Cytotoxic Drug Treatment

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CME Journal of Gynecologic Oncology 6772 67

Cytotoxic drug treatment

of vulval and vaginal cancer

GAVIN M. MAR X, M.D., MICHAEL L.

FRIEDLANDER, M.D., NEVILLE F. HACKER, M.D.

ABSTRACT Patients with operable vulval cancer without nodal

involvement usually have excellent survival rates, but this falls

significantly in those patients with nodal involvement. The role

of cytotoxic drug treatment in vulval cancer is limited. There are

few data on the role of chemotherapy in the management of

patients with vulval cancer. The available data relate to preop-

erative chemotherapy, usually used in combination with radio-

therapy, to downstage advanced tumors in an attempt to ren-

der them operable, reduce the extent of surgery, or the need for

permanent stomas. There are also some data on concurrent

chemo-radiotherapy as an alternative to surgery in selected

patients. There a re virtually no definitive studies in patients with

metastatic vulval cancer. This paper highlights some of these

treatment options using chemotherapy in combination with

radiation as neoadjuvant and definitive therapy. Chemotherapy

has a very limited role in the management of vaginal cancer.

Key words vaginal, vulval, chemotherapy, radiotherapy, metas-tatic

VULVAL CANCER Vulval cancer accounts for about 4% of gyne-

cological malignancies and is highly curable when diagnosed

early. In patients with operable vulval cancer without nodal

involvement the overall survival rate is about 85-90%, but this

falls to 50-60% in those patients with nodal involvement.

Radical radiotherapy, usually combined with surgical resec-

tion of the tumor bed, can result in long-term survival in those

patients in whom surgical resection would necessitate some

type of pelvic exenteration and a permanent stoma.

The role of cytotoxic drug treatment in vulval cancer is limi-

ted. There are few data on the role of chemotherapy in the

management of patients with vulval cancer. The available

data relate to preoperative chemotherapy, usually used in

combination with radiotherapy, to downstage advanced

tumors in an attempt to render them operable, reduce the

extent of surgery, or the need for permanent stomas. There

are also some data on concurrent chemo-radiotherapy as an

alternative to surgery in selected patients. There are virtually

no definitive studies in patients with metastatic vulval cancer

making it impossible to make any evidence-based decisions in

this setting.

PREOPERATIVE TREATMENT A number of investigators have evalu-

ated the potential role of neoadjuvant chemotherapy in

patients with advanced vulval cancer. There have been no

randomised controlled trials assessing the impact of preoper-

ative trea tment. It ha s generally been used in those pa tients in

whom primary surgery was likely to require exenteration or

formation of permanent stomas or if patients were deemed

medically unfit to undergo a major surgical procedure.

COMBINATION CHEMOTHERAPY Combination chemotherapy alone inthe preopera tive setting has been studied by the Italian group

under Benedetti Panici (1). They treated 21 patients with

advanced (FIGO stage IVA) vulval squamous cell carcinoma

with 2-3 cycles of neoadjuvant cisplatin (100 mg/m 2 day 1),

bleomycin (15 mg day 1 and 8) and methotr exate (300 mg/m2

day 8). Ten percent had a partial response in the primary and

67% had a complete or partial response in the nodes. They

reported a 3-year survival rate of 24%, which was influenced

by stage, pathological downstaging and nodal involvement.Sixty-eight percent of the operated patients recurred 3-17

months from the completion of treatment with half having

distant relapses. These results were disappointing and the

authors concluded that there was no substantial benefit from

the addition of chemotherapy, without concurrent radiation,

prior to surgery.

COMBINATION CHEMO-RADIATION The combination of chemotherapywith radiation has been used in an attempt to improve the

results of radiation alone. A number of agents have been used

which act as radiation sensitisers and also may have some

impact on systemic disease.

Moore et al. (2) assessed the impact of neoadjuvant chemo-

radiotherapy on reducing the need for rad ical surgery in T3 and

T4 primary tumors. Seventy-three patients with FIGO stage

III/IV vulval cancer were enrolled in a prospective multi-insti-

tutional study. Treatment consisted of a split course of con-

current chemotherapy with cisplatin and 5-FU and radiother -

apy, followed by surgery to the primary lesion and inguinal

and femoral nodes. Radiation was delivered to the primary

tumour volume via anterior-posterior and postero-anterior

fields in 1.7 Gy fractions to a dose of 47.6 Gy. At surgery

Address correspondence to:

Gavin Mar x, M.D.

Departme nt of Medical Oncology

Prince of Wales Hospital

High St, Randwick NSW 2031, Sydney, Australia

Phone (44 207) 955 5000 Fax (44 207) 955 4939

E-mail [email protected]


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68 CME Journal of Gynecologic Oncology 6772

Cytotoxic drug treatment of vulval and vaginal cancer

46.5% had no visible vulval cancer and 53.5% (38 patients)

had gross residual disease. Seven patients did not undergo

surgery for various reasons. Five of the 38 patients with gross

residual disease had positive re section margins requiring fur-

ther therapy; wide local excision, radiotherapy or vaginecto-

my. Using this therapeutic approach only 2/71 (2.8%) had

residual unresectable disease. Urinary and fecal continence

was preserved in all but 3 patients. They concluded that this

approach was feasible and may reduce the need for more rad-

ical surgery in patients with locally-advanced vulval cancer.

Scheistroen and Trop(3) from the Norwegian Radium H ospi-

tal treated 42 pat ients with advanced squamous cell carcinoma

of the vulva (20 primary lesions and 22 recurrent disease), with

the combination of preoperative bleomycin (180 mg) and

radiotherapy (30-45 Gy). The median survival in the pa tients

with primary disease was only 8 months and did not suggest

any value of neoadjuvant therapy (3). Only a small proportion

of patients in this study actually went on to have surgery

(4 patients with primary disease and no patients who were

treated for recurrent disease). The authors concluded that

even though the patients in their study had advanced disease,

the results were d isappointing and suggested tha t an increase

in the radiation dose and more aggressive surgery might have

improved the results.

Two groups have studied the combination of 5-fluorouracil

with mitomycin-C in combination with r adiation as preopera-

tive or neoadjuvant therapy.Lupi et al. (4) reported on com-

bined preoperative chemo-radiotherapy in 31 patients withlocally-advanced vulval cancer. They were treated with

2 courses of combination chemotherapy with mitomyin-C

(15 mg/m2 day 1) and 5-FU (750 mg/m2 continuous infusion

days 1-5) and concurrent radiotherapy to the inguinal and

pelvic nodes and vulva to a total dose of 36 Gy. Ninety-two

percent of primary cases and all patients with recurrent dis-

ease had an objective response. However, the postoperative

morbidity rate was 56% and mortality was 13.8%. At a median

follow up of 34 months the recurrence rate was 31.8%. They

concluded that if treatment related morbidity could be

decreased this combined approach might have a role in pa-

tients with locally-advanced vulval cancer.

Landoni et al. (5) prospectively evaluated the feasibility and

efficacy of neoadjuvant chemo-radiothe rapy in pa tients with

locally-advanced or recurrent disease. Fifty-eight patients

were treated with preopera tive external radiation to a dose of

54 Gy, divided into 2 cour ses with an inte rval of 2 weeks. 5-FU

(750 mg/m2 daily for 5 days) and mitomycin-C (15 mg/m 2 sin-

gle bolus) were commenced at the start of each course.

Eighty-nine percent of patients completed treatment and

72% underwent surgery. An objective response rate of 80%

was observed and pathologic complete responses were seen in

31%. Early severe toxicity occurred in 3 patients and there

was 1 treatment-related death. They felt that this treatment

provided good local control with acceptable toxicity (5).

Recent results presented at the ASTRO 1999 meeting in

abstract form also suggested a possible role for neoadjuvant

therapy.Montana and colleagues (6) on behalf of the Gyneco-

logic Oncology Group used a split course of chemo-radiothe-

rapy preoperatively in patients with locally-advanced disease.

Forty-six patients were treated with 2 cycles of combination

cisplatin-5-FU and radiotherapy. The radiotherapy was deliv-

ered using a AP/PA technique, delivering a dose of 23.8 Gy in

1.7 Gy per fraction bid on days 1-4 and 1.7 Gy per day for the

remainder of the treatment. The patients then had a 2-week

rest period then an additional treatment of radiation to bring

the total dose to 47.6 Gy. The chemotherapy was adminis-

tered at the start of each course of radiation. Cisplatin was

administered as 50 mg/m2 on days 1-4 and 5-FU was adminis-

tered as 1000 mg/m2/day on days 1-4, in week 1 of each cycle.

All but 6 patients were able to complete the chemo-radiothe-

rapy treatment. The response rate was promising with local

control in the nodal areas in 97% and in the primary in 76%.

Although there are some data to suggest that neoadjuvant

(preoperative) chemotherapy, in combination with radiation,

may downstage advanced vulval cancers and possibly permit

less aggressive surgery in selected patients this is still consid-

ered investigational, and only recommended in the context of

a clinical trial. There is no evidence to suggest that this

approach is associated with a survival bene fit. Clearly patientsneed to be carefully selected in view of the potential morbid-

ity associated with these treatments.

CONCURRENT CHEMO-RADIATION AS PRIMARY TREATMENT The role

of concurrent chemo-radiotherapy as a primary treatment

option is also unclear and has also not been studied in large

randomized trials. There is however reasonably extensive

experience with this approach as it is often used as an alter-

native to radical surgery in those patients deemed inoperable,

for various reasons.

Berek et al. (7) at UCLA conducted a phase II study of com-bination chemo-radiotherapy in 12 patients with FIGO stage

III-IV squamous cell carcinoma of the vulva. They used a

combination of cisplatin and 5-FU as a radiosensitizer. Cis-

platin was administered as an intravenous dose of 50 mg/m2/day

on day 1 and 2, or as 100 mg/m2 on day 1 or 2. The 5-fluoroura-

cil was administered as a continuous infusion of 1000 mg/m2/day

for 4-5 days. These treatments were given on the first and

28th day of radiation therapy. Pelvic radiation to a dose of

44-54 Gy was administered to the primary, groin and iliac ves-

sels to the level below the common iliac nodes. Responses

were seen in 92% with complete responses in 67%. At the


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Chapter 18


completion of chemo-radiation radical vulvectomy or excision

was used in 3 patients and 1 patient had a posterior exentera-

tion. The treatment was well tolerated with no treatment-

related deaths. This group concluded that this combination

may provide an alternative to primary radical surgery in

patients with advanced cancer o f the vulva.

In a retrospective single institution study by Koh et al. (8) the

combination of chemo-radiotherapy was shown to be effec-

tive in the management of locally-advanced cancer of the

vulva. Twenty patients with locally-advanced or recurrent dis-

ease, who were not considered candidates for primary

surgery, were treated with concurrent 5-FU and radiotherapy.

Five patients also received cisplatin and 1 received mitomy-

cin-C. Ten pa tients had a complete response and 8 had partial

responses. Six patients with partial responses had re sidual tu-

mor successfully resected. The 5-year local control rate was

48%. Overall the trea tment was well tolerated with cutaneous

toxicities being the most common side effect observed.

Whalen et al. (9) concluded that combined chemo-radiation

was a reasonable alterna tive to radical vulvectomy in patients

with advanced disease (AJCC stage II-III). They evaluated

the combination of radiotherapy given concurrently with 5-FU

and mitomycin-C in 19 patients. With a median follow-up of

34 months a complete response rate of 53% and partial

response rate of 37% was observed. The combined modality

of chemo-radiation with or without wide local excision resulted

in a local control rate of 74% (14/19). Four of the 5 patients

with local recurrences were rendered disease free after radi-

cal surgery, for an overall local control rate of 95%.

Investigators from theMD A nderson Cancer Center(10) simi-

larly demonstrated that the combination of cisplatin/5-FU

Table 1. Neoadjuvant treatment

Study Patients Chemotherapy Radiotherapy Results Toxicity Conclusions

Moore et al. 73 patients Split course 47.6 Gy to P 7 no surgery 3/71 unable to Preop chemoradiation is fea-

1998 FIGO III/IV Cisplatin and groins if nodes 33/71 no visible disease preserve urin/fecal sible and may decrease need

(2) Squamous 5-FU inoperable 38/71 gross residual disease continence for more radical surgery

Prospective 5/38 positive margins

multicentre 2/71 resid unresect disease (2.8%)

Benedetti- 21 patients 2-3 cycles Nil 2/21 (10%) PR at primary Acceptable morbidity Chemotherapy did not addPanici et al. FIGO IVA Cis 100 mg/m2 day 1 14/21 (67%) PR at nodes significant benefit to surgery

1993 Squamous bleo 15 mg day 1 and 8 3-year survival 24%

(1) MTX 300 mg/m2 day 8 68% recurrence at 3-17 months

Scheistroen 42 patients Bleomycin 180 mg 30-45 Gy P RR 15/20 (75%) 5 CR 10 PR Acceptable toxicity Results disappointing

et al. 1993 20 P, 22 Recurrent P MS 8 months No treatment related deaths ? Benefit if increase RT dose

(3) Squamous Rec 13/22 (59%) 2 CR 11 PR

Recurrent MS 6.4 months

Lu pi et al. 31 patients 2 cycles P inguinal and pelvic P R R 22/24 ( 92% ) Postoperative morbidity 65% Chemoradiation effective

1996 24 P, 7 recurrent Mito-C 15 mg/m2 day 1 nodes up to 36 Gy Rec RR 7/7 (100%) Mortality rate 13.8% May be an option if reduction

(4) Locally advanced 5-FU 750 mg/m2 CI day 1-5 2nd course after 55% nodal pathologic CR in morbidity/mortalitySquamous 2 weeks break to Recurrence rate 32% at

vulva only 18 Gy median FUP 34 months

Lando ni et al. 58 patients 2 cycles 54 Gy in 2 divided RR 80% 89% completed treatment Allows good control with

1996 41 P, 17 recurrent 5-FU 750 mg/m2 CI day 1, 5 doses Pathologic CR 31% 72% underwent postop surgery acceptable toxicity

(5) Squamous mito-C 15 mg/m2 day 1 Early severe tox in 3 patients Further FUP and long-term

Locally advaced 1 treatment-related death outcome FUP required

P primary Cis cisplatin Bleo bleomycin MTX methotr exate Mito-C mitomycin-C 5-FU 5-fluorouracil PR partial response MS median survival Resid residual

Rec recurrent CR complete response FUP follow-up CI continuous infusion RR response rate


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with rad iation was well tolerated with high response ra tes in

patients with loco-regionally advanced vulval cancer. Eleven

out of 12 patients had at least a partial clinical response. Of

the 8 patients who had post-therapy resection 50% had a

pathological complete response. Half the patients remained

disease free at 17-30 months post-treatment .

Cunningham et al. (11) evaluated a combination of chemo-

therapy and radiation as an alternative for those patients in

whom the location or extent of disease made pelvic exentera tion

the only surgical option. Fourteen patients with stage III-IV

vulval carcinoma were treated with cisplatin/5-FU and radia-

tion (vulva and groins 50-65 Gy, and pelvic doses of 45-50 Gy).

They reported a response rate of 92% with complete respon-

ses in 64%. In those patients with complete responses there

has only been 1 recurrence with a follow-up of 7-81 months.

All patients with partial responses died with a mean survival of

15.7 months (8-25). They concluded tha t surgical resection was

not necessary in patients with complete response.

In patients deemed inoperable for various reasons (presence

of initially unresectable disease, disease extent which would

necessitate part ial or tota l exenteration, severe comorbid ill-

ness precluding surgical management), combination chemo-

therapy and radiotherapy was studied by Russell et al. (12).

They trea ted 25 patients with stage II-IV squamous cell vul-

Table 2. Primary chemoradiotherapy

Study Patients Chemotherapy Radiotherapy Results Toxicity Conclusions

Berek et al. 12 patients 2 cycles 44-54 Gy CR 8/12 (67%) No treatment deaths Data support use of

(7) Phase II, Cis 50 mg/m2 day 1 and 2 to P. groin and PR 3/12 (25%) No grade IV toxicity this combination as

retrospective or 100 mg/m2 day 1 iliac nodes 10 pts disease-free Grade III desq 2 pts alternative to surgery

Sur g F IG O II I/I V 5-F U 1 g/m2 CI day 1-4 1 DVT

Med FUP 37 months

Koh et al. 20 patients 2-3 cycles 54 Gy CR 10/20 (50%) Well tolerated An effective option in Mx

(8) Retrospective 5-FU PR 8/20 (40%) Major acute toxicity was

FIGO III/IV 5 pts received cisplatin 5-year DFS (49%) skin

Non-surgical candidates 1 pt received mito-C

Med FUP 37 months

Whalen et al. 19 patients 2 cycles 45-50 Gy CR 10/19 (53%) Concurrent chemoradiation with

(9) AJCC II-III 5-FU 1 g/m2 CI day 1-4 to pelvis and grain nodes PR 7/19 (37%) local excision as required

Med FUP 34 months from 1991 1 dose of 10 pts had boosts Local control in 14/19 is a reasonable alternative

mito-C 10 mg/m2 day 1 6 had local resection 4/5 failures rendered disease- to radical surgery

free with surgery 95%

Eifel 12 patients 4 cycles (weekly) 40-50 Gy PR 11/12 (92%) Well tolerated Well tolerated

(10) Locally advanced Cis 4 mg/m2/d day 1-4 4/8 patho logical CR Min he mato l toxicity High R R in large vulval

5-FU 250 mg/m2/d day 1-4 6/12 disease-free 17-30 months No tr eatme nt delays tumors

Cunningham 14 patients 2 cycles 50-65 Gy RR in 92% Treatment delays in 5 pts Combination effectiveet al. Non-surgical candidates Cis 50 mg/m2 day 1 to vulva/groins CR in 9/14 (64%) DVT in 1 pt Acceptable toxicity

(11) Stage III/IV 5-FU 1 g/m2 CI day 1-4 45-50 Gy CR pts 1 recurrence Colonic stricture in 1 pt Surg excision not required in CR

to pelvis PR all died, MS 15.7 months

Russell et al. 25 patients P CR 16/18(89%) May hold a curative potential

(12) Non-surgical candidates Rec 4/7 (57%) for pts with unresectable or

Stage II-IV 14 disease-free medically inoperable disease

at median FUP 24 months

Med median FU P follow-up Surg surgery Cis cisplatin 5-FU 5-fluorouracil D day mito-C mitomycin-C CI continuous infusion PR partial response CR complete

response DVT deep venous throm bosis pts patients MS median survival DSF disease-free survival Mx management RR respon se rate


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Chapter 18


val cancer. Seven patients had recurrent disease. Complete

responses were seen in 16/18 (89%) of previously untreated

patients and in 4/7 (57%) with recurrent disease. Fourteen

patients remained disease free 2-52 months (median 24

months) after tr eatment. They suggested that this might be an

alternative treatment option for such patients (12).

Results from the Yale group (13) were reported at ASTRO 1999.

They analyzed the impact of chemo-radiation in 54 patients with

locally-advanced vulval cancer. Fourteen patients were treated

with primary chemo-radiation, 12 with primary radiation, 6 with

adjuvant chemo-radiation and 22 with adjuvant radiation thera-

py. Chemotherapy consisted of infusional 5-FU and either cis-

platin or mitomycin-C, at the discretion of the physician. Radi-

ation doses when given with chemotherapy ranged from 45-46

Gy to the pelvis, vulva and inguinal regions with a boost of 56-

60 Gy to all gross disease. Those patients treated with radiation

alone were treated with 40-50 Gy with a boost to gross disease

to 60 Gy. Although this data was not randomised the primary

chemo-radiotherapy group had a statistically significant

increase in cause-specific survival, relapse-free survival and

overall survival over the primary radiotherapy group.

Combination chemo-radiation may be an alternative to exten-

sive surgery in patients with locally-advanced vulval cancer

but needs to be evaluated in randomized controlled studies.

For those pat ients unsuitable for pr imary radical surgery, con-

current chemo-radiotherapy may be a reasonable alternative

approach. Clearly, however, early detection with curative

surgery remains the optimal approach.

METASTATIC DISEASE The prognosis of patients with systemic

metastases from vulval cancer is poor. There are few data

available on effective treatment options for this group of

patients and no recommendations can be made due to the

paucity of published series. Most patients have squamous cell

carcinomas and it is the authors opinion that if chemotherapy

is to be used the approach should be similar to that taken for

patients with metastatic squamous cell cancer arising at other

sites.

VAGINAL CANCER Cancer of the vagina is an uncommon gyne-cological malignancy and it accounts for about 1-2 % of gyne-

cological malignancies. Squamous cell cancer is the most

common histological subtype. The standard treatment for

stage I disease is surgery or radiotherapy, which is associated

with a high rate of cure. Patients with stage IIA-IVA disease

are treated with radiation alone. No satisfactory treatment

exists for stage IVB and recurrent d isease.

There are only limited data available on the role of chemo-

therapy in these patients. Chemotherapy has generally only

been used in the salvage setting and the results have been

poor. Prior irradiation or surgery may reduce the delivery of

these agents to the tumor. Patients also tend to be older and

prior rad iation may also impact on hematologic reserves mak-

ing them less suitable candidates for chemotherapy.

Although numbers are small, there are reported studies of

both single-agent and combination chemotherapy in patients

with vaginal cancer. Overall the results have been disappoint-

ing. Mitoxantrone was assessed by the Gynecologic Oncology

Group (15). Nine patient s with advanced vaginal cancer were

treated with 12 mg/m2 mitoxantrone at 3 weekly intervals.

There were no responses to treatment and the median sur-

vival in patients with vaginal cancer was 2.7 months. Piver et

al. (16) demonstrated some activity in a small number of

patients with single-agent adriamycin. Etoposide has also

been studied and has not demonstrated any activity in

patients with advanced or recurrent vaginal tumors. Slayton et

al. (17) treated 16 pat ients with e toposide 100 mg/m2 on days

1, 3, 5 and demonstrated no anti-tumor activity.

Cisplatin as a single agent ha s also been shown to be ineffec-

tive in the trea tment of advanced or recurrent vaginal cancer.

The GOG (18) performed a phase II study of cisplatin

(50 mg/m2 q 3/52) in 22 evaluable patients with advanced or

recurrent cancer no longer amenable to control with surgery

or radiotherapy. Toxicity was acceptable but this agent did not

demonstrate activity in patients with vaginal cancer.

Newer agents may have some potential activity and Umesaki

et al. (19) repor ted the efficacy of the combination of cisplatinand irinotecan as neoadjuvant therapy in a pa tient with stage

II vaginal cancer. This patient had a clinical and pathological

complete response after 1 cycle of treatment.

There are few data regarding the role of combination chemora-

diation in vaginal cancer.Evans et al. (20) treated 7 patients with

stage II and III squamous cell vaginal cancer with mitomycin-C

and 5-fluorouracil with concurrent radiation. Fifty-seven per-

cent (4/7) achieved a complete response and remained disease

free at 8-39 months. Roberts et al. (21) treated 1 patient with

concominant radiation and cisplatin/5-fluorouracil and had a

complete response for an undefined period of time.

The prognosis for patients with metastatic disease remains

poor with no chemotherapeutic agents consistently demon-

strating efficacy in these patients. The introduction of newer

agents provides the opportunity for multi-institutional cooper-

ative clinical trials to identify agents with activity in this disease.

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