Whole pelvic helical tomotherapy for locally advanced cervical cancer: technical implementation of IMRT with helical tomothearapy

Between November 1st, 2006 to May 31, 2009, 10 patients undergoing whole pelvic HT (WPHT) for locally advanced cervical cancer without pelvic or paraarotic lymphadenopathy at Far Eastern Memorial Hospital (FEMH) were retrospectively enrolled. Staging investigations included complete history and physical examination, fiberoptic endoscopic evaluation, complete blood counts, liver and renal function tests, chest X-ray, magnetic resonance imaging (MRI) scans or computed tomography (CT) scans of the pelvic region. The disease was staged according to the International Federation of Gynecology and Obstetrics (FIGO) criteria [15].

Radiotherapy was administered to the whole pelvic region in 28 fractions totaling 50.4 Gy followed by intracavitary brachytherapy. The total dose of brachytherapy delivered was 30 Gy/6 fractions in patients. The total dose delivered to point A (a reference location 2 cm lateral and 2 cm superior to the cervical os) was 80.4 Gy in patients; the total dose delivered to point p (the pelvic wall) was 55.0 Gy in patients. Cisplatin (CDDP) was administered during external radiation, beginning on the first day of radiation for 5 weeks concurrent with WPHT. A dose of 40 mg/m² CDDP (maximum dose, 70 mg) was used and administered via a peripheral vein to patients.

A BlueBAG™ immobilization system (Medical Intelligence, Schwabmünchen, Germany) was used for each of these patients to fix pelvic and extremities. Positioning was supine with arms up, and feet placed in an ankle holder. All patients underwent a CT planning scan with our departmental scanner (Siemens Somatom Plus 4 CT scanner) from the diaphragm to 5 cm below the ischial tuberosities. Localization marks were placed on anterior and lateral sides of the patients at the mid-plane and midline at the level of L4-L5 vertebral body interspace. CT with 5-mm slice thickness was taken for treatment planning. Target objects and normal structures were contoured on a Pinnacle3 treatment planning system (Philips Healthcare, Madison, Wisconsin, USA). The MRI or CT images were retrieved on a Pinnacle workstation and fused with the CT images for contouring of the tumor volume.

Delineation and constraints was according to Radiation Therapy Oncology Group (RTOG) 0418 protocol and the International Commission on Radiation Units and Measurements reports 50 [16] and 62 [17] recommendations. The Gross Tumor Volume (GTV) was defined as all known gross disease determined from CT, clinical information, and MRI. The Clinical Target Volume (CTV) was defined as areas considered containing potential microscopic disease. Internal Target Volume (ITV) was defined as the volume of the vagina and paravaginal soft tissues that is in both the empty and full bladder CT scans that were done at the time of simulation and fused together. The Planning Target Volume (PTV) would provide a 7 mm margin (anteriorly, posteriorly, laterally, as well as in the superior and inferior directions) around the nodal CTV and ITV. The treatment plan would be done on the full bladder scan. The treatment plan used for each patient would be based on an analysis of the volumetric dose, including dose volume histogram (DVH) analyses of the PTV and critical normal structures. The GTV plus a 7-mm expansion was defined as the primary tumor CTV to account for microscopic spread, excluding the bowel, bladder, and rectum if they were not clinically involved); The nodal CTV should include the internal (hypogastric and obturator), external, common iliac lymph nodes perinodal tissue, pertinent clips and down to the level of S3. Identification of the CTV usually began with the identification of the iliac vessels. The average margin would be 7 mm. Bone and intraperitoneal small bowel should be excluded from the CTV; also, iliopsoas muscle that lies adjacent to clinically negative lymph nodes should also be excluded from the CTV. Approximately 1.5 cm of tissue anterior to the S1, S2 and S3 sacral segments was usually added to the CTV in order to include the presacral lymph nodes and uterosacral ligaments. The most antero-lateral external iliac lymph nodes that lied just proximal to the inguinal canal should be excluded from the CTV. The CTV of the nodes should end 7 mm from L4/L5 interspace to account for the PTV. The PTV for nodes stopped at L4/L5 interspace. The vaginal and parametrial CTV should actually be an ITV, which will account for internal organ motion. The inferior limit was usually around the level of the upper third of the symphysis pubis but could be individualized based on inferior spread of the patient's tumor. The lateral margin of the vaginal PTV should be to the obturator muscle. However, at least 3 cm of the vagina needed to be treated or at least 1 cm below the obturator foramen. The 90% isodose surface covered between 95% and 98% of the PTV 50.4, or volumes of overdose exceed 115% < 5% of the PTV 50.4 volume could be considered acceptable. The field width, pitch, and modulation factor (MF) usually used for the WPHT treatment planning optimization were 2.5 cm, 0.32 and 3.0, respectively. All patients received daily megavoltage computed tomography (MVCT) acquisitions for setup verification [18].

Normal structures will be contoured using the full-bladder CT scan. The OARs (i.e., bladder, rectum, sigmoid, small bowel, and femoral heads) were contoured as solid organs. Dose-volume constraints for normal tissues were as follows: small bowel (2 cm above the most superior vessel contour) < 30% to receive ≥ 40 Gy, minor deviation 30% to 40 Gy; Rectum < 60% to receive ≥ 30 Gy, minor deviation 35% to 50 Gy; Bladder < 35% to receive ≥ 45 Gy, minor deviation 35% to 50 Gy; Femoral head ≤ 15% to receive ≥ 30 Gy, minor deviation 20% to 30 Gy.

An iridium-192 (high-dose-rate) source was used with standard Fletcher-Suit-Delclos intracavitary applicators. Patients were treated twice a week after WPHT completed for 3 weeks, with a prescribed dose of 500 cGy per fraction to Point A. The high-dose rate (HDR) source dwell times were manually calculated based on our institutional system of empiric intracavitary irradiation rules. Postimplantation dosimetry was performed with the GENIE treatment planning system v1.0.4 (Nucletron, Netherland), and included calculation of dose to the "classical" Point A bilaterally (a reference location 2 cm lateral and 2 cm superior to the cervical os), pelvic sidewall bilaterally (Point P, defined as the point 2 cm above the top of the colpostat and 6 cm lateral to midline), and the rectal point and bladder point as defined by the International Commission on Radiation Units and Measurements [19]. For each implant, point doses to Points A and P, the bladder point, and the rectal point were recorded; after completion of therapy, the doses for the six implants were summed. There is no standard or universally accepted fraction size for HDR brachytherapy. At our institution we have chosen to use the fraction size of 500 cGy.

Conventional whole pelvic radiation therapy (WPRT) plans were generated using Pinnacle3 treatment planning system (Philips Healthcare, Madison, Wisconsin, USA). The isocenter was placed at the geometric center of the PTV. A 4-field "box" plan was designed using 6-MV photons with apertures shaped to the PTV in each beam's eye-view. The pelvic field extended from the upper margin of L5 to the midportion of the obturator foramen or the lowest level of disease, with a 2-cm margin, and laterally 1.5 cm beyond the lateral margins of the bony pelvic wall (at least 7 cm from the midline). For the lateral fields, the anterior border was the pubic symphysis and the posterior border was the space between S2 and S3. The fields could be modified to include areas of known tumor and wedges were used as needed. All plans were normalized to cover 98% of the PTV with 50.4 Gy. The 2% underdose represents those voxels at the periphery. This normalization provided conformal coverage while minimizing dose nonuniformity within the target.

Dose-volume histograms (DVHs) of the PTVs and the critical normal structures were analyzed accordingly. For PTVs, we evaluated the volume, the volume covered by 95% of the prescription dose (V95), and the minimum doses delivered to 5% (D₅) and 95% (D₉₅) of the PTV. The critical organs with functional subunits organized in a series were examined. The conformal index (CI) and the uniformity index (UI) had been used to evaluate the conformity and uniformity of the plan. The volume received the mean dose for PTV generated from the DVH. The conformal index (CI) for PTV was calculated using the formula CI_ICRU = V _TV /V _PTV , where V _TV was the ratio of the treated volume enclosed by the prescription isodose surface and V _PTV was the planning target volume [17]. The uniformity index (UI) was defined as UI = D₅/D₉₅, where D₅ and D₉₅ were the minimum doses delivered to 5% and 95% of the PTV reported previously [20].

Interruptions in radiotherapy might be necessitated by uncontrolled diarrhea, or other acute complications. If radiation therapy was held, then chemotherapy would also be held. Chemotherapy stopped at the completion of RT. If chemotherapy was held, radiation therapy would continue. Radiation was only stopped in cases of grade 4 hematologic or non-hematologic toxicity until toxicity resolved to at least grade 3. CDDP was withheld in any case involving grade 3 toxicity until the toxicity regressed to any grade of <3; in patients with grade 3 toxicity that persisted >2 weeks, chemotherapy was no longer administered.

Upon treatment completion, patients were evaluated every 3 months for the first year, every 4 months during the second year, every 6 months during the third year, and annually thereafter. At each visit, a physical and pelvic examination, blood counts, clinical chemistry, and chest x-rays were performed. Computed tomography (CT) scan, ultrasound (US), and other imaging studies were conducted when appropriate. Suspected cases of persistent or recurrent disease were confirmed by biopsy whenever possible. Acute and late toxicities (occurring >90 days after beginning RT) were defined and graded according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0).

Descriptive statistics (mean, median, proportions) were calculated to characterize the patient, disease, and treatment features as well as toxicities after treatment. The overall survival (OS), progression-free survival (PFS), locoregional progression-free (LRPF), and distant metastases-free (DMF) rates were estimated using the Kaplan-Meier product-limit method. Progression was defined as a 50 percent increase in the product of the two largest diameters of the primary tumor or metastasis. Progression-free survival was calculated from the date of pathologic proof to the date of the first physical or radiographic evidence of disease progression, death, or the last follow-up visit. Survival was calculated from the date of pathologic proof to the date of death or the last follow-up visit. All analyses were performed using the Statistical Package for the Social Sciences, version 12.0 (SPSS, Chicago, IL, USA).

Ten women were included. They had a median age of 58 years (range, 33-72 years). All belong to FIGO Stage IIB and IIIB. The medium tumor volume was 45.9 cm³. The medium weekly cycles of chemotherapy were 5 weeks. Seventy percent of patients could complete 4 weekly cycles of chemotherapy. All of the patients were treated with definitively concurrent chemotherapy with WPHT followed by brachytherapy. (Table 1)

The mean survival was 25 months (range, 3 to 27 months). The actuarial 2-year overall survival, progress-free survival, locoregional control and distant metastasis-free rates were 67%, 77%, 90% and 88%, respectively. The 2-year survival, progression-free, locoregional-progression-free and distant metastasis-free patient number over all patients are 9/10, 8/10, 9/10 and 9/10, respectively. Ninety percent of patients were surviving at the time of this report.

The WPHT for UI and CI was 1.07 ± 0.05 and 1.01 ± 0.05, respectively. The UI and CI for individual patient are plotted in Figures 1A and 1B, respectively. Dose-volume histograms statistics for the organs at risk are described in table 2. WPHT provided better critical organs sparing than WPRT in the mean dose and the other parameters for rectum, bladder and intestine with a statistically significant level (p value < 0.01), respectively. WPHT provided impressive ability of high dose declining for OARs than WPRT. However, WPHT had poorer results for right and left side pelvic bone sparing than WPRT due to lacking of V10 and V20 constraint for planning initially.

Acute toxicity of radiation therapy within chemotherapy and late toxicity is detailed in Additional file 1. One grade 3 of acute toxicity for diarrhea, thrombocytopenia and three grade 3 of leucopenia were noted during CCRT. Only one grade 3 of subacute toxicity for thrombocytopenia was noted. There was no grade 3 or 4 subacute toxicities for anemia, leucopenia, genitourinary or gastrointestinal.