curves of group I and group II were compared with a Chi-square analysis.
Results
From April 1989 to December 1993, 74 consecutive patients with cervical carcinoma were treated with concurrent chemo- and radiotherapy. The characteristics of these patients (group I) and of 39 consecutive patients treated similarly from 1986-1989 but without chemotherapy served as historical controls (group n) are summarized in Table 1. The characteristics did not differ for stage, grade and performance status between Treatment the two groups. The mean age of patients in group II is higher (58 versus 47 years), whereas the patients in Radiotherapy group I had larger tumors, namely 59 (80%) versus 26 Radiation therapy was delivered by a 6 megavolt (MeV) photon (66%) of patients with a tumor > 4 cm. Eight patients in linear accelerator. The 'box' technique was used comprising an group I had enlarged pelvic lymph nodes on CT-scan, anterior, posterior and two lateral fields. The superior limit of the which is a poor prognostic parameter. Enlarged paraantero-posterior fields was the upper border of the fourth lumbar aortic nodes were absent on the CT-scan. vertebra, the lower limit was the lower margin of the obturator foramen (or, in stage I1I-A, the distal vagina). The lateral margin was The median follow-up for group I at evaluation is 28 2 cm lateral from the transverse diameter of the pelvic brim. For the months (range: 12-68+ months), and for group II 23 lateral fields, the ventral limit was the upper margin of the symphysis months (range 14-90+ months). and the dorsal limit was the front of the os coccyx. Radiation was In group I all patients completed the full course of given by 1.8 Gy daily fractions, five days per week for a total dose of 45 Gy. All fields were treated daily. Two weeks after completing the radiotherapy without interruption. Treatment was well external beam irradiation, a second examination under general tolerated. Leukocyte nadir grade I occurred in 18 anaesthesia was performed and if technically feasible, a 137Cesium (25%), grade H in 34 (46%), grade m in 20 (27%), and application of 17.5 Gy to point A, was repeated after one week for a grade IV in two patients (3%). Thrombocytopenia total dose of 35 Gy. If brachytherapy was impossible or inappropriate in case of tumor extension into the parametria or lymph nodes, grade I was observed in 58 (78%), grade II in 12 (16%), patients received an additional external boost of 35 Gy over 2 weeks grade in in one and grade IV in two patients. In 22/ for a total dose of 70.2 Gy. 222 (10%) chemotherapy cycles carboplatin was delayed 1 week for insufficient leucocyte recovery at the Chemotherapy start of a cycle. Cycle 3 was deleted in one patient for grade IV thrombocytopenia. No bleeding or leukoPatients in group I received chemotherapy comprising 3 cycles of penic fever were observed. Nausea and vomiting were carboplatin and 5-FU. Carboplatin, 300 mg/m2, was dissolved in 250 mL 5% glucose and given over 30 min intravenously (i.v.) on day mild (gTade 0: 35%; grade I: 37%; grade II: 28%), nor 1. 5-FU, 600 mg/m2, was dissolved in 2 1 normal saline and ad- was there enhanced diarrhea due to chemotherapy. ministered a continuously i.v. days 2-5. Cycles were repeated after One patient died suddenly at home after completion of 28 days for a total of 3 during the first, fifth and ninth week of treat- treatment but before tumor evaluation. She was known ment. Dose modifications only concerned carboplatin. If at the start to have suffered a prior myocardial infarction. In a secof the second or third cycle the leukocyte count remained below 2.5 x lO'/l, the chemotherapy administration was postponed 1 week. If ond patient there occurred one silent recurrent myo-
513 Table 2. Results of histopathological evaluation, and site of tumor relapse in group I.
Table 1. Patient characteristics at diagnosis. Group
P-value Evaluation
Tumor response
Follow-up NED
Number of patients Age (years) Mean Range FIGO stage IB HA IIB IHB Tumor size <4 cm > 4 cm Histology at diagnosis Squamous Adenosquamous Small-cell Neuro-endocrine Adenocarcinoma Radiation boost External Brachytherapy Combined Hysterectomy
74
39
47 28-73
58 29-78
7 5 44
3 5 24
i 17
2 5
15 (20%) 59 (80%)
13 (33%) 26 (66%)
60 3 5 2 4
30 2 4
25 38 11 43
16 23 19
pCR <0.001
ns <0.05 <0.05
ns - not significant Group I - combined chemo-radiotherapy, group II - historical controls receiving radiotherapy.
cardial infarction as determined based on electrocardiogram changes before hysterectomy. One patient died after hysterectomy due to septicemia from small bowel lesions due to multiple adhesions in a cervical stump carcinoma- One patient had an accidental ureteral lesion during laparotomy which was treated with a temporary ureteral splint. One patient had a postoperative period of paralytic ileus which resolved with conservative therapy. Two patients developed deep venous thrombosis. No enhanced local toxicity from radiation was observed on the skin, rectum and bowel, or bladder compared with group n. The extent of skin fibrosis was not considered to be different from the group n. Most patients had mild diarrhea which was easily controlled with loperamide. In each groups two patients developed radiation enteritis. In group II one patient has developed a colon carcinoma 3 years later and another a uterine sarcoma 6 years after treatment In group I 73 patients are evaluable for tumor response. In 43 patients, a hysterectomy proved to be feasible. On pathological examination no tumor was found in 28 patients, 25 of whom still have no evidence of disease. At autopsy the patient who died postoperatively, proved to be free of tumor. Of the 15 patients with viable tumor cells in the hysterectomy specimen, 11 are still alive without evidence of disease (Table 2). One patient also had viable tumor cells in enlarged para-aortic lymph nodes found at laparotomy, which
Hysterectomy
43
Biopsy
29
Clinical Total
15
25' 11
6
14 1
23 1
1 73
PROG Local
PR
28
51 (71%)
22
Site of relapse L + D Distant
1 51 21 (71%) (29%)
10
pCR - pathological complete remission; PR - partial remission; NED - no evidence of disease; PROG - progression; Local - local relapse; L + D - local and distant relapse; Distant - distant relapse. 1 One patient died of surgical complications.
were removed and treated with additional para-aortic radiation (45 Gy). In 29 patients no hysterectomy but only cervical biopsies were performed 4-6 weeks after treatment In 23 no tumor was found of whom 14 are still disease free. Of the six with residual viable tumor cells only one is still free of disease progression. In one patient no histology was obtained as she developed lung metastases at the end of treatment. The predictive power of negative histology of the hysterectomy specimen is higher than that of biopsy, as 25/28 (89%) patients who had a histopathological complete remission remained disease free versus 14/23 (61%) patients who had negative biopsy findings (P < 0.05) (Table 2). Performing a salvage hysterectomy gives a therapeutic advantage as well, as 11/15 patients remained disease free despite positive pathology. In the 21 patients who had a relapse there were eight local, three combined local and distant and 10 in distant sites only. Thus, the local control in group I is 84% (Figure 4). Overall Survival
Figure 1. Overall survival in patients of group I and group II, comprising historical controls receiving only radiotherapy (P < 0.0032).
514 Fourteen patients had unfavorable histology: adenoLocal Recurrence Free Survival squamous in three, small-cell squamous in five, neuroendocrine type carcinoma in two and adenocarcinoma in four patients, patients. Five of them have relapsed, all at distant sites. At 5 years the overall survival rate is 69% (Figure 1) This was for stage IB and UA: 75%; stage UB 75%; stage IUA+B: 47% (Figure 2). The disease free survival at 5 years is 67% (Figure 3). The local recurrence free survival at 5 years is 84% with no relapses occurring after 1 year (Figure 4). Overall, 51 of 72 patients (71%) still are without evidence of disease and 21 patients (29%) have had disease progression. All local relapses occurred within 1 year after treatment, but distant metastases were seen up to 3 years thereafter. In the historical control group, group n, 19 out of 39 Figure 4. Local recurrence free survival in group I and group n, underwent hysterectomy (ns versus group I). In nine comprising historical controls receiving only radiotherapy (P< 0.0001). Overall survival for tumor stage at diagnosis
patients residual viable tumor cells were present and of these patients only two are still alive without evidence of disease. In four there was a local relapse, in one a distant relapse and in one a combination of both. Compared to group I there is a reduced overall survival at 5 years (38% versus 69%), a lower percentage of local tumor control at 5 years (43% versus 84%), and a reduced progression free survival (43% versus 67% in group II (Figures 1, 3, 4). In contrast to group I, in group II local relapses occurred also after more than one year. Comparison of the log-rank curves for group I and II by Chi-square analysis yields a better overall survival ( P < 0.003), local control (P< 0.0001) and progression-free survival (P < 0.005). n - A n >o
14 37 '0
18 44 1?
7 29 7
4 20 6
2 13 4
Figure 2. Overall survival of patients in group I for FIGO stage IB + QA, FIGO stage UB and FIGO stage in.
Discussion
Chemotherapy can be used in several ways as an adjunct to local treatment of cervical cancer, e.g., as an Disease Free Survival adjuvant treatment, neo-adjuvant or concurrently with radiotherapy. When chemotherapy is used as an adjuvant after surgery, the results are not better than those achieved by local therapy as the only modality [22, 23]. Based on three randomized studies, the use of neoft adjuvant chemotherapy was discouraged because it resulted in an inferior local control and possibly even I worse overall survival. This is probably due to the 40 delayed start of the local treatment and reduced radiation dose-intensity [24]. Another approach is the simultaneous use of radio?0 and chemotherapy, in which the systemic treatment is mainly applied as a radiation enhancer. Clinical studies have suggested a local benefit of the combination cisplatin with radiotherapy in other rumors, for example in advanced head and neck cancer and non-small cell Figure 3. Progression-free survival in group I and group II, com- lung cancer [25, 26]. In cervical carcinoma a combination of radiation with 5-FU has shown interesting prising historical controls receiving only radiotherapy (P < 0.005). 64-,
515 results [27]. Combinations of radiotherapy with cisplatin and 5-FU for cervical cancer resulted in 60%100% local control and 50%-90% disease free progression at 12-29 months follow-up [28-34]. Some authors have warned against for the limited tolerance of cisplatin plus 5-FU combined with full dose radiotherapy. Resbeut et al. observed local control in 80% after radiotherapy with cisplatin and 5-FU, but had to reduce the dose of both cisplatin and 5-FU and apply hyperfractionation of radiotherapy because of gastrointestinal toxicity [34]. Radiation delay occurred in 78% and in 54% of patients in a second study [35]. There is one phase HI study that suggests an improved response rate by cisplatin concurrently with radiotherapy [36]. Full reports on other ongoing randomized studies with combined radio-chemotherapy are not yet available. In the present study the effect of radiotherapy with carboplatin and 5-FU plus salvage hysterectomy is compared with the same treatment without chemotherapy in a prior group used as historical controls. Radiotherapy could be administered uninterrupted and could be given in full dose. Local toxicity was not enhanced by combined treatment. Systemic toxicity was manageable as 90% of all chemotherapy cycles could be given without delay and there was no severe myelotoxicity. The late toxicity in this study appears to be mild, as the same frequency of radiation enteritis occurred in each treatment group. This schedule is markedly better tolerated than cisplatin as a single agent [37] or some cisplatin-based combinations [32-35]. The addition of carboplatin plus 5-FU resulted in a better overall survival, disease free survival and local control. After 1 year no local relapse have occurred. The local control by combined treatment was especially remarkable in view of the advanced tumor stage in most patients. Pearcey et al., in their relatively large series of 60 patients, combined concurrent cisplatin and radiation therapy and observed no further local relapses after 26 months [37]. They found a pelvic control rate of 78%. Adjuvant hysterectomy as a salvage treatment can play a role in selected cases with positive biopsy, as 77% patients with residual vital tumor in the resected specimen have remained disease free. Arai et al. have reported that positive biopsies 1-2 months after treatment invariably predict recurrence and are a strong indication for salvage surgery [38]. The main problem remains the fact that distant metastases will still occur in 16% of our patients, indicating that the present regimen is still not sufficiently effective to eradicate disseminated tumor cells, especially in the group with unfavorable histology, the small cell and neuro-endocrine variants. In this category other, more aggressive systemic treatment might be indicated. In conclusion, combined chemo-radiotherapy with carboplatin plus 5-FU appears to be an effective mode of treatment with remarkably limited toxicity in patients with an unfavorable prognosis cervical carcinoma.
Acknowledgments
We would like to thank our colleagues, especially Dr. J. Bouma, for their consistent support in the treatment of these patients, Mrs. KA. ten Hoor for the collection of patient data and A. Canrinus for his support in the statistical data analysis. References 1. Stehman FB, Thomas GM. Prognostic factors in locally advanced carcinoma of the cervix treated with radiation therapy. Semin Oncol 1994; 21: 25-9. 2. Pettersen F. 21th Annual report of the results of treatment in gynaecological cancer. Int J Obstet Gynecol 1991; 36 (Suppl): 27-130. 3. Van Nagell JR, Raybura W, Donaldson ES et al. Therapeutic implications of patterns of recurrence in cancer of the uterine cervix. Cancer 1979; 44: 2354-61. 4. Morley GW, Seski JC. Radical pelvic surgery versus radiation therapy for stage I carcinoma of the cervix (exclusive of microinvasion). Am J Obstet Gynecol 1976; 126: 785-98. 5. Russel AH. Contemporary radiation treatment planning for patients with cancer of the uterine cervix. Semin Oncol 1994; 21: 30-41. 6. Vermorken JB. The role of chemotherapy in squamous cell carcinoma of the uterine cervix: A review. Int J Gynaecol Cancer 1993; 3:129-42. 7. Thigpen JT, Blessing JA, DiSaia PJ et al. A randomized comparison of a rapid versus prolonged (24-hours) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: A Gynaecologic Oncology Group study. Gynecol Oncol 1989; 32:198-202. 8. Bonomi P, Blessing JA, Stehman FB et aL Randomized trial of three cisplatin dose schedules in squamous cell carcinoma of the cervix: A Gynaecologic Oncology Group Study. J Clin Oncol 1985; 3:1079-85. 9. Arseneau J, Blessing JA, Stehman FB et al. A phase II study of carboplatin in advanced squamous cell carcinoma of cervix (a Gynecologic Oncology Group study). Invest New Drugs 1986; 4:187-91. 10. Noda K, Kato T, Ikeda M et al. Phase n study of carboplatin in cervical carcinoma. Gan to Kagaku Ryoho 1988; 15: 3067-72. 11. McGuire WP HI, Blessing JA, Arseneau J et al. A randomized comparative trial of carboplatin and iproplatin in advanced squamous cell carcinoma of the uterine cervix; A Gynecologic Oncology Group Study. J Clin Oncol 1989; 7:1462-8. 12. Weiss GR, Green S, Hannigan EV et al. A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: A SWOG study. Gynecol Oncol 1990; 39: 332-6. 13. Lira-Puerto V, Silva A, Morris M et al. Phase II trial of carboplatin or iproplatin in cervical cancer. Cancer Chemother Pharmacol 1991; 28: 391-6. 14. Rustin GJ, Newlands ES. Phase I-n study of carboplatin, vincristine, methotrexate and bleomycin (COMB) in carcinoma of the cervix. Br J Cancer 1988; 58:818-9. 15. Junor E, Davies J, Habeshaw T et al. Carboplatin-based combination chemotherapy for advanced carcinoma of the cervix. Cancer Chemother Pharmacol 1991; 27:484-6. 16. Kuehnle H, Meerpohl H-G, Eiermann W et al. Neoadjuvant therapy for cervical cancer. Semin Oncol 1992; 19:94-8. 17. Murad AM, Triginelli SA, Ribalta JC. Phase II trial of bleomycin, ifosfamide and carboplatin in metastatic cervical cancer. J Clin Oncol 1994; 12: 55-9. 18. Alvarez MV, Cobreros EA. Studies on cis-dichlorodiammineplatinum (H) as a radiosensitizer. Br J Cancer 1978; 37:68-72. 19. Douple EB, Richmond RC. Radiosensitization of hypoxic
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Received 27 February 1996; accepted 30 April 1996. Correspondence to: P. H. B. Willemse, MD, PhD Division of Medical Oncology Department of Internal Medicine University Hospital P.O. Box 30.001 9700 RB Groningen The Netherlands
Original article Concurrent chemo- and radiotherapy in patients with locally advanced carcinoma of the cervix E. Pras,1 P. H. B. Willemse,2 H. Boonstra,4 H. Hollema,3 M. A. A. M. Heesters,1 B. G. Szabo,1 H. W. A. de Bruijn,4 J. G. Aalders4 & E. G. E. de Vries2 Departments of * Radiotherapy, Netherlands
2
Medical Oncology,
3
Pathology and * Gynecological Oncology, University Hospital Groningen, The
68+) and in group II 23 months (14-90+ months). The 5-year overall survival, progression-free survival and local reBackground: The feasibility of concurrent chemotherapy and currence free survival for group I and II are, respectively, radiotherapy for advanced primary carcinoma of the cervix 69% versus 38% (P < 0.003), 67% versus 38% (P < 0.005) was evaluated and the results were compared to historical and 84% versus 43% (P< 0.0001). Two patients in each group developed posttreatment enteritis. controls. Patients and methods: In a single institution study, patients Conclusions: Radiotherapy with concurrent carboplatin (n — 74) with primary cervical carcinoma received 3 cycles and 5-fluorouracil resulted in a better overall survival, discarboplatin/5-fluorouracil concurrent with radiotherapy, fol- ease free survival and local disease free survival compared to lowed by salvage hysterectomy (group I). Treatment results historical controls. The toxicity of this schedule did not exwere compared with those of a historical control group ceed that of radiation alone in historical controls. (n - 39) (group n), treated similarly but without chemotherapy. Key words: carboplatin, cervical cancer, chemotherapy, Results: In group I median follow-up is 28 months (12- 5-fluorouracil, radiotherapy Summary
Although cisplatin is the most active drug in cervical cancer, its analog carboplatin will achieve 15%-25% Although the overall mortality of carcinoma of the response when used as a single agent and 26%-60% uterine cervix has been markedly reduced by the wide- combined with other drugs [6-18]. spread availability of effective cytologic screening proFor the (neo-)adjuvant setting, there is no agreement grams, survival by stage has not changed significantly on the optimal drug or drug combination, the timing or over the past 15 years [1, 2]. Forty to fifty percent of the sequence of chemotherapy and irradiation. The patients treated for invasive cervical cancer eventually most marked effects are found when chemotherapy relapse and the prognosis of these patients is extremely given simultaneously with radiotherapy. Cisplatin is a poor with only 6% of patients surviving more than 3 well-known radio-sensitizer [18]. Carboplatin shares years [3]. the radio-sensitizing potential with cisplatin in experiThe results of surgery in the early stages of invasive mental systems [19]. 5-Fluorouracil also has radiation cervical cancer have hardly changed [4]. Modern radio- enhancer capacities in vitro and clinically [20]. therapy techniques have achieved better local control Based on these data, a study was initiated combining than in older series [1, 5]. However, depending on simultaneous radio- and chemotherapy, its main aim tumor stage and size, radiotherapy may fail in 10%- being the improvement of local control. A combination 50%. This has stimulated the design of studies combin- of carboplatin and 5-FU was expected to induce less ing radiotherapy and chemotherapy. Combination with gastrointestinal and renal toxicity with moderate chemotherapy might improve local control and en- myelotoxicity than the reported side effects of cisplatin hance radiation effects, simultaneously affecting sub- in this setting. The use of this combination has not been clinical metastases [6]. reported earlier for patients with cervical carcinoma. A The value of chemotherapy has been most exten- group of patients which was treated previously in the sively studied in patients with metastatic disease. Single same institution with the same radiotherapeutic schedagents will result in remissions in 10%—25% of pa- ule without chemotherapy served as a control group. In tients, but the duration of most responses is limited and both groups, an additive hysterectomy was considered this will have only a modest effect upon survival [6]. after completion of combined treatment. Introduction
512 Patients and methods Patients with FIGO bulky stage IB and HA disease (>4 cm), and tumors stage I B , III and FVA were eligible for this single institution study. Entry criteria comprised a histopathologic proven diagnosis of primary carcinoma of the uterine cervix; age younger than 70 years with no past history of malignancy, no prior surgery, radiotherapy or chemotherapy. Patients with a WHO performance status 3 and 4 were excluded, as were patients with a leukocyte count <3.0 x 109/l and/or platelet counts < 125 x 109/l, serum creatinine >120 u.mol/1 and/or creatinine clearance <60 ml/min and patients with severe cardiac or infectious diseases. The staging of all patients was performed by a gynecologic oncologist together with a radiation oncologist under general anaesthesia. Pretreatment assessment included complete blood counts and blood chemistry, creatinine clearance, chest X-ray, abdominal and pelvic CT-scan, intravenous pyelography and on indication cystoscopy. Assessment of rumor response was performed 6 weeks after completion of radiotherapy, clinically according to the WHO/UICC criteria and histologically by biopsy or hysterectomy. For the evaluation of toxicity, the WHO criteria were adopted. Blood counts were performed weekly, and serum creatinine and liver functions monthly during treatment. Follow-up consisted of general and gynecologic examinations with cytology, blood counts and SCC-ag every 3 months during the first 2 years and every 6 months thereafter. Chest X-ray and CT abdomen were performed every year. The study was approved by the local Medical Ethical Committee and all patients gave informed consent before entry. The characteristics and treatment results of the patients receiving combined treatment (group I) are compared with a control group, comprising all consecutive patients who were treated with the same radiotherapy schedule as the sole modality over the preceding period (group n). The criteria for performing surgery in these patients were the same as for the patients in group I.
after 1 week the leukocyte counts had not recovered, the carboplatin dose was 25% reduced. Cycle 3 was given together with the external boost or in sequence to the second application of 137Cesium brachytherapy. Surgery
The feasibility of surgery was evaluated by a gynecologic examination under general anesthesia. If the gynecologist considered a radical resection possible and biopsies proved to be positive for tumor, a hysterectomy was performed about 6 weeks after completion of radiation. It comprised an extrafascial hysterectomy and removal of enlarged lymph nodes. In patients in whom a radical hysterectomy was not deemed feasible, or if multiple biopsies proved to be negative, a CT-scan was performed to evaluate the response. Statistical analysis
Local tumor control, recurrence-free and overall survival probability were determined from the first day of treatment until death or last follow-up by a log-rank analysis according to Kaplan and Meier [27]. The characteristics and log-rank curves of group I and group II were compared with a Chi-square analysis.
Results
From April 1989 to December 1993, 74 consecutive patients with cervical carcinoma were treated with concurrent chemo- and radiotherapy. The characteristics of these patients (group I) and of 39 consecutive patients treated similarly from 1986-1989 but without chemotherapy served as historical controls (group n) are summarized in Table 1. The characteristics did not differ for stage, grade and performance status between Treatment the two groups. The mean age of patients in group II is higher (58 versus 47 years), whereas the patients in Radiotherapy group I had larger tumors, namely 59 (80%) versus 26 Radiation therapy was delivered by a 6 megavolt (MeV) photon (66%) of patients with a tumor > 4 cm. Eight patients in linear accelerator. The 'box' technique was used comprising an group I had enlarged pelvic lymph nodes on CT-scan, anterior, posterior and two lateral fields. The superior limit of the which is a poor prognostic parameter. Enlarged paraantero-posterior fields was the upper border of the fourth lumbar aortic nodes were absent on the CT-scan. vertebra, the lower limit was the lower margin of the obturator foramen (or, in stage I1I-A, the distal vagina). The lateral margin was The median follow-up for group I at evaluation is 28 2 cm lateral from the transverse diameter of the pelvic brim. For the months (range: 12-68+ months), and for group II 23 lateral fields, the ventral limit was the upper margin of the symphysis months (range 14-90+ months). and the dorsal limit was the front of the os coccyx. Radiation was In group I all patients completed the full course of given by 1.8 Gy daily fractions, five days per week for a total dose of 45 Gy. All fields were treated daily. Two weeks after completing the radiotherapy without interruption. Treatment was well external beam irradiation, a second examination under general tolerated. Leukocyte nadir grade I occurred in 18 anaesthesia was performed and if technically feasible, a 137Cesium (25%), grade H in 34 (46%), grade m in 20 (27%), and application of 17.5 Gy to point A, was repeated after one week for a grade IV in two patients (3%). Thrombocytopenia total dose of 35 Gy. If brachytherapy was impossible or inappropriate in case of tumor extension into the parametria or lymph nodes, grade I was observed in 58 (78%), grade II in 12 (16%), patients received an additional external boost of 35 Gy over 2 weeks grade in in one and grade IV in two patients. In 22/ for a total dose of 70.2 Gy. 222 (10%) chemotherapy cycles carboplatin was delayed 1 week for insufficient leucocyte recovery at the Chemotherapy start of a cycle. Cycle 3 was deleted in one patient for grade IV thrombocytopenia. No bleeding or leukoPatients in group I received chemotherapy comprising 3 cycles of penic fever were observed. Nausea and vomiting were carboplatin and 5-FU. Carboplatin, 300 mg/m2, was dissolved in 250 mL 5% glucose and given over 30 min intravenously (i.v.) on day mild (gTade 0: 35%; grade I: 37%; grade II: 28%), nor 1. 5-FU, 600 mg/m2, was dissolved in 2 1 normal saline and ad- was there enhanced diarrhea due to chemotherapy. ministered a continuously i.v. days 2-5. Cycles were repeated after One patient died suddenly at home after completion of 28 days for a total of 3 during the first, fifth and ninth week of treat- treatment but before tumor evaluation. She was known ment. Dose modifications only concerned carboplatin. If at the start to have suffered a prior myocardial infarction. In a secof the second or third cycle the leukocyte count remained below 2.5 x lO'/l, the chemotherapy administration was postponed 1 week. If ond patient there occurred one silent recurrent myo-
513 Table 2. Results of histopathological evaluation, and site of tumor relapse in group I.
Table 1. Patient characteristics at diagnosis. Group
P-value Evaluation
Tumor response
Follow-up NED
Number of patients Age (years) Mean Range FIGO stage IB HA IIB IHB Tumor size <4 cm > 4 cm Histology at diagnosis Squamous Adenosquamous Small-cell Neuro-endocrine Adenocarcinoma Radiation boost External Brachytherapy Combined Hysterectomy
74
39
47 28-73
58 29-78
7 5 44
3 5 24
i 17
2 5
15 (20%) 59 (80%)
13 (33%) 26 (66%)
60 3 5 2 4
30 2 4
25 38 11 43
16 23 19
pCR <0.001
ns <0.05 <0.05
ns - not significant Group I - combined chemo-radiotherapy, group II - historical controls receiving radiotherapy.
cardial infarction as determined based on electrocardiogram changes before hysterectomy. One patient died after hysterectomy due to septicemia from small bowel lesions due to multiple adhesions in a cervical stump carcinoma- One patient had an accidental ureteral lesion during laparotomy which was treated with a temporary ureteral splint. One patient had a postoperative period of paralytic ileus which resolved with conservative therapy. Two patients developed deep venous thrombosis. No enhanced local toxicity from radiation was observed on the skin, rectum and bowel, or bladder compared with group n. The extent of skin fibrosis was not considered to be different from the group n. Most patients had mild diarrhea which was easily controlled with loperamide. In each groups two patients developed radiation enteritis. In group II one patient has developed a colon carcinoma 3 years later and another a uterine sarcoma 6 years after treatment In group I 73 patients are evaluable for tumor response. In 43 patients, a hysterectomy proved to be feasible. On pathological examination no tumor was found in 28 patients, 25 of whom still have no evidence of disease. At autopsy the patient who died postoperatively, proved to be free of tumor. Of the 15 patients with viable tumor cells in the hysterectomy specimen, 11 are still alive without evidence of disease (Table 2). One patient also had viable tumor cells in enlarged para-aortic lymph nodes found at laparotomy, which
Hysterectomy
43
Biopsy
29
Clinical Total
15
25' 11
6
14 1
23 1
1 73
PROG Local
PR
28
51 (71%)
22
Site of relapse L + D Distant
1 51 21 (71%) (29%)
10
pCR - pathological complete remission; PR - partial remission; NED - no evidence of disease; PROG - progression; Local - local relapse; L + D - local and distant relapse; Distant - distant relapse. 1 One patient died of surgical complications.
were removed and treated with additional para-aortic radiation (45 Gy). In 29 patients no hysterectomy but only cervical biopsies were performed 4-6 weeks after treatment In 23 no tumor was found of whom 14 are still disease free. Of the six with residual viable tumor cells only one is still free of disease progression. In one patient no histology was obtained as she developed lung metastases at the end of treatment. The predictive power of negative histology of the hysterectomy specimen is higher than that of biopsy, as 25/28 (89%) patients who had a histopathological complete remission remained disease free versus 14/23 (61%) patients who had negative biopsy findings (P < 0.05) (Table 2). Performing a salvage hysterectomy gives a therapeutic advantage as well, as 11/15 patients remained disease free despite positive pathology. In the 21 patients who had a relapse there were eight local, three combined local and distant and 10 in distant sites only. Thus, the local control in group I is 84% (Figure 4). Overall Survival
Figure 1. Overall survival in patients of group I and group II, comprising historical controls receiving only radiotherapy (P < 0.0032).
514 Fourteen patients had unfavorable histology: adenoLocal Recurrence Free Survival squamous in three, small-cell squamous in five, neuroendocrine type carcinoma in two and adenocarcinoma in four patients, patients. Five of them have relapsed, all at distant sites. At 5 years the overall survival rate is 69% (Figure 1) This was for stage IB and UA: 75%; stage UB 75%; stage IUA+B: 47% (Figure 2). The disease free survival at 5 years is 67% (Figure 3). The local recurrence free survival at 5 years is 84% with no relapses occurring after 1 year (Figure 4). Overall, 51 of 72 patients (71%) still are without evidence of disease and 21 patients (29%) have had disease progression. All local relapses occurred within 1 year after treatment, but distant metastases were seen up to 3 years thereafter. In the historical control group, group n, 19 out of 39 Figure 4. Local recurrence free survival in group I and group n, underwent hysterectomy (ns versus group I). In nine comprising historical controls receiving only radiotherapy (P< 0.0001). Overall survival for tumor stage at diagnosis
patients residual viable tumor cells were present and of these patients only two are still alive without evidence of disease. In four there was a local relapse, in one a distant relapse and in one a combination of both. Compared to group I there is a reduced overall survival at 5 years (38% versus 69%), a lower percentage of local tumor control at 5 years (43% versus 84%), and a reduced progression free survival (43% versus 67% in group II (Figures 1, 3, 4). In contrast to group I, in group II local relapses occurred also after more than one year. Comparison of the log-rank curves for group I and II by Chi-square analysis yields a better overall survival ( P < 0.003), local control (P< 0.0001) and progression-free survival (P < 0.005). n - A n >o
14 37 '0
18 44 1?
7 29 7
4 20 6
2 13 4
Figure 2. Overall survival of patients in group I for FIGO stage IB + QA, FIGO stage UB and FIGO stage in.
Discussion
Chemotherapy can be used in several ways as an adjunct to local treatment of cervical cancer, e.g., as an Disease Free Survival adjuvant treatment, neo-adjuvant or concurrently with radiotherapy. When chemotherapy is used as an adjuvant after surgery, the results are not better than those achieved by local therapy as the only modality [22, 23]. Based on three randomized studies, the use of neoft adjuvant chemotherapy was discouraged because it resulted in an inferior local control and possibly even I worse overall survival. This is probably due to the 40 delayed start of the local treatment and reduced radiation dose-intensity [24]. Another approach is the simultaneous use of radio?0 and chemotherapy, in which the systemic treatment is mainly applied as a radiation enhancer. Clinical studies have suggested a local benefit of the combination cisplatin with radiotherapy in other rumors, for example in advanced head and neck cancer and non-small cell Figure 3. Progression-free survival in group I and group II, com- lung cancer [25, 26]. In cervical carcinoma a combination of radiation with 5-FU has shown interesting prising historical controls receiving only radiotherapy (P < 0.005). 64-,
515 results [27]. Combinations of radiotherapy with cisplatin and 5-FU for cervical cancer resulted in 60%100% local control and 50%-90% disease free progression at 12-29 months follow-up [28-34]. Some authors have warned against for the limited tolerance of cisplatin plus 5-FU combined with full dose radiotherapy. Resbeut et al. observed local control in 80% after radiotherapy with cisplatin and 5-FU, but had to reduce the dose of both cisplatin and 5-FU and apply hyperfractionation of radiotherapy because of gastrointestinal toxicity [34]. Radiation delay occurred in 78% and in 54% of patients in a second study [35]. There is one phase HI study that suggests an improved response rate by cisplatin concurrently with radiotherapy [36]. Full reports on other ongoing randomized studies with combined radio-chemotherapy are not yet available. In the present study the effect of radiotherapy with carboplatin and 5-FU plus salvage hysterectomy is compared with the same treatment without chemotherapy in a prior group used as historical controls. Radiotherapy could be administered uninterrupted and could be given in full dose. Local toxicity was not enhanced by combined treatment. Systemic toxicity was manageable as 90% of all chemotherapy cycles could be given without delay and there was no severe myelotoxicity. The late toxicity in this study appears to be mild, as the same frequency of radiation enteritis occurred in each treatment group. This schedule is markedly better tolerated than cisplatin as a single agent [37] or some cisplatin-based combinations [32-35]. The addition of carboplatin plus 5-FU resulted in a better overall survival, disease free survival and local control. After 1 year no local relapse have occurred. The local control by combined treatment was especially remarkable in view of the advanced tumor stage in most patients. Pearcey et al., in their relatively large series of 60 patients, combined concurrent cisplatin and radiation therapy and observed no further local relapses after 26 months [37]. They found a pelvic control rate of 78%. Adjuvant hysterectomy as a salvage treatment can play a role in selected cases with positive biopsy, as 77% patients with residual vital tumor in the resected specimen have remained disease free. Arai et al. have reported that positive biopsies 1-2 months after treatment invariably predict recurrence and are a strong indication for salvage surgery [38]. The main problem remains the fact that distant metastases will still occur in 16% of our patients, indicating that the present regimen is still not sufficiently effective to eradicate disseminated tumor cells, especially in the group with unfavorable histology, the small cell and neuro-endocrine variants. In this category other, more aggressive systemic treatment might be indicated. In conclusion, combined chemo-radiotherapy with carboplatin plus 5-FU appears to be an effective mode of treatment with remarkably limited toxicity in patients with an unfavorable prognosis cervical carcinoma.
Acknowledgments
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Received 27 February 1996; accepted 30 April 1996. Correspondence to: P. H. B. Willemse, MD, PhD Division of Medical Oncology Department of Internal Medicine University Hospital P.O. Box 30.001 9700 RB Groningen The Netherlands