Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Proton therapy for gynecologic malignancies
Introduction
Each year more than 90,000 women are diagnosed with a gynecologic (ovarian, vulvar, vaginal, cervical, uterine, fallopian tube, or primary peritoneal) cancer in the United States. Radiotherapy is often used with curative intent with or without concurrent chemotherapy for locally advanced vulvar, vaginal, or cervical cancer. Women with high-risk features after surgery for cervical, uterine, or vulvar cancer may also receive adjuvant radiotherapy. The standard of care for women with locally advanced cervical cancer is external beam radiotherapy (EBRT) and intracavitary brachytherapy in conjunction with concurrent chemotherapy to increase local control and overall survival. For women with high-risk stage III/IV endometrial cancer, adjuvant pelvic or extended-field radiotherapy may be recommended, usually combined with systemic chemotherapy delivered either in a sandwich or sequential manner with or without concurrent radiosensitizing chemotherapy.
The target volume in women requiring pelvic radiotherapy includes the pelvic lymph nodes (obturator, external and internal iliac, and common iliac) as well as the presacral nodes in women with cervical cancer or those with endometrial cancer and cervical involvement. The primary target in women after hysterectomy includes the operative bed, which consists of the upper vagina and paravaginal tissues. For women with cervical cancer, the primary target would include the gross tumor volume, uterus, entire cervix, and parametrial tissues. The target would extend and cover the entire mesorectum with parametrial involvement. For women with involved or suspicious paraaortic lymph nodes, the field would extend to cover these nodes up to the level of the renal hilum.
EBRT was initially delivered with two or four fields to the pelvis or to the pelvis/paraaortic region, oftentimes with concurrent chemotherapy, for gynecologic cancers. Such a treatment combination can result in acute hematologic, gastrointestinal, and genitourinary toxic side effects as well as late morbidity. Recent randomized studies of intensity-modulated radiotherapy (IMRT) compared with three-dimensional conformal radiation therapy (3DCRT) for both uterine and cervical cancer after hysterectomy have demonstrated that IMRT can reduce the incidence of acute bowel toxicities. Importantly, acute hematologic toxicity in the setting of concurrent chemotherapy can result in dose reductions or delays in chemotherapy, which may result in compromised outcomes. Hematologic and gastrointestinal toxicities often limit the ability to deliver combined-modality therapy, as was observed when Duenas-Gonzalez et al. attempted to add weekly gemcitabine to weekly cisplatin concurrent with radiotherapy for locally advanced cervical cancer. Proton therapy for gynecologic malignancies has the potential to widen the therapeutic window and allow the testing of treatment intensification with novel therapies; it may also allow for potentially more conformal dose delivery and the possibility of dose escalation.
After hysterectomy
The radiotherapy technique for gynecologic malignancies has evolved in the last several decades. Initially, patients were treated with opposed fields or four-field conventional photon therapy, with fields defined by bony landmarks. With computed tomography (CT) imaging, the organs at risk (OARs) can be defined to reduce dose to nearby normal tissues. However, this still results in high doses of bowel irradiated. The recently completed NRG Oncology/Radiation Therapy Oncology Group TIME-C study (RTOG 1203) sought to test whether IMRT could reduce normal tissue toxicities in patients receiving posthysterectomy radiotherapy for either cervical or uterine cancer compared with 3DCRT. The primary end point was patient-reported bowel toxicity measured with the bowel domain on the EPIC (Expanded Prostate Cancer Index Composite) instrument. Results demonstrated that the EPIC bowel domain scores at 5 weeks of therapy for women receiving IMRT were higher (meaning less toxicity) than for women receiving 3DCRT. Given that smaller volumes of bowel receive radiation with protons, particularly in the low-dose region, it seems reasonable to test the hypothesis that proton therapy may further reduce bowel toxicity.
Lin et al. published the first clinical report on the use of pencil beam scanning (PBS) proton therapy for women who have undergone hysterectomy for either cervical or uterine cancer. In their series, 11 patients received PBS proton therapy using uniform scanning. They were treated using opposed lateral, two lateral and posterior, or two posterior oblique fields. Improved sparing in the low-dose region was noted for organs such as the small bowel, pelvic bone marrow, and bladder. Weekly or biweekly CT simulation scans were also obtained to confirm robustness relative to setup uncertainties.
Xu et al. reported on seven patients with endometrial cancer who were treated with PBS to an extended field to include the pelvis and paraaortic region. They demonstrated that dosimetrically, PBS resulted in lower volumes of exposed pelvic bone marrow, small bowel, and bladder. No significant (grade 3 or higher) toxicities were observed in this population. All patients were treated with two posterior oblique fields. These early studies demonstrate the feasibility of treating patients with proton therapy. Other prospective studies are ongoing. Fig. 11.1 shows a patient who received PBS proton therapy after radical hysterectomy for a FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stage IIB cervical carcinoma. She also had a pelvic kidney that necessitated proton therapy to minimize the dose to that kidney.
Intact cervical cancer
The use of brachytherapy is the standard of care in women with locally advanced cervical cancer receiving definitive chemoradiotherapy. Omission of brachytherapy has been associated with decreased survival. However, some rare situations may preclude the use of brachytherapy, such as a patient with bicornuate uterus (although interstitial brachytherapy may be an option), disease that obstructs the cervical os, or a patient who cannot tolerate sedation for the procedure. Arimoto et al. published the results of a series of 15 patients with gynecologic malignancies treated with high-energy proton beam radiotherapy in lieu of brachytherapy at Tsukuba University in the mid-1980s. Results at 2 years demonstrated local control rates and overall survival rates of 92.3% and 93.3%, respectively. All tumors were controlled if the dose was greater than 78 Gy. Two patients experienced transient radiation proctitis at 7 and 9 months after radiation. Clivio et al. also evaluated the use of intensity-modulated proton therapy (IMPT) in lieu of brachytherapy for locally advanced cervical cancer in a conceptual feasibility study. IMPT was planned with 5 fractions of 6 Gy to the cervix, including the macroscopic tumor as defined on magnetic resonance imaging (MRI) with a 5-mm margin. The doses to OARs, including the rectal wall, sigmoid wall, and bladder wall, were acceptable and within the dose constraints recommended by the GEC-ESTRO (Groupe Européen de Curiethérapie the European SocieTy for Radiotherapy and Oncology). , Given the toxicities associated with combined-modality therapy, it is reasonable to investigate radiotherapy techniques that would potentially reduce dose to OARs. Fig. 11.2 shows a representative example of a patient who was treated with PBS proton therapy for a FIGO stage IIIB cervical carcinoma. Posterior oblique beams were chosen with no exit radiation dose to the anterior abdominal organs. A multinational phase III study of concurrent cisplatin and gemcitabine with radiotherapy followed by consolidative cisplatin and gemcitabine for two cycles resulted in significantly higher toxicities and hospitalizations than the weekly cisplatin and radiotherapy, the standard of care. If we are to identify incremental improvements in combined-modality therapies for locally advanced cervical cancer, methods to reduce radiotherapy toxicities will be necessary.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here