Radiation Therapy Techniques
Currently, the two main modalities of irradiation are external photon beam and brachytherapy. External irradiation is
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used to treat the whole pelvis and the parametria including the common iliac and para-aortic lymph nodes, whereas central disease (cervix, vagina, and medial parametria) is primarily irradiated with intracavitary sources. The techniques described apply, with some individualization, to most patients with cervical carcinoma (Table 66.12).
External-Beam Irradiation
External-beam pelvic irradiation is delivered before intracavitary insertions in patients with
Bulky cervical lesions or tumors beyond stage IIA to improve the geometry of the intracavitary application;
Exophytic, easily bleeding tumors;
Tumors with necrosis or infection; or
Parametrial involvement.
Volume Treated
In treatment of invasive carcinoma of the uterine cervix, it is important to deliver adequate doses of irradiation not only to the primary tumor but to the pelvic lymph nodes to maximize tumor control (146,478). Greer et al. (193) reported on intraoperative retroperitoneal measurements carried out in 100 patients at the time of radical surgery. Both common iliac bifurcations were cephalad to the lumbosacral prominence in 87% of the patients. Therefore, the superior border of the pelvic portal should be at the L4-5 interspace to include all of the external iliac and hypogastric lymph nodes. This margin must be extended to the L3-4 interspace if common iliac nodal coverage is indicated. The width of the pelvis at the level of the obturator fossae averaged 12.3 cm, and the distance between the femoral arteries at the level of the inguinal rings averaged 14.6 cm. Posterior extension of the cardinal ligaments in their attachment to the pelvic side wall was consistently posterior to the rectum and extended to the sacral hollow. The uterosacral ligaments also extended posteriorly to the sacrum. These anatomic landmarks must be kept in mind in the correct design of lateral pelvic portals.
Greer et al. (194), based on anatomic and radiographic studies, used expanded pelvic radiation fields in 38 women with stage IIB and III cancers of the cervix. The median length and width of the anteroposterior–posteroanterior fields were 20 and 17.5 cm, respectively. Lateral fields had a median width of 16.5 cm and the posterior border encompassed the entire sacral silhouette.
Bonin et al. (45), in a review of 22 patients on whom detailed anatomic mapping of the anatomy of the pelvic lymph nodes was carried out by lymphangiography, concluded that if the criteria for adequacy of standard pelvic fields as defined by the GOG were applied (anteroposterior: 1.5-cm margin on the pelvic rim; lateral field anterior edge is a vertical line anterior to the pubic symphysis and posterior border), 10 patients (45%) would have had inadequate nodal coverage in the irradiation fields. The incompletely irradiated lymph nodes were in the lowest lateral external iliac group. However, if the irradiation portals are designed as we outline in this chapter and in previous publications, almost all of the pelvic lymph nodes would be within the irradiated volumes. With the advent of IMRT to treat gynecological tumors several authors have published guidelines emphasizing imaging methods to more accurately define target volumes, including lymph nodes (50, 601) .
For stage IB disease, conventional anteroposterior and posteroanterior portals 15 by 15 cm at the surface (approximately 16.5 cm at isocenter) are sufficient. For patients with stage IIA, IIB, III, and IVA carcinoma, somewhat larger portals (18 by 15 cm at surface, 20.5 by 16.5 cm at isocenter) are required to cover all of the common iliac nodes in addition to the cephalad half of the vagina (Fig. 66.7A). A 2-cm margin lateral to the bony pelvis is adequate. If there is no vaginal extension, the lower margin of the portal is at the inferior border of the obturator foramen.
When there is vaginal involvement, the entire length of this organ should be treated down to the introitus (Fig. 66.7B). It is very important to identify the distal extension of the tumor at the time of simulation by placing a radiopaque clip or bead on the vaginal wall or inserting a small rod with a radiopaque marker in the vagina (Fig. 66.8). Use of implanted cervical markers
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to localize the vaginal apex or the cervix during simulation is more accurate than using a vaginal rod, according to Kim et al. (316); all patients showed a mean displacement of the cervical markers by the vaginal rod of 1.9 cm (range, 0.6 to 3.6 cm). The greatest displacement was cephalad (mean, 1.5 cm; range, 0.5 to 2.4 cm). Displacement was anterior in 5/8 patients, posterior in three patients, and lateral in four patients.
In patients with tumor involving the distal half of the vagina, the portals should be modified to cover the inguinal lymph nodes because of the increased probability of metastases (Fig. 66.9).
The lateral ports anterior margin is placed at the pubic symphysis; the posterior margin usually is designed to cover at least 50% of the rectum in stage IB tumors, and it should extend to the sacral hollow in patients with more advanced tumors (Fig. 66.10). The use of lateral fields allows a decrease in dose to the small bowel, but care must be taken to include all structures of interest (193, 478, 535).
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Zunino et al. (671) reviewed the appropriateness of radiation therapy box technique for cancer of the cervix in 35 sagittal MRIs and 10 lymphangiograms. An anatomic evaluation was conducted in cadavers to identify aortic bifurcation, lymph nodes, and uterus flexion. Dissection of female pelvises showed that the aortic bifurcation occurred at the inferior plate of L4 in 80% of the cadavers. The anatomic borders of the box technique used were the superior border of the anteroposterior–posteroanterior fields at the inferior edge of L4; inferior border at the inferior edge of the ischium; the lateral borders 2.5 cm outside of the bone pelvis rim; the anterior border of the lateral fields over the anterior edge of the pubic symphysis; and the posterior at the S2-3 interspace. In 50% of the patients with FIGO IB and in 67% with stage IIA disease, the posterior border of the lateral field was inadequate to encompass the PTV. In stage IIB, the posterior border was inadequate in eight patients (42%). In patients with stage IIB and IVA disease, the PTV was not encompassed. On the 35 sagittal MRIs, the placement of the posterior border of the lateral field was inadequate in 49% and the anterior border in 9% of the cases. The standard design of the lateral fields of the four-field technique based on anatomic bone references failed to encompass the PTV in a significant number of patients.
Further, Knocke et al. (329) used standard simulator planning, guided by bony landmarks for pelvic irradiation in 20 patients with primary cervical carcinoma, stages I to III, using four-field box technique. After defining the PTV with a three-dimensional (3D) planning system, the field configuration of the simulator planning was compared with a second one based on the defined PTV and evaluated regarding encompassment of the PTV by the treatment volume (International Commission on Radiation Units and Measurements [ICRU]). Planning by simulation resulted in one geographic miss, and in 10 more cases the coverage of the PTV by the treatment volume was inadequate. Three-dimensional treatment planning for pelvic irradiation of cervical carcinoma may reduce the treated volume, but further research must be done to determine whether the complication rate can be decreased as well.
Midline Shielding in Anteroposterior–Posteroanterior Portals
Depending on the institution and brachytherapy dose administered, midline shielding with rectangular or specially designed blocks are used for a portion of the external beam dose delivered with the anteroposterior–posteroanterior ports (478).
Wolfson et al. (658) compared the dose distribution in the pelvis with an individualized midline shield that conformed to the point A isodose line or a rectangular block in a retrospective review of 32 patients with invasive cervical carcinoma who underwent LDR brachytherapy. Patients were grouped as having a rectangular block (18 cases), customized block (five cases), or no block (nine cases). The point A isodose distribution from the implant was superimposed onto the whole pelvis simulation film. Approximately 72% of all cases (23/32) had tandem deviation up to 230 degrees, with a median of 50 degrees. This translated into a median percentage overdosage to point A right of 15% and left of 12.5%. Overall survival and incidence of chronic complications have not been affected by type of shielding (median follow-up of 17.7 months). Of 56 radiation facilities in the GOG surveyed concerning their use of a block, 34 (61%) responded; 88% (29/33) use a midline shield, most of them (76%) a rectangular central block that is not positioned with respect to possible tandem deviation.
Parametrial Boost
When parametrial tumor persists after 50 to 60 Gy is delivered to the parametria, an additional 10 Gy in five or six fractions may be delivered with reduced anteroposterior–posteroanterior portals (8 by 12 cm for unilateral and 12 by 12 cm portals for bilateral parametrial coverage). The central shield should be in place to protect the bladder and rectum.
Chao et al. (72) evaluated 343 patients with clinical stage IIIB cervical cancer treated with radiation therapy alone and identified 83 with clinical evidence of tumor in the uterosacral region. The average total dose, including external-beam and brachytherapy, to point A and the lateral pelvis was 80.3 to 86.5 Gy and 60.5 to 73.4 Gy, respectively. The external-beam dose to the lateral parametria was, on average, 10 Gy higher in patients with uterosacral involvement. The cumulative incidence of central/marginal failure at 5 years was significantly higher in the group of patients with uterosacral involvement (36%) compared with 21% for patients without involvement or unspecified involvement (p = 0.002). Lateral parametrial failure was similar for patients with and without uterosacral involvement (39% and 38% at 5 years, respectively; p = 0.42).
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Para-Aortic Lymph Node Irradiation
If para-aortic node metastases are present or suspected, patients are treated with 45 to 50 Gy to the para-aortic area plus a 5 to 10 Gy boost to enlarged lymph nodes through reduced lateral or rotational portals. With conventional techniques, the para-aortic lymph nodes are irradiated either with an extended field that includes both the para-aortic nodes and the pelvis or through a separate portal (Fig. 66.11) (478,492). In this case, a “gap calculation” between the pelvic and para-aortic portals must be performed to avoid overlap and excessive dose to the small intestines. The upper margin of the field is at the T12-L1 interspace and the lower margin at L5-S1. The width of the para-aortic portals (in general, 8 to 10 cm) can be determined by CT scans, MRI, lymphangiography, FDG-PET scans, or IV pyelography outlining the ureters. The spinal cord dose (T12 to L2-3) should be kept below 45 Gy by interposing a 2-cm wide 5–half-value layer (HVL) shield on the posterior portal (usually after 40-Gy tumor dose) or using lateral ports and the kidneys below 1,800 cGy. A technique using four isocentric fields weighted 2:1 anteroposterior–posteroanterior over lateral portals and 1.8-Gy fractions was described by Russell et al. (532) to deliver high-dose therapy (56 to 61 Gy), with 7/14 patients alive and free of disease from 11 to 78 months. Kodaira et al. (332) evaluated a four-field para-aortic irradiation technique with 10-MV photons (mean, 50.4 Gy) in 97 patients with cervical cancer. The 5-year cause-specific survival rate was 32.2%. Grade 1 or 2 stomach and duodenum sequelae developed in 26.8%, grade 2 sequelae of small bowel in 3.1%, and grade 2 sequelae of bone in 3.1%.
Esthappan et al. (150) described a technique using CT and FDG-PET retroperitoneal to treat the para-aortic lymph nodes (50.4 and 59.4 Gy) with IMRT (Fig. 66.12). Acceptable dose distribution of the target volumes and sparing of the stomach, liver, and colon was achieved. Sparing of the spinal cord was dependent on the number and arrangements of the beams, as was the small bowel, sparing of which was limited because of overlap with the target volume. Adjusting number of beams and prescription parameters minimally improved kidney sparing.
Beam Energies
Because of the thickness of the pelvis, with conventional irradiation high-energy photon beams (10 MV or higher) are especially suited for this treatment. They decrease the dose of radiation delivered to the peripheral normal tissues (particularly bladder and rectum) and provide a more homogeneous dose distribution in the central pelvis. With lower-energy photons (Cobalt-60 or 4- to 6-MV x-rays), higher maximum doses must be given, and more complicated field arrangements should be used to achieve the same midplane tumor dose (three-field or four-field pelvic box or rotational techniques) while minimizing the dose to the bladder and rectum and to avoid subcutaneous fibrosis (Fig. 66.13) (253). Biggs and Russell (38) noted that the presence of a metallic prosthesis when using lateral fields or a box pelvic irradiation technique may result in a dose decrease of approximately 2% for 25-MV x-rays and average increases of 2% for 10-MV x-rays and 5% for 60Co.
Allt (11) and Johns (285), in an update of a randomized study, reported better pelvic tumor control and survival and fewer complications in 65 patients with stage IIB and III cervical carcinoma treated with 23-MV photons compared with 61 treated with external irradiation with 60Co, in addition to brachytherapy in both groups. In contrast, Holcomb et al. (253) compared outcome of 195 patients with stage IIB-IVA cervical carcinoma treated with 60Co radiation therapy (group 1) and 53 treated with linear accelerators (group 2). There was no significant difference in overall survival, although there was a trend toward increasing pelvic recurrence in the 60Co group (50.8%) compared with group 2 (35.8%; p = 0.08).
Hyperfractionated or Accelerated Hyperfractionated Radiation Therapy for Locally Advanced Cervix Cancer
MacLeod et al. (391) reported on a phase II trial of 61 patients with locally advanced cervical cancer treated with accelerated hyperfractionated radiation therapy (1.25 Gy administered twice daily at least 6 hours apart to a total pelvic dose of 57.5 Gy). A boost dose was administered with either LDR brachytherapy or EBRT to a smaller volume. Thirty patients had acute toxicity that required regular medication. One patient died of acute treatment-related toxicity. The overall 5-year survival was 27%, RFS was 36%, and actuarial local tumor control was 66%. There were eight severe late complications observed in seven patients, who required surgical intervention (actuarial rate of 27%). Five patients also required total hip replacement.
Viswanathan et al. (638) reported on 30 patients with stage II or III cervical cancer randomized to receive either hyperfractionation (15 patients) or conventional fractionation (15 patients). At 5 years, two patients in the hyperfractionation group and eight patients in the conventional treatment group had recurrent tumor (p = 0.04). Delayed bowel complications (grade 2 and 3) occurred in nine women in the hyperfractionation group and two patients in the conventional group (p = 0.0006).
The Radiation Therapy Oncology Group (RTOG 88-05) conducted a phase II trial of hyperfractionation (1.2 Gy to the whole pelvis twice daily at 4- to 6-hour intervals, 5 days per week) with brachytherapy in 81 patients with locally advanced carcinoma of the cervix. Total dose to the whole pelvis was 24 to 48 Gy, followed by one or two LDR intracavitary applications to deliver 85 Gy at point A and 65 Gy to the lateral pelvic nodes. Grigsby et al. (209) updated the results and noted that external
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irradiation was completed in 71 (88%). The 5-year cumulative rates of grade 3 and 4 late effects for patients with stages IB2 or IIB tumors was 7% and at 8 years 10%, and with stage III or IVA disease, 12% at 5 years. The absolute survival was 48% at 8 years, and disease-free survival 33%, respectively. Comparison with historical control patients treated on other RTOG showed equivalent rates of pelvic tumor control, survival, and grade 3 and 4 toxicities at 3, 5, and 8 years, respectively.
Concomitant Boost
Kavanagh et al. (306) reported on 20 patients with FIGO stage III squamous-cell carcinoma of the cervix who were irradiated in a clinical trial involving a concomitant boost regimen. Patients received 45 Gy to the pelvis in 25 fractions in 5 weeks. On Monday, Wednesday, and Friday of the last 3 weeks, an additional 1.6-Gy boost was given 6 hours after the whole pelvis treatment (14.4 Gy) through lateral fields encompassing the parametria and primary tumor, for a total tumor dose of 59.4 Gy. A single LDR brachytherapy procedure was performed within 1 week after the external-beam radiation therapy to raise the point A dose to 85 to 90 Gy in 42 days. Mean total treatment time was 46 days. Results were compared with patients treated with conventional radiation therapy during the same years. The 4-year actuarial tumor control rates were 78% in the concomitant boost and 70% in the conventional irradiation group (p = not significant). Only two patients receiving concomitant boost required a treatment break because of acute toxicity, but severe late
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complications occurred in 8/20 patients. Further investigations into external-beam dose intensification should be conducted only with a more sophisticated technique than what was available during the time of the study to reduce toxicity.
Three-Dimensional or Intensity-Modulated Radiation Therapy
There is increasing experience with 3D or IMRT in cervical cancer, although results are preliminary. Portelance et al. (493) carried out IMRT as well as conventional planning with two- and four-field techniques in 10 patients. Prescription was 45 Gy in 25 fractions to the uterus and the pelvic and para-aortic lymph nodes. All IMRT plans were normalized to obtain a full coverage of the cervix with the 95% isodose curve (Fig. 66.14A). The volumes of small bowel receiving the prescribed dose (45 Gy) with IMRT technique were, with four fields, 11%; seven fields, 15%; and nine fields, 13.5% (Fig. 66.14B). These dose distributions were all significantly better than with two-field or four-field conventional techniques (p <0.05.) Ahmed et al. (7) arrived at similar conclusions in five patients with para-aortic node metastasis, and they demonstrated the feasibility of escalating the dose to 60 Gy while sparing the kidneys, spinal cord, small bowel, and bone marrow. Heron et al. (245), in a study of 10 patients, showed that with IMRT there was a reduction of 52% in the small bowel volume receiving >30 Gy and a decrease of 66% for the rectum and 36% for the bladder, compared with 3D continuous radiation therapy (CRT). D'Souza et al. (105), in 10 patients, also noted a reduction of small bowel volume (33%) with IMRT compared with four-field pelvic RT; however, small volumes of bowel received 55 to 60 Gy with the IMRT plans. A patient prone position on a “belly board” was shown to reduce volume of small bowel irradiated (4).
Brixley et al. (55) and Lujan et al. (389) also used IMRT planning to spare the bone marrow of patients with gynecological tumors. Brixey et al. (55), in 36 patients, noted no significant difference in hematologic toxicity with IMRT or conventional RT alone; however, in patients receiving chemotherapy less grade 2 white blood cell toxicity was observed with IMRT (31.2% vs. 60%, respectively).
Uncertainties in the definition of target volumes when using 3D techniques have been identified (646). Bladder-filling control and accurate definition of margins for the PTV with image-guided position verification have been advocated to achieve a better application of IMRT (227). An example of dose distribution achieved with IMRT pelvic irradiation is illustrated in Fig. 66.15.
Early results with IMRT have been published. Kavanagh et al. (307) described the outcome of a small cohort of patients with stage IIB or IVA cervical cancer with medical illness or severe tumor-related anatomic distortion that limited delivery of brachytherapy. IMRT was used to provide a simultaneous boost dose to the primary tumor at the time of external-beam treatment to a larger pelvic field given in conventional fractions. The toxicity of IMRT was acceptable, and early tumor responses were encouraging.
Guerrero et al. (214) proposed using an IMRT simultaneous integrated boost (SIB) as an alternative to conventional whole pelvis irradiation and used the linear quadratic equation to calculate equivalent uniform dose in multiple plans. For example, an SIB plan with 25 fractions of 3.1 Gy (77.5 Gy) is equivalent to 45 Gy whole pelvis with external beam and 30 Gy HDR in five fractions brachytherapy boost.
Molla et al. (415) proposed fractionated stereotactic RT as an alternative to brachytherapy to boost the dose to the vaginal and medial parametria in patients with carcinoma of the cervix or endometrium (2 × 7 Gy to PTV with 4-to 7-day intervals postoperatively or in nonoperated patients 5 × 4 Gy with 2-to 3-day intervals). None of 16 patients treated developed urinary or intestinal morbidity.
Although not as critical in older patients, it is important to keep in mind that while IMRT has dosimetric advantages over conventional RT, IMRT exposes a greater amount of normal tissues to lower irradiation levels, which has the potential to increase the incidence of radiation-induced second cancers (224), a phenomenon already described with conventional RT techniques (43).
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