Palliative radiotherapy for gynecologic malignancies

Introduction

The five primary gynecologic malignancies (vulvar, vaginal, cervical, uterine, and ovarian) accounted for 12.2% ( n = 109,000) of new cancer diagnoses and 11.6% ( n = 33,100) of cancer deaths in American women in 2019. Uterine cancers are most commonly diagnosed ( n = 61,880), followed by ovarian ( n = 22,530) and cervical cancers ( n = 13,170). Five-year relative survival rates in the metastatic setting are 16% to 29% depending on primary gynecologic site. Treatment options vary based upon diagnosis, stage at presentation, comorbidities, and clinical symptoms. In locally advanced, recurrent, and metastatic disease, tumor burden may cause significant local symptoms related to mass effect, invasion of lymphatics or blood vessels, and adjacent organ invasion, including organs, bone, muscle, and nerve. While this chapter focuses on palliative radiotherapy (RT) for gynecologic cancers, a variety of options exist to address these symptoms. The Society of Gynecologic Oncology’s (SGO) position statement emphasizes a collaborative approach to address the physical, psychosocial, and existential needs of patients early in diagnosis and disease management. With this in mind, comprehensive palliative management decisions are made in the context of patient-specific factors, including performance status, age, socioeconomic challenges, comorbidities, stage, histology, life expectancy, symptom burden, response to prior therapy, risk of toxicity, and goals of care. ^, The SGO recommends early palliative care for all women with advanced or recurrent gynecologic cancers. ^, Fig. 16.1 shows an ideal model of resource allocation in cancer care.

Common histologies

The most common histologies encountered by primary site are summarized in Table 16.1 below.

Initial workup and indications for palliative radiation

Palliative RT is able to quickly treat symptoms that negatively impact a patient’s quality of life. In gynecologic cancers, these are commonly pain, bleeding, and obstruction. The initial assessment of any patient with a symptomatic cancer burden begins with their history and physical.

• Pain is encountered in a majority of cancer patients and is often multifactorial, resulting from nerve impingement, tumor invasion of soft tissues and muscle, bone pain from lytic lesions, and obstruction. Pain syndromes can be nociceptive, including somatic and visceral, or neuropathic. Etiology is often suggested by patient-reported symptoms. Neurologic examination should be performed on all patients presenting with new pain syndromes. Bone and soft tissue metastases are often associated with pain. Bone disease is infrequent in gynecologic cancers but is most often associated with cervical and uterine cancers. Positron emission tomography (PET), magnetic resonance imaging (MRI), or computed tomography (CT) can assess both bony and soft tissue structures, and bone scan for overall metastatic bone disease burden.

• Acute vaginal bleeding can be encountered in vulvar/vaginal, cervical, endometrial and cuff recurrence of ovarian cancers. Bleeding is assessed with a pelvic exam using a speculum for direct visualization. Counting of saturated maxi pads or weighing soiled items is recommended to aid in quantifying blood loss. Complete blood counts, coagulation panels, and a type and screen are collected for any patient presenting with acute vaginal bleeding. Imaging with CT angiography may aid in identifying bleeding vessels for embolization and/or to rule out intra-abdominal bleeding.

• Obstruction is a complication encountered at various anatomic sites, including bowel, lower urinary tract, and lymphatics. Malignant bowel obstruction is a hallmark of ovarian cancer. Ureteral obstructions appear in nearly 25% of locally advanced cervical cancer. Bulky lymphadenopathy from vulvar/vaginal, cervical, or advanced endometrial cancers contributes to lymphedema. Physical exam and imaging most often guide the practitioner on next steps, including CT with oral contrast for bowel evaluation and renal ultrasound and/or contrast CT for evaluation of hydroureteronephrosis and pelvic tumor burden. In case of bowel obstruction, electrolytes and lactate are important baseline lab values. Creatinine is followed for patients with suspected urinary tract obstruction. Lymphatic obstruction is often diagnosed with history and physical, though evaluation of serum albumin may be useful in differentiating anasarca from lymphedema.

Tools for prognostication

Clinician prediction of survival (CPS), the most common method used to estimate survival, is inaccurate and can impact delivery of the most appropriate care. As such, physicians are recommended to utilize objective predictors of outcome to inform management decisions.

While no prognostic tools have specifically been validated for gynecologic malignancies, a variety of models exist for patients with metastatic disease. With this in mind, Simmons et al. conducted a systematic review of prognostic tools in patients with advanced cancer and identified seven across different care settings. The authors concluded that while the Palliative Performance Scale (PPS, six parameters) was the most studied and predictive of survival, the Glasgow Prognostic Score (GPS, two parameters) was the most favorable in terms of its simplicity and prognostic value. Other evaluated measures include the Palliative Prognostic Score (PPrS, six parameters) and Palliative Prognostic Index (PPI, nine parameters).

Of note, factors comprising these tools include ambulation status, activity level, evidence of disease, self-care, oral intake, level of consciousness (PPS), C-reactive protein (CRP) and albumin levels (GPS), dyspnea, anorexia, Karnofsky Performance Status (KPS), CPS, leukocyte count, lymphocyte percentage (PPrS), and PPS, plus oral intake, edema, resting dyspnea, and delirium (PPI).

In summarizing an international prognostication workshop, Hui et al. note the Objective PPrS, Objective Prognostic Score, the Prognosis in Palliative Care Study (PiPS) model, and PRONOPALL as potentially useful measures of prognostication.

Review of studies: Palliative radiation therapy regimens

Multiple evidence-based gynecologic-specific radiation therapy (RT) regimens address locally advanced and metastatic gynecologic malignancies. They differ by timing of treatment, dose, modality, and fractionation but align appropriately in the usage of hypo-fractionated regimens, which are quick, less costly, and generally safe. Table 16.2 summarizes the highest-quality evidence available.

High-dose single fraction (10 Gy × 1)

An early and simple regimen includes the delivery of 10 Gy in 1 fraction to the whole pelvis.

Boulware et al. from MD Anderson Cancer Center delivered 10 Gy to the whole pelvis of 111 patients with locally advanced and metastatic gynecologic malignancy in 1979. When feasible, the treatment was delivered up to three times with intervals of 3 to 4 weeks. Of the 86 patients evaluated, the “best palliation” was seen in those who received three fractions ( n = 23), which yielded a disappearance of 75% to 100% of clinical signs/symptoms. As expected, two fractions ( n = 43) improved palliation compared to a single fraction ( n = 45). Nineteen percent (16/86) of patients had 50% to 75% reduction in tumor size after one fraction. Sixty percent of patients receiving a second fraction (33/55) had further regression, and 50% of those receiving a third fraction (10/20) had complete regression of pelvic tumor. Median survival was 3, 7, and 9 months in those receiving one, two, and three fractions, respectively. Acute complications were reported to be minimal, including vaginal mucositis, pelvic fibrosis, cystitis, and proctitis (grade not reported). Notably, late hemorrhagic proctitis or cystitis occurred in four patients, three of whom received the full 30 Gy. The authors thus concluded that the safest and most effective dose may be one to two fractions. The best responses were seen in those with tumors of the cervix, vagina, and vulva compared to uterine and ovarian cancers.

A subsequent Phase I/II trial, RTOG 7905, reported in 1987 on 46 patients with advanced pelvic cancers (43% gynecologic) utilized three fractions of 10 Gy with concurrent misonidazole (a radiosensitizer). 80.4% (37/46) patients received all three treatments. Of 37 evaluable patients, 6, 10, and 19 achieved complete, partial, and minimal/no response, respectively. The trial was stopped early due to increased rates of late gastrointestinal (GI) toxicity attributed to RT (11% grade 3, 19% grade 4, projected 49% grade 3 or 4 by 1 year).

Additional single-institution experiences adopting this regimen were published in the 1980s. Hodson et al. in Canada treated 27 patients with advanced gynecologic cancer with the same regimen (fractions repeated monthly) and demonstrated good tolerance and effective palliation. Complete response was in approximately one-third. Chafe and colleagues from the University of North Carolina (UNC) reported similar findings in 30 patients. Palliation of bleeding was achieved in all patients within 1 to 2 fractions, pelvic tumor size decreased in all patients, and progressive uropathy was halted in 70% of patients. Acute complications were minimal. Longer follow-up data from UNC with 42 patients noted 60% complete bleeding cessation (only 27% were permanently free of bleeding), 22% complete pain relief, and 25% tumor control rate at 6 months (reduced to 14% with median follow-up of 1 year). Five serious, adverse events were documented (one sacral ulcer, three fistulas, and one soft tissue necrosis), four of which were after 10 months of treatment. Contrary to the initial MD Anderson Cancer Center (MDACC) report, no correlation was documented between outcomes/toxicities and total fractions received. The authors ultimately concluded that the regimen would be most effective in those with life expectancies less than 1 year.

More recent data has been published utilizing high-dose radiation without the use of a radiosensitizing agent. A study from Norway published retrospective findings in 2001 ³³ of this regimen directed towards 64 patients with cervical and uterine cancer with estimated life expectancies less than 1 year. Vaginal bleeding and malodorous discharge ceased in 90% and 39% of patients, respectively. Twenty-two percent of those with advanced disease had complete tumor responses. Median time to progression was 6 months, and median survival was 9 months. Thirty-three percent had only minor GI toxicities, and 6% had serious late bowel complications 9 to 10 months post-treatment, one of which was fatal.

In the above studies, treatment was typically delivered with anteroposterior/posteroanterior (AP/PA) beams (see Fig. 16.2 below) or with a “four-field box” technique. The four-field borders include L5/S1 interspace superiorly, the lower aspect of the obturator foramen inferiorly, and 1 to 2 cm lateral to the pelvic brim. Field size was typically limited to 15 × 15 cm to spare bowel toxicity but was enlarged to 18 × 18 cm for nodal or vulvar/perineal coverage. Repeat fractions were delivered up to three times every 4 weeks with reduced field size (12 × 12 cm) for regressing disease. Modern RT can allow comparable doses with improved organ sparing.

The above data led to the development of a prospective randomized open label Phase III study at Tata Memorial Hospital (Rapid Palliation in Locally Advanced Cervical Cancer: A Phase III Randomized Trial, NCT03997110) that evaluates pain relief in patients with locally advanced cervical cancer. This is study is offered to patients who are not candidates for definitive chemoradiation or whose survival is expected to be less than 12 months. The study compares 10 Gy in one fraction every 3 weeks (up to three treatments) against a second arm delivering 25 Gy in 5 fractions with subsequent brachytherapy for those with almost clinical response. Patients in the first arm are eligible for brachytherapy after the second fraction if they demonstrate an almost complete clinical response.

This regimen’s convenience and high response rates with respect to bleeding, discharge, and pain is counterbalanced by significant late abdominopelvic toxicities (90% within 12 months). The data suggest its most appropriate usage is in those with limited life expectancy (less than 1 year).