Neoadjuvant chemotherapy in vulvar cancer: Avoiding primary exenteration

Gynecologic Oncology 100 (2006) 53 – 57 www.elsevier.com/locate/ygyno

Neoadjuvant chemotherapy in vulvar cancer: Avoiding primary exenteration John P. Geisler *, Kelly J. Manahan, Richard E. Buller Indiana Women’s Oncology, University of Iowa-Holden Comprehensive Cancer Center, Division of Gynecologic Oncology, St. Vincent Hospitals, 8301 Harcourt Road, Suite 201, Indianapolis, IN 46260, USA Received 8 October 2004 Available online 27 October 2005

Abstract Objective. To determine whether neoadjuvant cisplatin and 5-fluorouracil chemotherapy can be used to preserve the anal sphincter and/or urethra in patients with advanced vulvar cancer involving these sites. Methods. Fourteen patients with advanced vulvar cancer (1997 – 2003) involving the anal sphincter and/or urethra were given 3 – 4 cycles of neoadjuvant chemotherapy to attempt preservation of these pelvic structures rather than undergoing a primary pelvic exenteration. Following 3 cycles, a radical vulvectomy and groin lymph node dissection were planned. All patients had lesion size documented by measurement and photograph prior to and following chemotherapy. Results. The median age was 63 years (range 39 – 88). Thirteen patients received a median of 3 cycles (range 2 – 4) of neoadjuvant chemotherapy. Ten patients received cisplatin and 5-fluorouracil, while three received cisplatin alone. The median time from diagnosis to surgery was 77 days (range 54 – 143). All patients with cisplatin and 5-fluorouracil chemotherapy underwent surgery except one patient who had a synchronous renal cell carcinoma and died prior to surgery. Patients receiving cisplatin alone showed no measurable response, while all patients receiving cisplatin and 5-fluorouracil demonstrated at least a partial response. Two patients had no residual invasive carcinoma on final pathology. All patients receiving cisplatin and 5-fluorouracil followed by surgery are disease-free, while two of three receiving cisplatin have progressive disease. The anal sphincter and urethra were conserved in all patients receiving cisplatin and 5-fluorouracil. Conclusion. Neoadjuvant cisplatin and 5-fluorouracil in advanced vulvar cancer demonstrated a response rate of 100%. The anal sphincter and urethra were conserved in all patients receiving cisplatin and 5-fluorouracil. Responders are disease-free at this time. This response rate demonstrates superior activity of 5-fluorouracil in vulvar cancer and spares these patients the morbidity of exenteration or radiation. D 2005 Elsevier Inc. All rights reserved. Keywords: Neoadjuvant chemotherapy; Vulvar cancer; Exenteration

Introduction Vulvar cancer is a relatively uncommon gynecologic cancer. In the United States, an estimated 4000 new cases with 800 deaths will occur in 2003 [1]. Despite a frequent delay in diagnosis, the majority of these cancers are early in their presentation. Standard treatment for early disease has been refined from the original Bassett/Pringle procedure to a much more conservative approach involving obtaining

* Corresponding author. Fax: +1 317 415 6707. E-mail address: [email protected] (J.P. Geisler). 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.06.068

adequate margins but retaining more normal tissue than previously [2 –4]. When disease is locally advanced and not amenable to a conservative surgical approach, one of two options can be employed. The first approach is a primary exenteration. If the lesion involves the anus or rectum, permanent colostomy is required. If the lesion involves the proximal urethra or bladder, a urinary diversion is required. Not only is this approach disfiguring, it also carries with it an operative mortality of up to 10% [5]. Another possible approach has been advocated by the Gynecologic Oncology Group (GOG) and Moore [6]. Boronow pioneered this method first in 1973 and revisited it in his seminal articles in 1980s [7– 9]. This

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approach employs the use of preoperative chemoradiation for these patients. Although 53.5% had a complete response, nearly 12.7% were unresectable or had to undergo resection of the tissue which was trying to be preserved [6]. The purpose of this manuscript is report on our experience with neoadjuvant chemotherapy to avoid primary exenteration for locally advanced vulvar carcinoma. Methods This study involves all patients undergoing neoadjuvant chemotherapy for advanced vulvar cancer involving the rectum and/or proximal urethra/bladder at The Holden Comprehensive Cancer Center or St. Vincent Hospitals. All patients underwent informed consent regarding alternative treatment options (exenterative surgery, neoadjuvant chemotherapy, neoadjuvant chemoradiation). Patients chose the therapeutic modality after thorough discussion with their attending physician. The choice to use cisplatin alone or in combination with 5-fluorouracil was chosen by the patient’s staff physician. This was not a randomized trial. Photographs were taken of the lesions before chemotherapy (Figs. 1 and 2) to ensure resection of the appropriate areas after chemotherapy. All tumors were measured before each cycle of chemotherapy and before surgery. Measurements were made in two dimensions, and an area (cm2) was determined (Table 1). The general chemotherapeutic schema is given in Table 2. The cycles were given 3 weeks apart (day 1 to day 1). Doses of 5-fluorouracil were decreased for grade 4 toxicities (1000 mg/m2 Y 750 mg/m2 for the first time, 750 mg/m2 Y

Fig. 1. Photograph of patient 9’s vulvar cancer prior to cycle 1 of cisplatin/ 5-fluorouracil.

Table 1 Clinical response parameter definitions Parameter

Definition

Partial response Complete Stable disease Progression

50% decrease in lesion area (cm2) No measurable lesion <50% response to < 50% growth 50% growth in lesion area (cm2)

500 mg/m2 for the second time). No adjustments in cisplatin were made. Ondansetron and decadron were used as prechemotherapeutic anti-emetics, while metaclopramide and decadron were the standard post-chemotherapy anti-emetics prescribed (Table 2). Statistics, including Chi-square analysis, were performed utilizing SPSS for Windows version 9.0 (Chicago, IL). Toxicity criteria were studied using the Gynecologic Oncology Group’s standard toxicity guide. All pathology was reviewed by gynecologic pathologists at the institutional tumor boards.

Results Characteristics Thirteen patients underwent neoadjuvant chemotherapy for advanced vulvar cancer. The median age of the population was 63 years old (range 39– 88). The median age of the group receiving dual agent chemotherapy was 56 years old (range 39– 81), while the median age of the single agent group was 78 (range 78 – 88) (P = 0.043). The median follow-up (disease-free) for those receiving dual agent chemotherapy was 49 months (mean 41, range 3– 90 months). All patients had squamous cell carcinomas of the vulva (Table 3). Two of the cancers originated in the Bartholin’s glands (but were squamous lesions). Both of these had a partial response. The mean time from diagnosis to surgery in the dual agent arm was 82 days, while the mean time from diagnosis to surgery in the single agent arm was 88 days (P = 0.77). There was no difference in the rate of lymphovascular space invasion (P = 0.39) or depth of invasion above or below 5 mm (P = 0.62) between the two groups.

Fig. 2. Photograph of patient 9’s vulvar cancer prior to cycle 3 of cisplatin/ 5-fluorouracil.

J.P. Geisler et al. / Gynecologic Oncology 100 (2006) 53 – 57 Table 2 Chemotherapy schemaa

Table 4 Surgery and current status

Day 1 anti-emetics Day 1 chemotherapy Cisplatin 50 mg/m2 IV over 1 mg/min then 5-fluorouracil 1000 mg/m2 IV over 24 h Cisplatin 50 mg/m2 IV over 1 mg/min

Ondansetron 32 mg/ dexamethasone 20 mg

Ondansetron 32 mg/ dexamethasone 20 mg a

55

Days 2 – 5 anti-emetics

Days 2 – 5 chemotherapy

Dexamethasone 5-fluorouracil 8 mg qAM with 1000 mg/m2 metoclopramide IV over 24 h 20 mg q8 h

Patienta

Surgery

Preservation of urethra/ rectum

Status

1

Radical vulvectomy with bilateral groin dissection Radical vulvectomy with bilateral groin dissection Radical vulvectomy with bilateral groin dissection Radical vulvectomy with bilateral groin dissection Radical vulvectomy with bilateral groin dissection Radical vulvectomy with unilateral groin dissection N/A Radical vulvectomy Radical vulvectomy with unilateral groin dissection Radical vulvectomy N/A Radical vulvectomy with bilateral groin dissection Radical vulvectomy with bilateral groin dissection

Yes

NEDb

Yes

NED

Yes

NED

Yes

NED

Yes

NED

Yes

NED

N/A No Yes

DOCc DODd NED

No N/A Yes

DOD DOD NED

Yes

NED

2 3

Dexamethasone None 8 mg qAM with metoclopramide 20 mg q8 h

4 5

Repeat q 3 weeks.

6

Toxicities The only grade 3 or 4 toxicities which occurred in these patients were gastrointestinal-related. Two patients had grade 4 diarrhea (10 liquid stools in a day) requiring dosage adjustments. One patient had grade 4 stomatitis after 5-fluorouracil 1000 mg/m2 and even after dosage adjustment to 5-fluorouracil 500 mg/m2. There was no significant difference in the rate of grade 3 or 4 toxicities in this small study (P = 0.22).

7 8 9 10 11 12 13 a b c

Response/surgery

d

Ten patients underwent combination chemotherapy with cisplatin and 5-fluorouracil. All ten responded to therapy, while none of the patients receiving cisplatin alone responded. Nine of the ten patients (90%) underwent a partial clinical response, while 10% underwent a complete clinical response. Nine of ten patients receiving dual agent chemotherapy underwent radical surgery for their tumors. One died from advanced renal cell carcinoma prior to surgery. She was found to have advanced renal cell

Same patient numbers as in Table 3. No evidence of disease. Dead of other causes. Dead of disease.

carcinoma after undergoing a partial response to chemotherapy and never underwent surgery. The surgeries performed are in Table 4. Interestingly, four of the nine partial clinical responders (44.4%) had a complete pathologic response (only carcinoma in situ (multi-focal in two) remained without evidence of residual invasive cancer). Furthermore, the one patient who had a complete clinical response did not have a complete pathologic response.

Table 3 Patient characteristics and response data Patient

Age

Chemotherapy

1 2 3 4 5 6 7 8 9 10 11 12 13

81 48 59 51 41 77 65 76 39 78 88 63 53

Cisplatin/5-fluorouracil Cisplatin/5-fluorouracil Cisplatin/5-fluorouracil Cisplatin/5-fluorouracil Cisplatin/5-fluorouracil Cisplatin/5-fluorouracil Cisplatin/5-fluorouracil Cisplatin  3 Cisplatin/5-fluorouracil Cisplatin  4 Cisplatin  3 Cisplatin/5-fluorouracil Cisplatin/5-fluorouracil

a b c d

      

3 2 3 3 3 3 3

3

3 3

Histology/original gradea

Clinical responseb

Pathologic response

Squamous/1 Squamous/2 Squamous/2 Squamous/2 Squamous/1 Squamous/2 Squamous/1 Squamous/3 Squamous/2 Squamous/2 Squamous/1 Squamous/2 Squamous/3

Partial Partialc Partial Completed Partial Partial Partial None Partialc None Progression Partialc Partialc

Partial Complete Partial Partial Partial Partial N/A None Complete None Progression Complete Complete

Graded on a three-grade scale. See Table 1. Although lesions were still visible (partial response), there was no residual invasive carcinoma found on final pathologic specimen. No residual lesion seen (complete response), but residual carcinoma was found in skin adnexal structures.

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Fig. 3. Kaplan – Meier analysis of survival. The dual agent arm had a mean survival of 79 months (median not yet reached), while the single agent arm had a mean of 9 months (median 7 months) ( P = 0.006).

Residual invasive carcinoma remained in a skin adnexal structure. All patients receiving dual agent chemotherapy and undergoing surgery are alive without recurrence. Interestingly, four patients receiving dual agent chemotherapy had clinically suspicious nodes that were confirmed as metastatic carcinoma histologically by fine needle aspiration prior to chemotherapy. All four patients had shrinkage of their nodes, and all were disease-free at time of surgery. None of the patients receiving cisplatin alone responded clinically. In fact, one of the patients progressed ( 50% increase) during three cycles. She still did not respond to a fourth cycle and was started on radiation therapy. Two underwent palliative radical vulvectomies and received radiation therapy after their surgery. All three patients are dead of disease. Survival analysis by Kaplan– Meier methods is shown in Fig. 3. The dual agent arm had a mean survival of 79 months (median not yet reached), while the single agent arm had a mean of 9 months (median 7 months) (P = 0.006).

bladder/rectum was accomplished in all but a few patients. However, major complications occurred in up to 43% of the patients. Many other papers have subsequently addressed the combination of chemoradiation as neoadjuvant treatment [6,10 – 15]. Multiple different chemotherapy and radiation therapy regimens have been tried. A combination of cisplatin/5-fluorouracil is the most regimen used, although the doses are different than those used in this study. Very good responses have been obtained, but the therapy-related mortality rate still ranges from 5 to 13% [6,10 – 15]. Few studies have looked at neoadjuvant chemotherapy in advanced vulvar cancer [16,17]. Shimizu et al. found that a combination of bleomycin, vincristine, mitomycin C, and cisplatin could be used to make a previously unresectable cancer resectable [16]. A similar regimen did not work on recurrent vulvar cancers though [18]. In a large study performed in Italy, only a 10% response rate was obtained [17]. The authors used only bleomycin, cisplatin, and methotrexate. We have found in our study that 5-fluorouracil appears to be the most important agent. While single agent cisplatin obtained no responses, a 100% response rate was found when a combination of cisplatin and 5fluorouracil was used. This small of a series is not enough to determine whether cisplatin is active as a single agent. Wahlen and colleagues treated nineteen patients with advanced cancer by a combination of primary chemotherapy and radiation [19]. They had five patients with previous complete responses that recurred within 6 months. Despite this fact, the authors recommended just the chemoradiation without planned surgical intervention. Our combination of cisplatin/5-fluorouracil followed by radical vulvectomy and groin lymphadenectomy has led to no recurrences at a median follow-up of 49 months. We believe that, whether neoadjuvant chemotherapy or neoadjuvant chemoradiation is used, a radical vulvectomy with or without node dissection should be included as consolidation therapy.

Acknowledgments Discussion Advanced vulvar carcinoma is not common, but it is a therapeutic dilemma. Although exenterative surgery can be curative, it carries with it both a high morbidity and mortality rate. Boronow first published a therapeutic alternative to exenterative surgery in 1973 [7]. In the 1980s, he published his experience with combined radiation therapy and less extensive surgery [8,9]. In his first series of 26 advanced primary carcinomas, twenty received preoperative radiation. Major complication occurred in 50% of the patients. Still, only one patient required exenteration, and preservation of bladder/rectum was the aim of treatment. Boronow and colleagues expanded upon the original series in the late 1980s [9]. In the series of 37 patients undergoing adjuvant or neoadjuvant, preservation of the

National Institute of Health training grant T32 CA 79445-01A1; St. Vincent Hospital Foundation.

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