Abstract
Cervical cancer constitutes 6% of all female cancers in the USA. It is responsible for 1.6% of all cancer-related mortality and 15% of all gynecologic cancer mortalities in women [1, 2]. It is the most common gynecological cancer in developing and underdeveloped countries.
9.1 Cervical Cancer
Cervical cancer constitutes 6% of all female cancers in the USA. It is responsible for 1.6% of all cancer-related mortality and 15% of all gynecologic cancer mortalities in women [1, 2]. It is the most common gynecological cancer in developing and underdeveloped countries.
The uterus is located in the middle of the true pelvis between the rectum and bladder, and makes a right angle with the vagina. The upper two-thirds of the uterus is called the corpus, and the lower one-third is known as the cervix.
The cervix has a cylindrical shape and extends into the upper vagina (Fig. 9.1). It passes between the vagina and the upper uterine cavity via the endocervical canal.
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The endocervical canal is covered with glandular and columnar cells, and the region around the cervical canal is called the endocervix.
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The region facing towards the vagina is termed the exocervix and is covered with squamous epithelial cells.
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Cervical cancers originating from the endocervix are adeno cancers, while those from the exocervix are squamous cell cancers.
9.1.1 Pathology
Cervical cancers are categorized into three major histological subtypes by the World Health Organization (WHO): squamous cell cancers, adenocarcinomas, and others. Approximately 70–80% of all cases are squamous cell cancers [2].
Squamous cell cancer almost always starts with abnormal metaplastic events in the transformation zone, resulting in sequential lesions from cervical intraepithelial neoplasias (CIN) of grades I, II and III, and microinvasive cancer.
9.1.3 General Presentation
Early period:
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(a)
Postcoital bleeding
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(b)
Irregular menstruation
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(c)
Bloody discharge
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(d)
Discharge with foul odor
Late period:
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(a)
Leg and groin pain
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(b)
Fistulas (cervicovesical, vesicovaginal, cervicorectal, rectovaginal)
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(c)
Hydronephrosis and renal dysfunction due to ureter obstruction
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(d)
Edema in lower extremities
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(e)
Anemia
9.1.4 Staging
The first important step is a bimanual rectovaginal gynecological exam under general anesthesia. The International Federation of Gynecology and Obstetrics (FIGO) revised cervical staging system in 2008 [4]. This staging is performed by the use of clinical exam (inspection, palpation, colposcopy), endoscopic exam (cystoscopy and rectoscopy), direct radiological exams (intravenous pyelography, chest X-ray), and findings from biopsy (tumor depth, size, etc.) [5]. Surgical findings should never be used in staging. The AJCC staging is consistent with FIGO staging.
9.1.7 Treatment Algorithm
The local treatment decision should be made based on tumor size, stage, histology, lymph node (LN) involvement, possible complications of local therapies, requirement for adjuvant therapy and patient choice. However, intraepithelial lesions are treated with superficial ablative modalities (cryosurgery or laser surgery); microinvasive cancers that are less than 3 mm in depth (stage IA1) with conservative surgery; early invasive cancers (stages IA2, IB1 and some small stage IIA tumors) with either radical surgery or radiotherapy; and locally advanced cancers (stages IB2–IVA) with concurrent chemoradiotherapy [6–9].
Radiotherapy and surgery are equally effective in patients with stage IB cervical cancer, and survival is nearly 80–90% whether radiotherapy or surgery is used (Table 9.1) [6–9].
Postoperative radiotherapy indications [12]:
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Lymphovascular space invasion (LVSI)
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Deep stromal invasion > one-third of stromal depth
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Tumor size > 4 cm
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Adenosquamous, clear cell, small cell, undifferentiated histology
Postoperative chemoradiotherapy indications [12]:
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Surgical margin (+)
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LN (+)
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Parametrial involvement
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Radical hysterectomy (Type III) and bilateral pelvic LN dissection. This is the standard surgical approach for stages IB1 and IIA [10]. Here, the uterus, surrounding tissues, and the upper 2–3 cm of the vagina are excised. The cardinal, sacrouterine and vesicouterine ligaments are completely dissected together with the uterus. Pelvic lymphadenectomy is part of radical hysterectomy.
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Vaginal hysterectomy (Schauta–Amreich operation) and radical trachelectomy are alternative surgical approaches to spare fertility in patients with a tumor that is less than 2 cm and at stage IB1 [11]. In radical trachelectomy, the uterus is not dissected, and 2–3 cm of the upper vagina together with the cervix and the cardinal–sacrouterine ligaments are excised.
9.1.10 Radiotherapy
9.1.10.1 External Radiotherapy
Lower vaginal involvement (+) → inferior border: includes inguinal LNs.
Anterior–posterior fields (Fig. 9.4 )
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Superior: L4–L5 intervertebral space
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Inferior: below the obturator foramens (vagina (−)) or ischial tuberosities (vagina (+))
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Lateral: bony pelvis +1.5–2 cm
Lateral fields (Fig. 9.4 )
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Superior and inferior: same as anterior–posterior fields.
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Anterior: posterior to pubis.
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Posterior: between the S2 and S3 vertebrae (midsacrum); maximum care should be given to posterior extension of tumor, and a margin of at least 1–2 cm should be given to the tumor.
Paraaortic LN (+); paraaortic field should be irradiated (Fig. 9.5).
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Prophylactic paraaortic field is not recommended since it has no effect on survival. It also decreases the tolerance of radiotherapy by increasing toxicity [13–16].
9.1.10.2 Brachytherapy
BT plays a very important role in the treatment of gynecological cancers, particularly cervical cancers [18]. Intracavitary and interstitial BT techniques are used in cervical cancers.
ICRU 38[19]
Since techniques, applicators, sources, and dose reference points of intracavitary applications may vary for gynecologic malignancies between institutions, details should be given according to the ICRU-38 report (Dose and Volume Specifications for Reporting Intracavitary Treatments in Gynecologic Malignancies) published in 1985. This report standardizes application differences and provides a common language for gynecologic BT applications.
Every application of BT should report five major issues according to this publication: technique, total reference air KERMA (TRAK), reference volume, reference points and doses, and dose rate.
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1.
Technique
The radioactive source, number and length of sources, and the type of applicator should be mentioned. Applicators are special devices that are placed into the organs to be treated, and the radioactive sources enter these applicators and exit out of them. These come in various shapes and types: metallic (Fletcher–Suit–Delclos); plastic (Delouche); individualized (Chassagne–Pierquin) (Fig. 9.7).
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2.
Reference air KERMA of source
KERMA (kinetic energy released in the medium): this is the combination of the initial kinetic energies of the charged ionizing particles that are liberated by an uncharged ionizing particle per unit mass of material. KERMA is measured in the same units as absorbed dose (Gy). The reference air KERMA is used to define visible activity. It is defined as the dose given at a distance of 1 m of air by a source with an activity of 1 MBq in 1 h. Its units are 1 µ/Gy m2 = 1 cGy/h cm2. Its value is 0.0342 for Ir-192.
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3.
Reference volume (Fig. 9.8)
This is the volume surrounded by the reference isodose, and is independent of technique. It is the combined volume in the 60 Gy isodose curve of external pelvic radiotherapy and intracavitary applications. The reference volume is defined in three planes by combining reference isodoses:
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dh: (height) maximum size parallel to the intrauterine applicator in the oblique frontal plane, including the intrauterine applicator
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dw: (width) maximum size vertical to the intrauterine applicator in the oblique frontal plane, including the intrauterine applicator
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dt: (thickness) maximum size vertical to the intrauterine applicator in the oblique sagittal plane, including the intrauterine applicator
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4.
Reference points (Fig. 9.9)
Bladder reference point. A Foley catheter is placed into the bladder. The Foley balloon is filled with 7 cm3 of radioopaque material. The catheter is pulled back and stabilized in the bladder neck. A straight line is marked in the anterior–posterior plane from the center of the balloon in a lateral graph. The reference point is the posterior point crossing the back of the balloon on this line. This is the center of the balloon in the anterior–posterior film.
Rectum reference point. An anterior–posterior straight line is marked from the bottom tip of the intrauterine tandem or the middle of the intravaginal ovoids. The point 5 mm back from the vaginal posterior wall is the rectum reference point.
Bony reference points; lymphatic trapezoid (Fletcher trapezoid) (Fig. 9.10). A line is marked 2 cm bilaterally from the middle of the L4 vertebra → points 1 and 2 are found. A line vertical from the middle of the S1 to S2 vertebrae to the top of the pubis symphysis is drawn, and two lines bilaterally from the middle of that line are drawn with a length of 6 cm → points 3 and 4 are found. Point 1 is combined with 3, and point 2 with 4. A trapezoid is formed by the combination of these lines; upper points→ lower paraaortic lymphatics; lower points → external iliac lymphatics; middle points → common iliac lymphatics.
Pelvic wall reference points. These are used to calculate the doses for the distal parametrium and obturator lymphatics (Fig. 9.11). Two tangential lines are drawn from the upper and the most medial parts of the acetabulum vertical to each other, and the points where they cross are the pelvic wall reference points (Chassagne point) in the anterior–posterior film. The most upper points of right and left acetabulum are marked, and the lateral projection of the pelvic wall occurs midway between these two points.
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5.
Dose rate
This is the dose given per unit time. BT applications are categorized into three subgroups according to dose rate (Table 9.3): low dose rate (LDR), 0.4–2 Gy/h; medium dose rate (MDR), 2–12 Gy/h; high dose rate (HDR), >12 Gy/h.
9.1.10.2.4 The Application of Intracavitary Brachytherapy
The patient should be informed about the procedure before BT, and informed consent must be obtained. A detailed gynecological exam should be performed, and the dimensions of the vagina, the size and position of the uterus, and the localization, size and extension of the tumor determined. The application of BT requires cervical dilatation, and thus general anesthesia, spinal anesthesia, paracervical blockage or systemic analgesia with sedation is needed. Treatment is performed on an outpatient basis; the patient should have an open IV line and an empty rectum under sterile surgical conditions.
The patient is positioned in the lithotomy position on a gynecological table. The vulva, perineum, and pelvic region are cleaned and a Foley catheter is placed into the bladder. Its balloon is filled with 7 cc of radioopaque material. A speculum is placed into the vagina, and the cervical os is visualized. The cervical canal is dilated sequentially with bougies of different thicknesses. Two metal markers are placed into the cervical os to verify the position of the intrauterine tandem. The length of the uterine cavity is determined by hysterometry, and the tandem and ovoids are lubricated with 1% viscous lidocaine. The tandem is first placed into the uterine cavity, and then the ovoids or ring are placed into the fornices and they are all stabilized. The angle between the longitidunal axis of the tandem and the diameter of the ring is always 90°. Then, rectal packing with a radioopaque gauze is placed between the rectal wall and the applicators, and the same packing is placed between the bladder and the applicators. A rectal tube is inserted into the rectum to measure the rectal dose in vivo. Dummy catheters are placed into the tandem and ring/or ovoids for dose calculations in orthogonal films. An anterior–posterior and a lateral film are taken at the same position, which shows all of the applicators and the bony points of the Fletcher trapezoid. CT slices can also be used when CT-applicable applicators are used, and 3D BT software is available. The dose is prescribed to point A. The dose distribution should be pear-shaped when the tandem is used. Its large side is located in the upper vagina, and its narrow edge is in the uterine fundus (Fig. 9.13).
The source, place and time are optimized in dosimetry; the plan that enables the maximum dose to be delivered to the target and the minimum dose to the bladder and rectum is selected, and the patient is taken to the treatment room. Applicators are connected to the treatment machine with special connecting cables. Health personnel move from the treatment room to the command room and start the BT session. One session takes between 5 and 15 min, depending on the source activity in that session of HDR BT. After the treatment has finished, the applicators are taken out. The same procedure is repeated during each session.
Tolerance doses [18]. Rectum, 75 Gy (mean 68 Gy, <80% of the dose at point A); bladder 80 Gy (mean 70 Gy, 85% of the dose at point A); vagina 120–140 Gy (mean 125 Gy). The vaginal mucosa is a critical organ in cervical cancer RT, and 140% of the dose at point A should not be exceeded. Vaginal mucosa is the target organ in endometrial cancer RT, since recurrence is most common in the vaginal cuff.
Point H [20]. This is recommended as an alternative to point A by the American Brachytherapy Society. The tips of the ovoids are connected with a horizontal line, and 2 cm superior and 2 cm lateral from the midpoint of this line are the H points on the right and left sides. They are practically 2 cm cranial to the top of the ovoids. They are not anatomical points like point A, and they may vary in position according to patient and application.
Point P. This is the most lateral point in the bony pelvis, and it defines the dose taken by external iliac LNs.
9.1.11 Selected Publications
Canada, 2002 → a systematic review of eight randomized trials of cisplatin administered concurrently with external-beam radiotherapy vs. radiotherapy without cisplatin for cervical cancer.
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A statistically significant effect in favor of cisplatin-based chemotherapy plus radiotherapy compared with radiotherapy without cisplatin (relative risk [RR] of death, 0.74).
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The pooled RR of death among the six trials that enrolled only women with locally advanced cervical cancer was 0.78. The pooled RR for the two trials in high-risk early-stage disease also demonstrated a statistically significant benefit of the addition of cisplatin-based chemotherapy to radiotherapy (RR = 0.56).
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Concurrent cisplatin-based chemotherapy plus radiotherapy improves overall survival over various controls in women with locally advanced cervical cancer, large stage IB tumors (prior to surgery), and high-risk early-stage disease (following surgery).
Lukka H et al (2002) Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer: a meta-analysis. Clin Oncol (R Coll Radiol) 14(3):203–212
England, 2001 → 17 published and two unpublished trials of chemoradiation for cervical cancer.
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The absolute benefits in progression-free and overall survival were 16 and 12%, respectively. Significant benefits of chemoradiation on both local (odds ratio 0.61, p < 0.0001) and distant recurrence (0.57, p < 0.0001) were also recorded.
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Grade 3 or 4 hematological (odds ratio 1.49–8.60) and gastrointestinal (2.22) toxicities were significantly greater in the concomitant chemoradiation group than the control group.
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Concomitant chemotherapy and radiotherapy improves overall and progression-free survival (PFS) and reduces local and distant recurrence in selected patients with cervical cancer, which may give a cytotoxic and sensitization effect.
Green JA et al. (2001) Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 358(9284):781–786
Milan, 1997 → 343 patients with stage IB and IIA cervical carcinoma were randomized to surgery and to radical radiotherapy. Adjuvant radiotherapy was delivered after surgery for women with surgical stage pT2b or greater, less than 3 mm of safe cervical stroma, cut-through, or positive nodes.
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After a median follow-up of 87 (range 57–120) months, 5-year overall and disease-free survivals were identical in the surgery and radiotherapy groups (83 and 74%, respectively, for both groups).
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Significant factors for survival in univariate and multivariate analyses were: cervical diameter, positive lymphangiography, and adenocarcinomatous histotype. 48 (28%) surgery-group patients had severe morbidity compared with 19 (12%) radiotherapy-group patients (p = 0.0004).
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The combination of surgery and radiotherapy has the worst morbidity, especially in relation to urological complications. The optimum therapy for each patient should take into account clinical factors such as menopausal status, age, medical illness, histological type, and cervical diameter to yield the best cure with minimum complications.
Landoni F et al. (1997) Randomised study of radical surgery versus radiotherapy for stage Ib–IIa cervical cancer. Lancet 350(9077):535–540
GOG 92, 2006 → 277 patients with stage IB cervical cancer with negative LNs but with two or more of the following features: more than one-third (deep) stromal invasion, capillary lymphatic space involvement, and tumor diameter of 4 cm or more. 137 randomized to pelvic irradiation (RT: 46 Gy in 23 fractions to 50.4 Gy in 28 fractions) and 140 randomized to observation (OBS).
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The RT arm showed a statistically significant (46%) reduction in risk of recurrence (hazard ratio [HR] = 0.54, p = 0.007) and a statistically significant reduction in risk of progression or death (HR = 0.58, p = 0.009).
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The improvement in overall survival with RT did not reach statistical significance (p = 0.074).
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Pelvic RT after radical surgery significantly reduces the risk of recurrence and prolongs PFS in women with stage IB cervical cancer.
Rotman M et al (2006) A phase III randomized trial of postoperative pelvic irradiation in stage IB cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 65(1):169–176
GOG 109/Intergroup 0107/SWOG 8797/RTOG 9112, 2000 → 268 patients with clinical stage IA2, IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic LNs and/or positive margins and/or microscopic involvement of the parametrium, were randomized to receive RT or RT + CT.
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The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.
Peters WA III et al (2005) Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18(8):1606–1613
Monk BJ et al (2005) Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical-pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial. Gynecol Oncol 96(3):721–728
GOG 71/RTOG 84-12, 2003 → 256 patients with exophytic or “barrel”-shaped tumors measuring ≥4 cm were randomized to either external RT and intracavitary irradiation or attenuated irradiation followed by extrafascial hysterectomy.
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There was no clinically important benefit of the use of extrafascial hysterectomy. However, there is good evidence to suggest that patients with 4, 5, and 6 cm tumors may have benefited from extrafascial hysterectomy.
Keys HM et al (2003) Radiation therapy with and without extrafascial hysterectomy for bulky stage IB cervical carcinoma: a randomized trial of the Gynecologic Oncology Group. Gynecol Oncol 89(3):343–353
GOG 123, 1999 → women with bulky stage IB cervical cancers (tumor, ≥4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg/m2 of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed 3–6 weeks later.
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Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.
Keys HM et al (1999) Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340(15):1154–1161
GOG 141, 2007 → patients with bulky FIGO stage IB cervical cancer, tumor diameter ≥4 cm. Prospective random allocation was to either NACT (vincristine–cisplatin chemotherapy every 10 days for three cycles) before exploratory laparotomy and planned RHPPL (NACT + RHPPL), or RHPPL only.
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There is no evidence from this trial that NACT offered any additional objective benefit to patients undergoing RHPPL for suboptimal stage IB cervical cancer.
Eddy GL (2007) Treatment of (“bulky”) stage IB cervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: a phase III trial of the gynecologic oncology group. Gynecol Oncol 106(2):362–369
NCI Canada, 2002 → 259 patients with stage IB to IVA squamous cell cervical cancer with central disease ≥5 cm or histologically confirmed pelvic LN involvement were randomized to receive RT (external-beam RT plus BT) plus weekly CDDP chemotherapy (40 mg/m2) (arm 1) or the same RT without chemotherapy (arm 2).
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This study did not show a benefit to either pelvic control or survival upon the addition of concurrent weekly CDDP chemotherapy at a dose of 40 mg/m2 to radical RT.
Pearcey R (2002) Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20(4):966–972
RTOG 90-01, 2004 → 403 women with stage IIB to IVA disease, stage IB to IIA disease with a tumor diameter ≥5 cm, or positive pelvic LNs were randomly assigned to receive either EFRT or CTRT.
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The addition of fluorouracil and cisplatin to radiotherapy significantly improved the survival rate of women with locally advanced cervical cancer without increasing the rate of late treatment-related side effects.
Eifel PJ et al (2004) Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol 22(5):872–880
EORTC, 1998 → 441 patients with stage I and IIB with proximal vaginal and/or parametrial involvement with positive pelvic LNs either on lymphangiogram or at surgery, stage IIB with distal vaginal and/or parametrial involvement, and III regardless of pelvic node status on lymphangiogram were randomized between pelvic irradiation and pelvic and paraaortic irradiation. Patients with clinically or surgically involved paraaortic nodes were not included. The external beam dose to the paraaortic area was 45 Gy.
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Routine paraaortic irradiation for all high-risk patients with cervical carcinoma is of limited value.
Haie C et al (1988) Is prophylactic para-aortic irradiation worthwhile in the treatment of advanced cervical carcinoma? Results of a controlled clinical trial of the EORTC radiotherapy group. Radiother Oncol 11(2):101–112
RTOG 79-20, 1995 → 367 patients with FIGO stage IB or IIA primary cervical cancers measuring 4 cm or greater in lateral diameter or with FIGO stage IIB cervical cancers were randomized to RTOG protocol 79-20 to receive either standard pelvic only irradiation or pelvic plus paraaortic irradiation.
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There was a statistically significant difference in overall survival at 10 years for the pelvic plus paraaortic irradiation arm, without a difference in disease-free survival.
Rotman M et al (1995) Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20. JAMA 274(5):387–393
GOG 191, 2008 → patients with stage IIB–IVA cervical cancer and HGB <14.0 g/dL were randomly assigned to CT/RT±recombinant human erythropoietin (R-HUEPO) (40,000 units s.c. weekly). R-HUEPO was stopped if HGB >14.0 g/dL.
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The impact of maintaining HGB level >12.0 g/dL on PFS, OS and LC remains undetermined.
Thomas G (2008) Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol 108(2):317–325
India, 1994 → randomized trial of HDR vs. LDR BT.
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HDR intracavitary BT was found to be an equally good alternative to conventional LDR BT in the treatment of carcinoma of the uterine cervix.
Patel FD et al (1994) Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial. Int J Radiat Oncol Biol Phys 28(2):335–341
Hacettepe, 2007: 141 patients with stage I–II cervical cancer without paraaortic LN metastases and treated by surgery and postoperative radiotherapy (RT). Indications for postoperative external RT were LN metastasis, positive surgical margins, parametrial involvement, pT2 tumor, and presence of any two minor risk factors like lymphovascular space involvement, deep stromal invasion, and tumor diameter between 2 and 4 cm. Median follow-up time was 55 months.
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Five-year OS, DFS, loco-regional recurrence-free, and distant metastases-free survival rates were 70, 68, 77, and 88%, respectively.
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Multivariate analyses revealed that the level and number of metastatic LNs and concomitant CT were unique significant prognostic factors for OS, DFS, and LRFS.
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Endometrial involvement was proven to be significant for DFS and DMFS.
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Patients with less than three LN metastases or those with only obturator LN involvement showed a similar prognosis to their counterparts with no LN metastases.
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Patients with either common iliac LN or more than three LN metastases had a significantly worse outcome.
Atahan IL et al (2007) Radiotherapy in the adjuvant setting of cervical carcinoma: treatment, results, and prognostic factors. Int J Gynecol Cancer 17(4):813–820
9.2 Endometrial Cancer
Endometrial cancer is the fourth most common female cancer following breast, lung and colon cancers. Such cancers have shown a prominent increase in incidence in developed countries, and have become the most common gynecologic cancer. Although its incidence is high, it is only the seventh most common cause of cancer-related mortality, due to early diagnosis and treatment [21].
The corpus is the major part of the uterus, and it extends into the fundus, where uterus combines with the Fallopian tubes. The isthmus is 0.5 cm long and located between the cervix and corpus (Fig. 9.14).
Histologically, the uterine corpus consists of three layers; from innermost to outermost, these are:
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1.
Endometrium: consists of a basal layer and a functional layer that includes endometrial glands.
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2.
Myometrium: consists of smooth muscle and lymph vessels.
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3.
Serosa: the peritoneum that covers the uterine corpus from anterior and posterior, and the cervix only from posterior.
9.2.1 Pathology
Endometrial cancers are generally adenocarcinomas [22]. The basic developmental mechanism is a long period of unbalanced estrogenic excitation with progesterone. This excitation may be exogenous or endogenous. Estrogen-secreting ovarian neoplasms (granulosa cells or functional thecomas) and polycystic ovarian syndrome (Stein–Leventhal syndrome), resulting in the secretion of high levels of estrogen, may cause endometrial hyperplasia and subsequent carcinoma.
Endometrial adenocarcinomas are classified into two groups according to their histomorphological features, pathogenesis and prognosis.
Type 1 endometrial adenocarcinomas. These generally develop from endometrial hyperplasia. There are hyperplasia foci around the carcinoma. Type 1 endometrial carcinomas are well-differentiated and are difficult to distinguish from normal endometrial glands. This type of carcinomas are also called “endometrioid-type” adenocarcinomas.
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They generally do not invade deep myometrium, and they have a good prognosis.
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They constitute 80–95% of all endometrial carcinomas.
Type 2 endometrial adenocarcinomas. These have no associated hyperplasia. Patients are older than those with type I cases. They are less differentiated neoplasias.
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Constitute 10–15% of endometrial cancers, and have a poor prognosis.
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No association with estrogen.
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High grade and high malignant potential.
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Serous and clear cell carcinomas belong in this group of neoplasias.
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Types other than adenocarcinomas have high risks of recurrence and distant metastasis.
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Prognosis is poor in adenosquamous, clear cell and papillary types.
9.2.3 General Presentation
Particularly in older women, cervical stenosis causing hematometrium or pyometrium may not result in bleeding. This sign is a poor prognostic factor. More than 50% of cases with pyometrium and associated vaginal discharge have carcinoma in D&C (dilatation and curettage), and most have squamous carcinoma, which is a very rare form of endometrial carcinoma.
More than 90% of patients with endometrial cancer complain only of vaginal bleeding.
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Most such bleeding is postmenopausal in origin.
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Premenopausal cases have abnormal uterine bleeding.
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Rarely, patients have a feeling of pelvic compression or discomfort, which is a sign of extrauterine disease extension.
Five to seventeen percent of patients are asymptomatic. In asymptomatic cases, the disease is frequently discovered through abnormal PAP smears, incidentally in hysterectomy specimens, or via abnormal radiological findings in the uterus (e.g., thickening of the endometrial wall in pelvic USG).
9.2.4 Staging
Uterine cavity size, endocervical curettage findings, cystoscopy and rectoscopy findings were used in the clinical staging of endometrial cancer until 1988. However, this system could not determine some important prognostic factors such as myometrial invasion depth and lymph node metastasis and had downstage the tumor (22% lower stages than surgical staging).
Surgical staging of endometrial cancer should include peritoneal lavage for cytological exam, biopsy of all suspicious lesions by abdominal and pelvic exploration, radical hysterectomy, bilateral salpingo-oopherectomy and bilateral pelvic paraaortic lymph node dissection.
Uterus is thoroughly examined for tumor size, myometrial invasion depth, cervical stromal and glandular extension. All suspicious pelvic and paraaortic lymph nodes should be examined pathologically.
Prognostic parameters like myometrial invasion depth, peritoneal cytology, lymph node involvement, cervical and adnexal extension were added into 1988 surgical-pathological staging system [23–26] FIGO recently changed the endometrial cancer staging system in 2009.
9.2.8 Treatment Algorithm
9.2.9 Radiotherapy
Simulation is performed in the supine position; vaginal and rectal markers are placed into the patient. Oral contrast material may be beneficial for the visualization of intestines.
Anterior–posterior fields (Fig. 9.17)
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Superior: between the L4 and L5 vertebrae (common iliac LN [+] → L3–4)
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Inferior: below obturator foramen if vagina (−), below ischial tuberosities if vagina (+)
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Lateral: bony pelvis + 2 cm
Lateral fields
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Superior and inferior: same as anterior–posterior fields
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Anterior: anterior to symphysis pubis
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Posterior: between the S2 and S3 vertebrae (or 2 cm posterior to tumoral extension)
Paraaortic/upper pelvic LN (+) → paraaortic RT (extended field RT)
Dose–Fractionation
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Postoperative RT:
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Pelvic RT: 45 Gy/1.8 Gy
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Pelvic extension: total dose 50.4 Gy
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Vaginal cuff BT: 3 × 6–7 Gy (HDR)
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BT alone: 6 × 5.5–6 Gy (HDR)
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Preoperative RT:
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Pelvic RT: 45 Gy/1.8 Gy
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Vaginal extension; total dose 50.4 Gy.
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Intracavitary BT: 3 × 6–7 Gy (HDR)
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Paraaortic LN (+) (Fig. 9.18):
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Pelvic/paraaortic RT + vaginal cuff BT
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Whole-abdomen RT (Fig. 9.19):
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30 Gy/1.5 Gy; then paraaortic and pelvic fields 45 Gy for uterine papillary serous carcinoma (Stage III–IV)
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The superior border in whole abdomen is 1 cm above the diaphragm
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9.2.10 Selected Publications
PORTEC, 2005 → 714 stage I endometrial carcinoma patients randomly assigned to postoperative pelvic radiotherapy (RT) or no further treatment, excluding those with stage IC, Grade 3, or stage IB, Grade 1 lesions.
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Ten-year loco-regional relapse rates were 5% (RT) and 14% (controls; p < 0.0001), and 10-year overall survivals were 66 and 73%, respectively (p = 0.09).
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In view of the significant loco-regional control benefit, radiotherapy remains indicated in stage I endometrial carcinoma patients with high-risk features for loco-regional relapse.
Scholten AN (2005) Postoperative radiotherapy for Stage 1 endometrial carcinoma: long-term outcome of the randomized PORTEC trial with central pathology review. Int J Radiat Oncol Biol Phys 63(3):834–838
GOG 99, 2004 → 448 patients with “intermediate risk” endometrial adenocarcinoma were randomized after surgery to either no additional therapy (NAT) or whole pelvic radiation therapy (PRT). A high intermediate risk (HIR) subgroup of patients was defined as those with (1) moderate to poorly differentiated tumor, presence of lymphovascular invasion, and outer third myometrial invasion; (2) age 50 or greater with any two risk factors listed above; or (3) age of at least 70 with any risk factor listed above. All other eligible participants were considered to be in a low intermediate risk (LIR) subgroup.
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Adjunctive RT in early-stage intermediate risk endometrial carcinoma decreases the risk of recurrence, but should be limited to patients whose risk factors fit the definition of HIR.
Keys HM et al (2004) A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 92(3):744–751
JGOG 2033, 2007 → adjuvant PRT vs. cyclophosphamide–doxorubicin–cisplatin (CAP) chemotherapy in women with endometrioid adenocarcinoma with deeper than 50% myometrial invasion.
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No statistically significant differences in PFS and overall survival (OS) were observed.
-
Among 120 patients in a high- to intermediate-risk group defined as (1) stage IC in patients over 70 years old or with G3 endometrioid adenocarcinoma or (2) stage II or IIIA (positive cytology), the CAP group had a significantly higher PFS rate (83.8 vs. 66.2%, p = 0.024) and higher OS rate (89.7 vs. 73.6%, p = 0.006).
-
Adverse effects were not significantly increased in the CAP group vs. the PRT group.
-
Adjuvant chemotherapy may be a useful alternative to radiotherapy for intermediate-risk endometrial cancer.
Susumu N (2008) Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate-and high-risk endometrial cancer: A Japanese Gynecologic Oncology Group study. Gynecol Oncol 108(1):226–233
Sorbe et al. 2005 → 290 low-risk endometrial carcinomas (stages IA–IB and Grades 1–2). The HDR MicroSelectron afterloading equipment (iridium-192) was used. Perspex vaginal applicators with diameters of 20–30 mm were used, and the dose was specified at 5 mm from the surface of the applicator. Six fractions were given, and the overall treatment time was 8 days. The size of the dose per fraction was randomly set to 2.5 Gy (total dose of 15.0 Gy) or 5.0 Gy (total dose of 30.0 Gy).
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The overall loco-regional recurrence rate of the complete series was 1.4% and the rate of vaginal recurrence was 0.7%. There was no difference between the two randomized groups.
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The vaginal shortening (measured by colpometry) was not significant (p = 0.159) in the 2.5 Gy group (mean, 0.3 cm) but was highly significant (p < 0.000001) in the 5.0 Gy group (mean 2.1 cm) after 5 years.
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Mucosal atrophy and bleedings were significantly more frequent in the 5.0 Gy group. Symptoms noted in the 2.5 Gy group were no different from those that could be expected in a normal group of postmenopausal women.
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The fractionation schedule recommended for postoperative vaginal irradiation in low-risk endometrial carcinoma is six fractions of 2.5 Gy when the HDR technique is used.
Sorbe B (2005) Intravaginal high-dose-rate brachytherapy for stage I endometrial cancer: a randomized study of two dose-per-fraction levels. Int J Radiat Oncol Biol Phys 62(5):1385–1389
GOG 122, 2006 → 422 patients with stage III or IV endometrial carcinoma having a maximum of 2 cm of postoperative residual disease were randomized to whole-abdominal irradiation (WAI) and doxorubicin–cisplatin (AP) chemotherapy. RT dose was 30 Gy in 20 fractions, with a 15 Gy boost. Chemotherapy consisted of doxorubicin 60 mg/m2 and cisplatin 50 mg/m2 every 3 weeks for seven cycles, followed by one cycle of cisplatin.
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Chemotherapy with AP significantly improved progression-free and overall survival compared with WAI.
Randall ME et al (2006) Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 24(1):36–44
Hacettepe, 2008 → 128 patients with intermediate- to high-risk stage I endometrial adenocarcinoma (any stage I with Grade 3 histology or stage IB Grade 2 or any stage IC disease) were treated with HDR BT alone after complete surgical staging. A total dose of 27.5 Gy with HDR BT, prescribed at 0.5 cm, was delivered in five fractions on 5 consecutive days. Median follow-up was 48 months.
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Six (4.7%) patients developed either local recurrence (n = 2) or distant metastases (n = 4).
-
Five-year OS and DFS rates were 96 and 93%, respectively.
-
Only age was found to be a significant prognostic factor for DFS. Patients younger than 60 years had significantly higher DFS (p = 0.006).
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None of the patients experienced Grade 3/4 complications due to the vaginal HDR BT.
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Vaginal cuff BT alone is an adequate treatment modality in stage I endometrial adenocarcinoma patients with intermediate- to high-risk features after complete surgical staging with low complication rates.
Atahan IL, Ozyar E, Yildiz F, Ozyigit G et al (2008) Vaginal high dose rate brachytherapy alone in patients with intermediate- to high-risk stage I endometrial carcinoma after radical surgery. Int J Gynecol Cancer 18(6):1294–1299
9.3 Vaginal Cancer
Vaginal cancer is rarely seen, and comprises 1–2% of all gynecological cancers [30]. They are classified into primary and secondary vaginal cancers. Primary vaginal cancer originates from the vagina, while secondary vaginal cancer usually originates from the metastases of cervical and vulvar cancers.
The vagina is a 7–9 cm long cylindrical organ extending from the vestibule to the uterine cervix (Fig. 9.21). Its wall consists of glandular mucous membrane, a muscular layer rich in vascular structures, and adventitial connective tissues. Vaginal mucosa contains mucosal-type stratified nonkeratinized squamous cells that are sensitive to hormones and show cyclic changes. They also have multiple mucosal ridges called rugae.
Primary vaginal cancers are mostly seen in patients over 60 years of age [30].
Lower third of vagina develops from urogenital sinus, and upper two thirds of vagina develops from Mullerian canal similar to inner genital organs such as uterus, Fallopian tubes and ovaries during embryogenesis.
9.3.1 Pathology
Mostly embryonal sarcomas and endodermal sinus tumors in are observed in childhood, adenocarcinomas related to diethylstilbestrol (DES) in adolescence, and squamous cell cancer in adults. Although vaginal cancers are generally seen in older patients, their frequency among young females has increased in recent years due to HPV infections.
Primary vaginal cancers have several subtypes: pure epithelial, mesenchymal, mixed epithelial and mesenchymal, and germ cell tumors.
Nearly 80–90% of all pathological cases are squamous cell cancers, and most of these are Grade II–III lesions [30].
Invasive squamous cell cancer. This is observed mostly in the posterior wall as an exophytic mass. Lesions may be 3–5 cm long and ulcerated. Advanced lesions are those that easily bleed. Endophytic tumors are less commonly seen. Most of them are microscopically moderately differentiated and show destructive infiltrative growth patterns in vaginal and paravaginal soft tissues.
Verrucous carcinoma. This is the least common variant of squamous cell cancer. They present with postmenopausal bleeding or vaginal discharge, and 0.8–10 cm in diameter, 2–3 cm long verrucous lesions. These tumors grow slowly and rarely metastasize.
Malignant melanoma. These constitute 3% of all vaginal epithelial tumors. They originate from melanocytes found in various places in the vagina. Cases usually occur in the late reproductive or perimenopausal period. It behaves very aggressively and extends early.
Adenocarcinoma. This is observed in 10–15% of cases. It originates from the Bartholin and Skene glands.
-
Clear cell carcinoma develops due to DES exposure in utero.
Mesenchymal cancers. Pure primary tumors are very rare, and follow an aggressive and lethal course. Sarcoma botryoides and leiomyosarcomas are the most frequent. In addition, lymphomas, malignant fibrous histiocytomas and postradiotherapy angiosarcomas may be seen.
Germ cell tumors. These are rarely seen in the vagina. Malignant ones are embryonic cell cancers and endodermal sinus tumors. They are observed in newborns.
9.3.2 General Presentation
Most patients present with abnormal vaginal bleeding and discharge. Pelvic pain and other symptoms change according to tumoral extension into surrounding tissues and organs. Anterior tumors produce bladder and urinary symptoms, while posterior ones yield tenesmus and defecation problems.
-
Dyspareunia is observed in sexually active females.
-
The disease is rarely diagnosed through abnormal PAP smear findings.
-
The tumor is grossly exophytic in general, but it may be endophytic. Superficial ulcerations usually occur in advanced stages.
-
Most of them localize in the upper one-third of the posterior vaginal wall.
-
Chronic pelvic pain is observed in 5% of cases at diagnosis.
9.3.3 Staging
9.3.4 Treatment Algorithm
9.3.5 Radiotherapy
Inguinal/femoral LN (+) or lower vaginal tumor; RT field should be extended to include inguinal/femoral lymphatics (Fig. 9.25).
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Therefore, simulation is performed in the frog-leg position.
LN (−/+); posterior field should include only pelvis (not inguinal regions) to protect femur heads, since inguinal LNs are located superficially.
9.3.6 Selected Publications
M.D. Anderson, 2005 → 193 patients were treated with definitive radiation therapy for squamous cell carcinoma of the vagina.
-
Five-year DSS rates were 85% for the 50 patients with stage I, 78% for the 97 patients with stage II, and 58% for the 46 patients with stage III–IVA disease (p = 0.0013).
-
Five-year DSS rates were 82 and 60% for patients with tumors ≤4 cm or >4 cm, respectively (p = 0.0001).
-
Five-year pelvic disease control rates were 86% for stage I, 84% for stage II, and 71% for stage III–IVA (p = 0.027).
-
Excellent outcomes can be achieved with definitive radiation therapy for invasive squamous cell carcinoma of the vagina.
-
Treatment must be individualized according to the site and size of the tumor at presentation and the response to initial external-beam radiation therapy.
Frank SJ (2005) Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys 62(1):138–147
MSKCC, 1992 → 36 patients were treated with combined external RT and BT, 11 patients were treated with external RT alone, and two patients were treated with BT alone.
-
Five-year survival was 44% for stage I, 48% for stage II, 40% for stage III, and 0% for stages IVa and IVb.
-
There was a significant increase in the 5-year actuarial survival for those patients who had BT as part of their treatment compared to those patients treated with external RT alone (50 vs. 9%) (p < 0.001). For stages II and III, there was a trend toward improved actuarial and crude disease-free survival with the use of a temporary Ir-192 interstitial implant as part of the treatment compared to the use of intracavitary BT as part of the treatment (80 vs. 45%) (p = 0.25) and (75 vs. 44%) (p = 0.08), respectively.
-
BT plays an important role in the management of primary vaginal cancer. A temporary interstitial implant should be used over an intracavitary form of therapy for more invasive disease.
Stock RG (1992) The importance of brachytherapy technique in the management of primary carcinoma of the vagina. Int J Radiat Oncol Biol Phys 24(4):747–753
Washington University, 1988 → 165 patients with vaginal cancer.
-
Ten-year disease-free survivals were: stage 0, 94%; stage I, 75%; stage IIA, 55%; stage IIB, 43%; stage III, 32%; stage IV, 0%.
-
RT dose delivered to the primary tumor or the parametrial extension was critical in achieving successful results.
-
Conclusion: high incidence of distant metastases underscored the need for earlier diagnosis and effective systemic cytotoxic agents if survival is to be significantly improved in these patients.
Perez CA (1988) Definitive irradiation in carcinoma of the vagina: long-term evaluation of results. Int J Radiat Oncol Biol Phys 15(6):1283–1290
Ontario, 2007 → 12 patients were treated with concurrent weekly chemoradiotherapy. Median follow-up was 50 months. All patients received pelvic external RT (EBRT) concurrently with weekly intravenous cis-platinum chemotherapy (40 mg/m2) followed by BT (BT). The median dose of EBRT was 4,500 cGy given in 25 fractions over 5 weeks.
-
Five-year overall survival, PFS, and loco-regional PFS rates were 66, 75, and 92%, respectively.
-
It was found to be feasible to deliver concurrent weekly cis-platinum chemotherapy with high-dose radiation, leading to excellent local control and an acceptable toxicity profile.
Samant R (2007) Primary vaginal cancer treated with concurrent chemoradiation using cis-platinum. Int J Radiat Oncol Biol Phys 69(3):746–750
UC Davis, 2004 → 14 patients were treated with primary therapy consisting of concurrent radiation and chemotherapy.
-
Chemoradiotherapy was found to be an effective treatment for squamous carcinoma of the vagina.
Dalrymple JL (2004) Chemoradiation for primary invasive squamous carcinoma of the vagina. Int J Gynecol Cancer 14(1):110–117
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Beyzadeoglu, M., Ebruli, C., Ozyigit, G. (2010). Gynecological Cancers. In: Basic Radiation Oncology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-11666-7_9
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