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Table 1 Main characteristics of 38 patients.

AgeMedian 44Range 27-71

StageIb2-IIa a 27lib 2Illb 8IVa 1

Preoperative node assessmentLymphangiography + 7Lymphangiography - 30Lymphangiography not performed 1

Tumor grade

2 163 18

a > 4 cm diameter.

with 1 1 of nor mal saline added with 10 mEq/1 of potassium chlorideand 10 mEq/1 of MgSO 4 , followed by a post-hydration with 1 1 of 5dextrose solution added with 20 mEq/1 of KC1 and 20 mEq/1 ofMgSO 4 given over two hours.

After post-hy dration, ifosfamide 5 g/m 2 and mesna 5 g/m 2 wereinfused i.v. over 24 hours in 1 1 of nor mal saline, followed, on day 3, bymesna 3 g/m 2 given i.v. in 1 1 of nor mal saline over 24 hour s. Treatmentwas repeated every three weeks for a total of three cycles.

Complete blood counts were performed weekly or more often ininstances of toxicity, and blood count, serum creatinine and creatinineclearance were repeated before each cycle.

Treatment was delayed by one week in instances of a granulocytecount of 1500/uL and/or platelet count of < 100000/uL; reduction ofdoses was not planned. On the basis of physician judgment, recombi-nant human G-CSF, while not part of the standard treatment, was

administered in instances of persistent grade 4 myelotoxicity.Pelvic examination was performed before each course; tumor

response was assessed clinically and by MRI after three courses.Response and toxicity were defined accordin g to WHO criteria [12].Optimal partial response was defined as a residual disease of less than5 mm of diameter or as in situ carcinoma of the cervix with negativenodes.

Except in cases of progression or of stable disease of primarilyunresectable tumor, all patients underwent radical hysterectomy andpelvic lymphadenectomy three to four weeks after administration ofthe third cycle. Subsequent treatment consisted of external beamirradiation in patients with macroscopic positive nodes, parametrialinvolvement, cut-through or sub-optimal response, or, in patients withoptimal partial response of primary tumor but still positive nodes, oftwo further cycles of chemotherapy.

Follow-up procedures with pelvic examination and vaginal cytol-ogy were planned forl mon th after the end of the treatment and everytwo mon ths thereafter . In patient s without clinically evaluable diseaseMRI or CT scan of pelvis and abdomen were repeated every threemonths.

The duration of partial and complete response was calculated fromthe first documentation of response until documentation of recur-rence/progression. Survival was defined as the interval from entry intothe study to death or to the date of last follow-up visit.

Results

All patients completed the planned three courses oftreatment and were evaluable for response and toxicity.Eleven achieved clinical complete responses, 21 partial

Table 2 Correlation between clinical response and pathology re-sponse.

Clinicalresponse

PDNCPRCR

Pathology response

No CR Optimal Suboptimal NC Total

surgery PR PR

19

52111

Table 3 Main toxicities in 38 patients.

LeukopeniaNeutropeniaThrombocytopeniaRenalPeripheral neuropathyFeverNausea/vomitingAllergyMucositis

Number of patients with toxicity grade

0

_

-12353032-

3432

1

1-

12365-46

2

151110-216--

3

2120

3---

30--

4

171---2--

responses, five had stable disease and one showed tumourprogression, for an overall clinical response rate of 84(95 CI: 68.7 -94 ). Of 34 patients who underwent

surgery, six (16 ) achieved pathology-documented com-plete responses, seven (18 ) optimal partial responseswith negative nodes, four showed optimal response inthe cervix with positive nodes, 15 macroscopic partialresponses, and two stable disease, for an overall pathol-ogy response rate of 84 . Table 2 shows the correlationbetween clinical and pathology responses. All of theclinical partial responses were confirmed by pathology,while in five of 11 clinical CR only minimal residualdisease was found in the primary tumours.

Grade 3-4 neutropenia occurred in 27 patien ts (71 ),grade 3-4 thrombocytopenia in four (10.5 ), and grade2 peripheral neuropathy in two (5 , Table 3). No signifi-cant difference in toxicity was observed between thepatients receiving cisplatin at 50 mg/m2 and those re-ceiving 75 mg/m2.

Five women (13 ) required one-week delays in theirtreatment and two (5 ) required two-week delays; inboth of the latter the ifosfamide in the last courses wasreduced by 25 .

Surgery consisted of class radical hysterectomy[13] in 30 patients, class IV in two and anterior pelvicexenteration in two; nine women had lymphonodalmetastases (five of them with preoperative positive lym-phangiography and four with negative lymphangiog-raphy), two of them received additional cycles of chemo-theraphy, while seven had external beam irradiation. Allof the four women who did not have surgery received

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external beam irradiation , and two of them have died oftumour recurrence.

At a median follow-up of 6 months (range 7-22), 36patients are alive, 29 of them (76 ) without evidence ofdisease; the sites of recurrence, which occurred in pa-tients with partial response only, were pelvis in four

patients, groin in one and lung in two.

Discussion

Neoadjuvant chemotherapy represents a promising al-ternative to surgery or radiotherapy as initial treatmentof locally advanced cervical cancer because of the possi-bility, in responding patients, of obtaining wider unin-volved surgical margins.

The impact on survival of this relatively new approachis still a matter of discussion, and different treatmentstrategies may be considered. Some authors have ob-served that neoadjuvant chemotherapy followed by radi-ation has yielded neither higher response rates norlonger survival [14], possibly due to the development ofselective resistance to radiation after chemotherapy. Theoption of reducing the amount of tumor before surgicalremoval, however, remains theoretically and clinicallyattractive, the main limitation being the inability ofthe available regimens to achieve adequate tumourshrinkage. Some authors have reported that neoadju-vant chemotherapy followed by surgery may improvesurvival in locally advanced cervical cancer as comparedto radical surgery [15, 16]. We had also previously re-

ported that neoadjuvant platinum-based chemotherapyfollowed by radical surgery was associated with higherthree-year survival rates than radiotherapy alone inlocally advanced squamous-cell cervical cancer [17].

An up to 92 overall response rate has been reportedfor a variety of neoadjuvant regimens [ 4] with pathology-complete responses in a limited number of cases. Ac-cording to some authors, only patients in complete oroptimal partial response (minimal foci of microscopictumor in the removed uterus) can benefit significantly interms of disease-free survival [2, 18]. In a retrospectiveanalysis of our experience with neoadjuvant chemother-

apy for locally advanced cervical carcinoma, achieve-ment of an optimal response (absent or microscopicresidual disease at surgery) was an independent favor-able prognostic factor for survival for patients treatedwith cisplatin, bleomycin and vincristine (POB regimen)[19]. Kim et al. also described a 100 survival rate inpatients achieving a complete pathology or optimal re-sponse (only microscopic foci of residual tumor) irrespec-tive of the stage [2], while Giaroli et al. reported a disease-free interval of 97.7 in patients with residual tumorssmaller than 0.5 cm after neoadjuvant chemotherapy [18].

With the regimen of the present study, we observed ahigh rate (34 ; 95 CI: 19.6 -51.4 ) of complete andoptimal partial responses, higher than the one we re-ported with the POB regimen [20]; this result suggeststhat the combination of cisplatin, paclitaxel and ifosfa-

mide represents a very effective neoadjuvant regimenand may achieve greater control of the disease.

Paclitaxel is an active drug in Mullerian tumors suchas ovarian [21] and endometrial carcinomas [22]. Analo-gous to cisplatin, which was initially tested in ovariancancer, then proven effective in endometrial cancer and

eventually became the cornerstone of chemotherapy forcervical carcinoma, paclitaxel might find a role in thelatter tumour type. Paclitaxel has not yet been testedextensively in cervical carcinoma [10, 11], but it showedan objective response rate of 17 in the only availablelarge study, performed in advanced or recurrent squa-mous-cell carcinoma. This data supports the inclusionof paclitaxel in combination chemotherapies; the lowdose (135 mg/ m2) given to the majority of patients andthe lack of information on response rate in irradiatedareas render it difficult to assess its antitumour activitymore precisely.

Our report suggests that the use of paclitaxel incombination with cisplatin and ifosfamide is feasibleand tolerable and results in a high response rate, partic-ularly in terms of pathology-complete response. To provethe superiority of this combination and to define theimpact of paclitaxel on survival, this regimen needs tobe prospectively compared to standard multidrug treat-ments without taxanes. Toxicity appears to be acceptablein view of the facts that all of the patients received thethree planned cycles, and that it was possible to completeall needed radiotherapies. Peripheral neuropathy wasreported in only 5 of cases, mainly because of theshort duration of treatment and of the low dose of

cisplatin administered. Severe neutropenia, which oc-curred in 70 of the patients, was of greater concern;nevertheless, no related complications were reported. Aprospective multicenter randomized trial comparingifosfamide and cisplatin with/without paclitaxel is al-ready ongoing.

References

1. Sardi JE, Di Paola GR, Cachau A et al. A possible new trend inthe management of carcinoma of the cervix uteri. G ynecol Oncol

1986; 25: 139-49.2. Kim DS, Moon H, Kim KTet al . Two-year survival: Preoperativeadjuvant chemotherapy in the treatment of cervical cancer stageIb and II with bulky tumor. Gynecol Oncol 1989; 33: 225-30.

3. Benedetti Panici P, Scambia G, Greggi S et al. Neoadjuvantchemotherapy and radical surgery in locally advanced cervicalcarcinoma: A pilot study. Obstet Gynecol 1988; 71: 344-8.

4. Thigpen T, Shingleton H, Homesley H et al. Cis dichlorodiamm i-noplatinum (II) in the treatment of gynecologic malignancies:Phase II trial by the Gynecologic Oncology Group . Cancer TreatRep 1979; 63: 1549-55.

5. Zanetta G, Torri W, Bocciolone L et al. Factors predictingresponse to chemotherapy and survival in patients with meta-static or recurrent squamous cell cervical carcinoma. A multi-variate analysis. Gynecol Oncol 1995; 58: 58-63.

6. Hann ing EV, Dinh TV, Doherty MG. Ifosfamide with Mesna insquamous carcinoma of the cervix. Phase II results in patientswith advanced o r recurrent disease. Gynecol O ncol 1991; 43:123-8.



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7. Buxton EJ, Meanwell CA, Hilton C. Combination bleomycin,ifosfamide and cisplatin chemotherapy in cervical cancer. J NatlCancer Inst 1989; 81: 359-61.

8. Zan etta G, Leventis C, Lomonico S et al. Bleomycin, ifosfamideand cisplatin chemotherapy in recurrent and persistent cervicalcancer. A prospective study. Int J Gynecol Cancer 1995; 5: 56-60.

9. Bolis G, van Zainten-Przybysz I, Scarfone G et al. Determinantsof response to a cisplatin-based regimen as neoadjuvant chemo-therapy in stage IB-IIB invasive cervical cancer. Gynecol Oncol1996; 63: 62-5.

10. Thigpen T, Vance RB, Khansur T. The platinum compounds andpaclitaxel in the management of carcinomas of the endometriumand u terine cervix. Semin Oncol 1995; 22 (Suppl 12): 67-75.

11. Me Guire WP, Blessing JA, Moore D et al. Paclitaxel h as moder-ate activity in squamous cervix cancer: A Gynecologic OncologyGro up study. J Clin Oncol 1996; 14: 792-5.

12. Miller AB, Hoogstraten B, Staquet et al. Reporting results ofcancer treatment. Cancer 1981; 47: 207-14.

13. Piver MS, Rutledge F, Smith JP. Five classes of extended hyster-ectomy for women with cervical cancer. Obstet Gynecol 1974; 44:265-72.

14. Tattersall MHN, Ram irez C, Coppleson H. A randomized trial

comparing platinum-based chemotherapy followed by radiother-apy versus radiotherapy alone in patients with locally advancedcervical cancer. Int J Gynecol Cancer 1992; 2: 244-51.

15. Serur E, Mathews RP, Gates J et al. Neoadjuvant chemotherapyin stage IB2 squamous-cell carcinoma of the cervix. GynecolOncol 1997; 65: 348-56.

16. Sardi JE, Giaroli A, Sananes C et al. Long-term follow-up of thefirst randomized trial using neoadjuvant chemotherapy in stageIb squamo us carcinoma of the cervix: The final results. GynecolOncol 1997; 67: 61-9.

17. Benedetti-Panici P, Landoni F, Greggi S et al. Randomized trial

of neoadjuvant chemotherapy (NACT) followed by radical sur-gery (RS) vs exclusive radiotherapy (RT) in locally advancedsquamous cell cervical cancer (LASCCC). An italian multicenterstudy. Int J Gynecol Cancer 1997; 7 (Suppl 2): 18.

18. Giaroli A, Sananes C, Srdi JE et al. Lymph node metastases incarcinoma of the cervix uteri. Response to neoadjuvant chemo-therapy and its impact on survival. Gynecol Oncol 1990; 39: 34-9.

19. Colombo N, Gabriele A, Lissoni A et al. Neoadjuvant chemo-therapy in locally advanced uterine cervical cancer: Correlationbetween pathological response and survival. Proc Am Soc ClinOncol 1998; 17: 352.

20. Zanetta G, Landoni F, Colombo A et al. Three-year results afterneoadjuvant chemotherapy, radical surgery and radiotherapy inlocally advanced cervical ca rcinom a. Obstet Gynecol 1993; 82:447-50

21. Eisenhauer EA, Ten Bokkel-Huinik WW, Swenerton K.D et al.European-Canadian randomized trial of paclitaxel in relapsedovarian cancer: high-dose versus low-dose and long versus shortinfusion. J Clin Oncol 1994; 12: 2654-66.

22. Lissoni A, Zanetta G, Losa G et al. Phase II study of paclitaxel assalvage treatment in advanced endometrial cancer. Ann Oncol1996; 7. 861-3.

Received 3 March 1998; accepted 23 June 1998.

Correspondence to:G. Zanetta, MDDivisione Ostetricia e GinecologiaOspedale San G erardoVia Solferino 1620052, MonzaItaly



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ann oncol 1998 zanetta 977 80

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