Chapter 38: Vaginal Cancer

Leslie Boyd; Franco Muggia

INTRODUCTION

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Epidemiology

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Epidemiology

Incidence:

3,170 (Estimated new cases for 2014 in the United States)

Incidence of clear cell adenocarcinoma as a result of in utero diethylstilbestrol

(DES) exposure estimated at 1/1000

Stage at presentation

Stage I:

28%

Stage II:

43%

Deaths:

Estimated 880 in 2014

Stage III:

16%

Median age:

Squamous cell cancer (60–65 years); DES-related adenocarcinoma/clear cell (19 years)

Stage IV:

13%

Daling JR et al. Gynecol Oncol 2002;84:263–270

Siegel R et al. CA Cancer J Clin 2014;64:9–29

Tedeschi C et al. J Low Genit Tract Dis 2005;9:11–18

Pathology

Histologic Classification of Vaginal Neoplasia

VAIN (VAginal Intraepithelial Neoplasms)

These are pre-malignant lesions of the vaginal squamous epithelium that can develop primarily in the vagina or as an extension from the cervix. Histologically, VAIN is defined in the same way as cervical intraepithelial neoplasia (CIN). Classification includes three grades: Grade 1 (VAIN I = mild dysplasia); Grade 2 (VAIN II = moderate dysplasia); and Grade 3 (VAIN III = severe dysplasia or carcinoma in situ)

Invasive carcinoma:

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1. Squamous cell carcinoma

88%

2. Adenocarcinoma

3. Other epithelial cell types (adenosquamous, adenoid cystic, undifferentiated)

1–2%

4. Mesenchymal tumors (leiomyosarcoma, sarcoma botryoides, endometrioid sarcoma)

5. Mixed epithelial and mesenchymal tumors

<1%

6. Other histologies (melanoma, sarcoma, yolk sac tumors, lymphoma, carcinoid, small cell)

3–4%

Higinia R et al. Vagina. In: Hoskins WJ, Perez CA, Young RC, eds. Principles and Practice of Gynecologic Oncology. 4th ed. Philadelphia: Lippincott-Raven, 2005:707–742

Zaino RJ, Robboy SJ, Kurman RJ. Diseases of the vagina. In: Blaustein's Pathology of the Female Genital Tract. 5th ed. New York: Springer-Verlag, 2002:178–195

Work-up

VAIN (vaginal intraepithelial neoplasia):

H&P, including bimanual examination, palpation, and colposcopic examination of the vagina, vulva, and cervix
Multiple site-directed biopsies, including cervical and vulvar biopsies, to rule out invasive disease and metastatic lesions

Invasive carcinoma:

H&P including bimanual examination and palpation of vagina
Multiple site-directed biopsies, including cervical biopsies to rule out invasive disease and primary cervical cancer
Studies allowable for staging as per FIGO^✫ guidelines: chest X-ray, cystoscopy, proctosigmoidoscopy, and intravenous pyelogram. Although not part of staging, pelvic MRI or CT scan may aid in planning of patient care
If clinically warranted, barium enema and CAT scan or MRI

Staging is best performed by gynecologic and radiation oncologists with the patient under general anesthesia. Additional biopsies of the vagina should be done to determine the limits of abnormal vaginal mucosa

Staging

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Staging

TNM Category

FIGO Stage

Primary Tumor (T)

Primary tumor cannot be assessed

No evidence of primary tumor

Tis

^✫

Carcinoma in situ

Tumor confined to vagina

Tumor invades paravaginal tissues but not to pelvic wall

III

Tumor extends to pelvic wall^†

IVA

Tumor invades mucosa of the bladder or rectum and/or extends beyond the true pelvis (bullous edema is not sufficient evidence to classify a tumor as T4)

^✫FIGO staging no longer includes Stage 0 (Tis)

^†Pelvic wall is defined as muscle, fascia, neurovascular structures, or skeletal portions of the bony pelvis

TNM Category

FIGO Stage

Regional Lymph Nodes (N)

Regional lymph nodes cannot be assessed

No regional lymph node metastasis

III

Pelvic or inguinal lymph node metastasis

TNM Category

FIGO Stage

Distant Metastasis (M)

No distant metastasis (no pathologic M0; use clinical M to complete stage group)

IVB

Distant metastasis

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010

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Staging

Staging^✫

Tis

III

T1–T3

IVA

Any N

IVB

Any T

Any N

^✫FIGO staging no longer includes Stage 0 (Tis)

Expert Opinion

General:

Vaginal neoplasms are quite rare and are considered primary only if neither the vulva nor the cervix is involved at the time of diagnosis
A carcinoma involving the upper vagina and cervix should be considered a cervical primary and managed accordingly
Histologically most vaginal carcinomas are squamous, and chemotherapeutic management is usually based on extrapolation from experience with cervical carcinoma, given similarities in location, pattern of spread, histologic appearance, relation to HPV, and response to radiation therapy

Therapeutic Principles:

Vaginal intraepithelial neoplasia (VAIN): Treated with local modalities such as CO₂ laser ablation, topical fluorouracil, local radiation, imiquimod, or surgical excision. Regression rates are excellent. Close cytologic surveillance is warranted
Stages I and II: Standard treatment by gynecologic or radiation oncologists is highly effective
Stages III and IVA: Radiation therapy alone has yielded suboptimal results. Reports of combined chemoradiation have been more encouraging, and because of similarities with cervical cancer, cisplatin-based chemoradiation has been advocated as standard therapy
Stage IVB and recurrences are not amenable to locoregional therapy: Anthracyclines and platinum compounds as single agents or in combinations have some activity, but experience is limited to small case series. Taxane-based therapy also is reasonable, particularly for adenocarcinoma. Considering the rarity of cases, care providers should consider clinical trials

Curtin JP et al. J Clin Oncol 2001;19:1275–1278

Dancuart F et al. Int J Radiat Oncol Biol Phys 1988;14:745–749

Davis KP et al. Gynecol Oncol 1991;42:131–136

Evans LS et al. Int J Radiat Oncol Biol Phys 1988;15:901–906

Grisbgy PW. Curr Treat Options Oncol 2002;3:125–130

Kucera H, Vavra N. Gynecol Oncol 1991;40:12–16

Piver MS et al. Am J Obstet Gynecol 1978;131:311–313

Vagina. In: Hoskins WJ, Perez CA, Young RC, eds. Principles and Practice of Gynecologic Oncology. 4th ed. Philadelphia: Lippincott-Raven Publishers, 2005:708–714

REGIMEN: DOXORUBICIN (SINGLE AGENT)

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Regimen: Doxorubicin (Single Agent)

Piver MS et al. Am J Obstet Gynecol 1978;131:311–313

Doxorubicin 60–90 mg/m²; administer by slow intravenous injection over 3–5 minutes on day 1, every 4 weeks (total dosage/cycle = 60 to 90 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Toxicity

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Toxicity

Myelosuppression

Dose-limiting toxicity. Leukopenia more common than thrombocytopenia or anemia. Nadir usually on days 10–14, with recovery by day 21 after treatment

Nausea and vomiting

Moderate severity on the day of treatment; delayed symptoms (>24 hours after treatment) uncommon

Mucositis and diarrhea

Common, but not dose limiting

Cardiotoxicity (acute)

Incidence not related to dosage. Presents within 3 days after treatment as arrhythmias, conduction abnormalities, ECG changes, pericarditis, and/or myocarditis. Usually transient and asymptomatic

Cardiotoxicity (chronic)

Dosage-dependent dilated cardiomyopathy associated with congestive failure. Risk increases with cumulative doses >550 mg/m²

Strong vesicant

Avoid extravasation

Skin

Hand-foot syndrome, with skin rash swelling, erythema, pain, and desquamation. Onset at 5–6 weeks after starting treatment. Hyperpigmentation of nails, rarely skin rash, urticaria. Potential for radiation recall

Alopecia

Common, but generally reversible within 3 months after discontinuing doxorubicin

Infusion reactions

Signs and symptoms include flushing, dyspnea, facial swelling, headache, back pain, chest and/or throat tightness, and hypotension. May occur with a first treatment. Symptoms resolve within several hours to a day after discontinuing doxorubicin

Urine discoloration

Red-orange discoloration usually within 1–2 days after drug administration

Chu E, DeVita VT Jr, eds. Physicians' Cancer Chemotherapy Drug Manual 2001. Sudbury, MA: Jones and Bartlett

Patient Population Studied

Cervical or vaginal malignancies; 7 of 100 patients with advanced vaginal squamous cell carcinoma

Efficacy: (N = 7 Patients with Vaginal Cancer)

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Efficacy: (N = 7 Patients with Vaginal Cancer)

Complete response

1 patient

Partial response

1 patient^✫

^✫Treated with combination doxorubicin, cyclophosphamide, and fluorouracil

Treatment Modifications

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Treatment Modifications

Adverse Events

Treatment Modifications

WBC <3000/mm³ and platelet counts <100,000/mm³

Delay start of next cycle until WBC >3000/mm³ and platelet counts >100,000/mm³

>2-week delay in start of cycle

Reduce doxorubicin dose by 15 mg/m²

Doxorubicin total cumulative lifetime dosage ≥550 mg/m²

Obtain frequent MUGA scans to monitor cardiac function

Therapy Monitoring

Before each treatment with doxorubicin (every 4 weeks): H&P, CBC with differential, serum electrolytes, LFTs, BUN, and serum creatinine
After patients receive a total cumulative lifetime doxorubicin dose of 550 mg/m²: Check radionuclide left ventricular ejection fraction periodically (every 2 cycles)

Piver MS et al. Am J Obstet Gynecol 1978;131:311–313

REGIMEN: CISPLATIN (SINGLE AGENT)

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Regimen: Cisplatin (Single Agent)

Thigpen JT et al. Gynecol Oncol 1986;23:101–104

Hydration before cisplatin: ≥1000 mL 0.9% sodium chloride injection (0.9% NS) administered intravenously over a minimum of 3–4 hours

Cisplatin 50 mg/m²; administer intravenously in 50–250 mL 0.9% NS at a rate of 1 mg/min on day 1, every 3 weeks, (total dosage/cycle = 50 mg/m²)

Hydration after cisplatin: ≥1000 mL 0.9% sodium chloride injection (0.9% NS) administered intravenously over a minimum of 3–4 hours. Encourage patients to increase oral intake of non-alcoholic fluids, and provide electrolyte replacement as needed (potassium, magnesium, sodium)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Study of 22 patients with advanced or recurrent vaginal cancers

Efficacy (N = 22)

One complete response out of 22 evaluable patients with vaginal cancer (most were heavily pretreated)

Toxicity (N = 22)

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Toxicity (N = 22)

Hematologic Toxicities

% G1

% G2

Leukopenia^✫

13.6

Thrombocytopenia^†

—

Nonhematologic Toxicities

Mild

Moderate

Severe

Nephrotoxicity^‡

—

Nausea/vomiting^§

4.5

Fatigue

4.5

^✫Lowest WBC nadir = 2000 leukocytes/mm³

^†Lowest platelet nadir = 126,000 platelets/mm³

^‡Dose-limiting toxicity in 35–40%

^§Most common adverse effect

Treatment Modifications

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Treatment Modifications

Adverse Events

Treatment Modifications

Serum creatinine ≥1.7 mg/dL (≥29.1 μmol/L)

Hold treatment until creatinine returns to pretreatment level, then reduce cisplatin dosage in subsequent cycles by 50%

G3/4 ototoxicity

Hold treatment until ≤ G2 then reduce cisplatin dosage in subsequent cycles by 50%

G3/4 neurotoxicity

Hold treatment until ≤ G2 then reduce cisplatin dosage in subsequent cycles by 50%

Toxicities Reported in other Studies

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Toxicities Reported in other Studies

Neurotoxicity

Usually peripheral sensory neuropathy with bilateral paresthesia and anesthesia in a "stocking-and-glove" distribution. Risk increases with high individual doses and cumulatively. Motor and autonomic neuropathies may also occur. Neurotoxic effects may be irreversible

Ototoxicity

High-frequency hearing loss and tinnitus

Hypersensitivity

Facial edema, wheezing, bronchospasm, and hypotension within minutes of drug exposure

Hepatic

Transient increases in LFTs

Gustatory

Dysgeusia (metallic taste) and loss of appetite

Chu E, DeVita VT Jr, eds. Physicians' Cancer Chemotherapy Drug Manual 2001. Sudbury, MA: Jones and Bartlett; 100–105

Thigpen JT et al. Gynecol Oncol 1986;23:101–104

Therapy Monitoring

Before each treatment with cisplatin (every 4 weeks): H&P, paying attention to history and objective findings of neurotoxicity, CBC with differential, LFTs, serum electrolytes, and creatinine

REGIMEN: PACLITAXEL (SINGLE AGENT)

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Regimen: Paclitaxel (Single Agent)

Curtin JP et al. J Clin Oncol 2001;19:1275–1278

Premedications:

Dexamethasone 20 mg per dose; administer orally or intravenously for 2 doses, 14 hours and 7 hours before starting paclitaxel

Diphenhydramine 50 mg; administer by intravenous injection 30 minutes before starting paclitaxel

Ranitidine 50 mg; administer intravenously in 25–100 mL of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W), over 30–60 minutes, 30 minutes before starting paclitaxel

Paclitaxel 170 mg/m²^✫; administer by continuous intravenous infusion diluted in 0.9% NS or D5W to a concentration within the range 0.3 and 1.2 mg/mL, over 24 hours on day 1, every 3 weeks (total dosage/cycle = 170 mg/m²^✫)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

Paclitaxel dosage levels:

110 mg/m² (minimum dosage to be administered)

135 mg/m²

170 mg/m²

200 mg/m² (maximum dosage to be administered)

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Treatment Modifications

Adverse Events

Treatment Modifications^✫

ANC <1500/mm³

Hold treatment until ANC ≥1500/mm³

Platelet count <100,000/mm³

Hold treatment until platelets ≥100,000/mm³

G1 hematologic toxicity

Increase paclitaxel dosage by 1 level

G2/3 hematologic toxicity

Administer same paclitaxel dosage

G4 hematologic toxicity

Decrease paclitaxel dosage by 1 level

G2 nonobstructive renal toxicity

Decrease paclitaxel dosage by 1 level

G3 hepatic toxicity

G3 mucositis

G4 GOG nonhematologic toxicity

^✫Based on adverse events during previous cycles

Patient Population Studied

Study of 42 patients with advanced nonsquamous cell cervical cancer who had either no benefit from or progressive disease on standard chemotherapy

Toxicity (N = 42)

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Toxicity (N = 42)

Toxicity Grades^✫

Toxicity^†

Hematologic Toxicities

Leukopenia

Neutropenia

Thrombocytopenia

Anemia

Nonhematologic Toxicities

Nausea/vomiting

Gastrointestinal

Alopecia

Neurotoxicity

Edema

^✫Number of patients with toxicity

^†The table identifies only toxicities where at least 1 patient experienced a G3 or G4 toxicity

Other Toxicities

Febrile neutropenia

8 patients

Alopecia

26 patients

Mucositis

2 patients

Myalgia and arthralgia

Infrequent

Bradycardia grade 2

Incidence not specified

Efficacy

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Efficacy

Complete response

9.5%

Partial response

21.5%

Median duration of response

4.8 months

Therapy Monitoring

Before each treatment: H&P, paying attention to history and objective findings of neurotoxicity, CBC with differential, LFTs, electrolytes, and creatinine

REGIMEN: CISPLATIN + FLUOROURACIL + RADIATION THERAPY

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Regimen: Cisplatin + Fluorouracil + Radiation Therapy

Roberts WS et al. Gynecol Oncol 1991;43:233–236

Hydration before cisplatin: 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously over a minimum of 2 hours

Cisplatin 50 mg/m²; administer intravenously in 100–1000 mL 0.9% sodium chloride injection (0.9% NS), over 6 hours on day 1, every 4 weeks for 2 cycles (total dosage/4-week cycle = 50 mg/m²)

Followed by:

Fluorouracil 1000 mg/m² per day; administer as a continuous intravenous infusion in 250–2000 mL 0.9% NS or 5% dextrose injection over 24 hours for 4 consecutive days, on days 1–4, every 4 weeks for 2 cycles (total dosage/4-week cycle = 4000 mg/m²)

Hydration after cisplatin: 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously over a minimum of 2 hours. Encourage patients to increase oral intake of non-alcoholic fluids, and provide electrolyte replacement as needed (potassium, magnesium, sodium)

Concurrent with chemotherapy administer radiation therapy as follows:

External beam radiation with 20-MeV linear accelerator, 180 cGy/day fractions to a total dose of 4000–5000 cGy to the whole pelvis, ± periaortic radiation to a dose of 3600–4500 cGy

Additional external pelvic irradiation to limited fields to a total dose of 6480 cGy

Additional brachytherapy starting 2–3 weeks after external beam radiation

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1: HIGH. Potential for delayed symptoms

Emetogenic potential on days 2–4: LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Study of 67 patients with advanced carcinomas of the lower female genital tract that were not amenable to resection were eligible, among whom 7 had vaginal cancers. Of the 7 patients with vaginal cancer, 5 had Stage III disease and 2 had recurrent disease

Efficacy^✫

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Efficacy^✫

Complete clinical response (all histologies)

85%

Partial response (all histologies)

Stable disease (all histologies)

^✫Not stated for the subset of patients with vaginal cancer. However, 3 of 7 patients with vaginal cancer were without recurrence or failure of the treatment for a median follow-up of 13 months

Treatment Modifications

Roberts WS et al. Gynecol Oncol 1991;43:233–236

Whitney CW et al. J Clin Oncol 1999;17:1339–1348^✫

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Treatment Modifications

Adverse Events

Treatment Modifications

Serum creatinine ≥1.7 mg/dL (≥29.1 μmol/L)

Hold cisplatin until serum creatinine returns to pre-treatment level, then reduce dosage by 50% in subsequent cycles

WBC ≤3000/mm³ or platelet ≤100,000/mm³

Delay cisplatin and fluorouracil until WBC ≥3000/mm³ and platelet count ≥100,000/mm³

>2-week delay in start of cycle

Reduce cisplatin and fluorouracil dosages by 50% each

G3/4 hematologic toxicity

Hold radiation therapy until hematologic toxicity is G ≤2

^✫Whitney et al. utilized a similar regimen for patients with cervical cancer; 91% completed both chemotherapy courses and had similar completion rates for radiation therapy

Toxicity

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Toxicity

Acute Toxicities

Neutropenia and thrombocytopenia

1 patient^✫

Radiation enteritis

5 patients^†

Nausea, vomiting, and diarrhea

Very common

Renal, hepatic, or neurologic

Not significant

Delayed Toxicities

Rectovaginal fistula

3 patients^‡

Radiation proctitis

1 patient^‡

Small bowel fistula

2 patients^‡

Soft tissue necrosis

2 patients^‡

Hemorrhagic cystitis

1 patient

^✫Resulted in 8- to 14-day treatment delay

^†Resulted in 8- to >14-day treatment delay

^‡Required surgery

Therapy Monitoring

Weekly: CBC with differential, LFTs, electrolytes, and creatinine

REGIMEN: NEODAJUVANT CISPLATIN + EPIRUBICIN

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Regimen: Neodajuvant Cisplatin + Epirubicin

Zanetta G et al. Gynecol Oncol 1997;64:431–435

Hydration before cisplatin with ≥1000 mL 0.9% sodium chloride injection intravenously over a minimum of 2 hours

Cisplatin 50 mg/m² per dose intravenously in 50–250 mL 0.9% NS over 30–60 minutes once weekly for 9 doses (total dosage/9-week course = 450 mg/m²)

Hydration after cisplatin with ≥1000 mL 0.9% NS intravenously over a minimum of 2 hours

Notes: Encourage increased oral intake of nonalcoholic fluids. Goal is to achieve a urine output ≥100 mL/hour. Monitor and replace electrolytes as needed (potassium, magnesium, sodium)

Epirubicin HCl 70 mg/m² per dose intravenously by injection over 3–5 minutes or in 25–250 mL 0.9% NS or 5% dextrose injection over 15–20 minutes every 3 weeks, weeks 1, 4, and 7, for 3 doses (total dosage/9-week course = 210 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with:

Filgrastim (G-CSF) 5 mcg/kg per day by subcutaneous injection daily for 5 days

Begin use on the day after cisplatin (± epirubicin) is administered
Discontinue daily filgrastim use at least 24 hours before administering myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Oral care

Prophylaxis and treatment for mucositis/stomatitis

General advice:

Encourage patients to maintain intake of nonalcoholic fluids
Evaluate patients for oral pain and provide analgesic medications
Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine) or a proton pump inhibitor for epigastric pain
Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

Patients with intact oral mucosa:

Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultrasoft toothbrush with fluoride toothpaste
Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth
Patients may use saline or commercial bland, nonalcoholic rinses
- Do not use mouthwashes that contain alcohols

If mucositis or stomatitis is present:

Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute
Rinse mouth several times a day to remove debris
- Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in 1 quart (~950 mL) of warm water. Follow with a plain water rinse
- Do not use mouthwashes that contain alcohol
Foam-tipped swabs (eg, Toothettes) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque
Advise patients who develop mucositis to:
- Choose foods that are easy to chew and swallow
- Take small bites of food, chew slowly, and sip liquids with meals
- Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs
- For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids
- Avoid sharp, crunchy foods; hot, spicy, or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Additional therapies given:

In operable patients, Piver 3 radical hysterectomy with pelvic lymphadenectomy and aortic node sampling was performed within 30 days after the completion of chemotherapy
Histologic analysis of all surgical specimens assessed the extent of cervical, vaginal, and parametrial disease and the status of all surgical margins and lymph nodes
Patients with surgical detection of positive lymph nodes, parametrial infiltration, or peritoneal spread received adjuvant treatments
Postoperative radiotherapy consisted of 4500 cGy with 18 MeV photons, given by means of a field up to L4–L5 in the case of negative nodes, and up to T11–T12 in the case of positive common iliac nodes for subjects with stable disease or minimal response
Subjects achieving a good clinical response to neoadjuvant treatment received additional chemotherapy "in order to confirm this response"

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

ANC <2000/mm³ or platelets <75,000/mm³ on day of treatment

Delay treatment for 1 week

Patient Population Studied

The study population included 20 patients with locally advanced cervical adenocarcinoma (bulky IB–IIA, IIB) and 2 subjects with vaginal adenocarcinoma; mean age was 51 years (range: 15–67 years). Disease histology was adenocarcinoma in 18 subjects and adenosquamous in 4 subjects. Those with stages IB–IIA cervical carcinomas and those with vaginal adenocarcinoma were required to have tumors >4 cm in diameter, as assessed by alginate mold. All patients had a performance status <2 according to the World Health Organization criteria. Staging was done according to the International Federation of Gynecology and Obstetrics.

Toxicity (N = 21^✫)

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Toxicity (N = 21)

Grade

G0–1

Leucopenia

2^†

Thrombocytopenia

Anemia

—

Mucositis

—

Nephrotoxicity

—

1^✫

—

Neurotoxicity

—

Fever

—

Nausea/vomiting

—

Cardiac

—

Alopecia

—

Completed 9 courses of treatment

19/22 (86%)

No delays in administration

3/19

Delays in administration

16/19

Duration of delays in administration

1-5 weeks

^✫One patient refused further treatment after first course (Note: a course of therapy was inconsistently defined as "… the administration of cisplatin and epirubicin [weeks 1, 4, and 7] or the administration of cisplatin alone [weeks 2, 3, 5, 6, 8, and 9].")

^†Two subjects requiring discontinuation of the treatment; 19 received the planned dose of drug without reduction

Efficacy

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Efficacy

Number enrolled

Received more than 1 dose of therapy

Competed all planned therapy

Underwent surgery

Complete clinical response

Complete response at surgery

Microscopic residual tumor

4^✫

Macroscopic residual tumor

With median follow up of 22 months for surviving patients

Experienced recurrence

8^†

Died of recurrent or persistent disease

Alive with tumor

Alive without evidence of recurrence

^✫At time of the report 2 were alive with no evidence of disease at 32 and 47 months; 1 was alive with tumor; and 1 died of disease at 33 months after first diagnosis

^†In 4/8 patients with positive nodes at time of surgery, 2/10 without nodal metastases, and 2/4 not undergoing surgery

Treatment Monitoring

Weekly CBC with differential
Weekly serum electrolytes, BUN, and creatinine

REGIMEN: TOPOTECAN + CISPLATIN (TOPOCIS)

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TOPOTECAN + CISPLATIN (TOPOCIS)

Zanaboni F et al. Eur J Cancer 2013;49:1065–1072

The regimen consists of 2 cycles of neoadjuvant chemotherapy followed by radical surgery in patients without disease progression. Postoperative adjuvant radiation therapy, with or without chemotherapy, may be administered in patients with poor prognostic factors such as cut-through surgical margins, positive lymph nodes, parametrial involvement, or vaginal involvement

Topotecan HCl 2 mg/m² per dose; administer intravenously in 50–250 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection over 30 minutes once weekly for 3 doses on days 1, 8, and 15, every 28 days for 2 cycles (total dosage/cycle = 6 mg/m²), followed by:

Hydration before cisplatin: ≥1000 mL 0.9% NS; administer intravenously over a minimum of 2–4 hours

Cisplatin 40 mg/m² per dose; administer intravenously in 50–500 mL 0.9% NS over 60 minutes once weekly for 3 doses on day 1, 8, and 15, every 28 days for 2 cycles (total dosage/cycle = 120 mg/m²)

Hydration after cisplatin: ≥1000 mL 0.9% NS; administer intravenously over a minimum of 2–4 hours. Encourage patients to increase oral intake of nonalcoholic fluids. Monitor serum electrolytes and replace as needed (potassium, magnesium, sodium)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A multicenter, nonrandomized, phase 2 study involved 92 patients with histologically confirmed, locally advanced squamous and adenosquamous cervical cancer. Eligible patients were aged >18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. All patients received 40 mg/m² cisplatin in 500 mL of sodium chloride solution intravenously over 1 hour and 2 mg/m² topotecan in 100 mL of 5% dextrose in water intravenously over 30 minutes on days 1, 8, and 15 of a 28-day cycle for 2 courses. Patients were premedicated with 8 mg ondansetron and 20 mg dexamethasone, given intravenously 30 minutes before each course

Efficacy (N = 92)

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Clinical response rate^✫

77%

Pathologic response rate^†

67%

Median time to relapse

22 months

Disease-free survival at 2 years

76%

Overall survival at 2 years

86%

^✫Clinical response rate is the percentage of patients who experienced a partial or complete response according to the Response Criteria in Solid Tumours (RECIST) 1.0 guidelines

^†Pathological response rate is the percentage of patients who experienced a microscopic partial response or a complete response according to the TNM classification

Note: Median follow-up time was 18 months

Therapy Monitoring

Once per week: CBC with differential and platelet count
Before the start of a cycle: CBC with differential, serum electrolytes, calcium, magnesium, BUN, and creatinine

Treatment Modifications

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TOPOTECAN + CISPLATIN DOSE MODIFCIATIONS

Starting topotecan dose

2 mg/m²

Topotecan dose level −1

1.6 mg/m²

Topotecan dose level −2

1.25 mg/m²

Starting cisplatin dose

40 mg/m²

Cisplatin dose level −1

30 mg/m²

Cisplatin dose level −2

20 mg/m²

Adverse Events

Treatment Modifications

Day of treatment (day 1, 8, or 15) ANC <1000/mm³ or platelets <100,000/mm³

Delay both topotecan and cisplatin treatment by 1 week

Febrile neutropenia (ANC <1000/mm³ with temperature >38°C or >100.4°F), or ANC <1000/mm³ for ≥7 days

Reduce topotecan dose by 1 level and consider adding filgrastim in subsequent cycles, if applicable. Continue with same cisplatin dosage

Febrile neutropenia (ANC <1000/mm³ with temperature >38°C or >100.4°F), or ANC <1000/mm³ for ≥7 days despite 1 dose reduction

Administer filgrastim in subsequent cycles. If already administering filgrastim, reduce topotecan dosage by 1 level

Platelet nadir <50,000/mm³, or platelets <100,000/mm³ for ≥7 days

Reduce topotecan dose by 1 level; continue with same cisplatin dosage

G2 peripheral neuropathy

Reduce cisplatin dose by 2 dose levels; if neuropathy improves, can consider increasing by 1 dose level

G3/4 peripheral neuropathy

Hold cisplatin until neuropathy G1; then reduce cisplatin dosage by 2 levels. If G3/4 toxicity persists >2 weeks beyond scheduled start of next cycle, discontinue cisplatin

Day of treatment (day 1, 8, or 15) serum creatinine ≥1.5 mg/dL

Ensure patient adequately hydrated. Hold cisplatin until serum creatinine ≤1.5 mg/dL (≤133 µmol/L); then resume treatment at same dose or 1 dose level lower. If creatinine >1.5 mg/dL >2 weeks beyond scheduled start of next cycle, discontinue cisplatin

G1 tinnitus

Reduce cisplatin dose by 1 level

≥G2 tinnitus or hearing loss

Hold cisplatin until ototoxicity ≤G1; then reduce cisplatin dosage by 2 levels. If G2–4 toxicity persists >2 weeks beyond scheduled start of next cycle, discontinue cisplatin

G2/3 mucositis or diarrhea

Reduce topotecan dosage by 1 level

G4 mucositis or diarrhea

Reduce topotecan dosage by 1–2 levels

Recurrent mucositis or diarrhea despite dosage reduction or persistence of mucositis/diarrhea >2 weeks beyond scheduled start of next cycle

Discontinue topotecan

Other G3/4 nonhematologic toxicity

Delay attributable medication(s) until resolution to ≤G1, then reduce dose of attributable medication(s) by 1 level

Topotecan dose adjustments for renal impairment [likely to be superseded by cisplatin]

Creatinine clearance 46–60 mL/min: reduce topotecan dose by 20%
Creatinine clearance 31–45 mL/min: reduce topotecan dose by 25%
Creatinine clearance ≤30 mL/min: reduce topotecan dose by 30%

Adverse Events (N = 92)

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Grade (%)^✫

Grade 1/2

Grade 3/4

Neutropenia

Anemia

Gastrointestinal

Thrombocytopenia

Alopecia

^✫According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Notes: All observed toxicities are included in the table. No treatment-related deaths occurred. Grade 3/4 adverse events occurred in 28% of patients and 5% of courses

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Chapter 38: Vaginal Cancer

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INTRODUCTION

Expert Opinion

REGIMEN: DOXORUBICIN (SINGLE AGENT)

REGIMEN: CISPLATIN (SINGLE AGENT)

REGIMEN: PACLITAXEL (SINGLE AGENT)

REGIMEN: CISPLATIN + FLUOROURACIL + RADIATION THERAPY

REGIMEN: NEODAJUVANT CISPLATIN + EPIRUBICIN

REGIMEN: TOPOTECAN + CISPLATIN (TOPOCIS)

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