Cervical Invasive – Primary Treatment with chemoradiation

Cervical carcinoma – Stage IB2 – IVA

1. What every clinician should know Are you sure your patient has disease? What should you expect to find?

Patients with carcinoma of the cervix usually present with abnormal bleeding or brownish discharge frequently noted after intercourse or occurring spontaneously between menstrual cycles. Other symptoms include pelvic pain, dyspareunia, bilateral ureteral obstructions with impending renal failure with no previous history of urinary symptoms, urinary frequency and urgency suggestive of early invasion of the bladder, and back pain. The triad of back pain, leg edema, and a non-functioning kidney is evidence of an advanced carcinoma with extensive pelvic wall involvement. Most patients diagnosed with invasive cervical cancer have not complied with recommended screening.

2. Diagnosis and differential diagnosis

Successful therapy for cervical cancer requires detailed evaluation of the patient’s general medical condition and the size and extent of disease. Previous surgical history, pelvic infections, medical illness (especially history of systemic auto-immune disease, ulcerative colitis, and diabetes), habits (including smoking history) and other conditions that may influence the patient’s tolerance of treatment and risk of complication should be carefully documented. An early assessment of the patient’s social circumstances is particularly important because women with cervical cancer often come from difficult social circumstances and have limited family support.

Physical examination is the most important part of the diagnosis and treatment of cervical cancer. The staging of cervical cancer is clinical and is based primarily on the physical exam, which should include careful inspection of the external genitalia, vagina and cervix. Biopsy of the lesion is needed to confirm diagnosis of the cancer. The exam should include a very thorough digital vaginal examination to determine any vaginal abnormalities, as well an initial assessment of the size and morphology of the cervical tumor. A rectovaginal examination should be performed to determine whether disease is involving the marametria, including the broad and uterosacral ligaments. The size of the cervical tumor is determined during this part of the exam.

Cystoscopy and proctoscopy are usually done if the patient is having symptoms suggestive of bladder or rectal involvement or if there is suggestion of involvement from imaging. All patients should have complete blood count to look for anemia, measurement of serum electrolytes, blood urea nitrogen, and creatinine levels at the time of diagnosis.

Chest X-ray and intravenous pyelography are the only radiographic examinations that can be used to determine the patient’s FIGO staging. However, other imaging studies are important to determine treatment and prognosis for patients with locally advance cervical cancer. Both MRI and CT scans are equally effective in diagnosing positive nodes; however, MRI is superior to CT scans in the evaluation of tumor location, tumor size, depth of stromal invasion, vaginal extension and parametrial extension of cervical cancer. Recently studies have found that positron emission tomography (PET) is more sensitive and specific for nodal involvement then either CT or MRI and is the preferred study to determine nodal involvement as well as to determine distant metastasis. Surgical staging remains the gold standard to determine nodal involvement.

3. Management

A. What therapies should you initiate immediately ie, emergently?

If a patient is actively bleeding and is anemic, the patient should be packed vaginally, admitted to the hospital and transfused. If the bleeding does not stop, then emergent radiation therapy may be initiated to help control the bleeding. If the patient has severe hydronephrosis, the affected kidney should be compressed via stent or nephrostomy placement.

B. What should the initial definitive therapy for the cancer be?

Patients with early stage tumors most often undergo surgical removal, but radiation remains a viable alternative in all patients. Age comorbidities and performance status of the patient should be considered when deciding the optimal therapy. Patients who have microinvasive cancers can have extrafascial hysterectomy or even conization. The depth of invasion, tumor size and lymphvascular space involvement (LVSI) determines if lymphadenectomy is required. Once a tumor is IA2 and beyond lymph node, resection is necessary if the choice of definitive therapy is surgical.

Patients with stage IB2 and minimal stage IIA are considered technically resectable and the ideal management of these tumors is a subject of considerable controversy. The approach of these tumors varies from center to center. In a randomized trial, Landoni and colleagues found equal survival in patients with stage IB2 treated with either definitive radiation therapy or radical surgery. However, 84% of patients who had surgery received post-operative radiation therapy and had a higher complication rate. Most clinicians opt for chemoradiation with tumors 5 cm or greater, as the rate of significant complications from radical hysterectomy followed by the need for adjuvant chemoradiation exceeds 10%.

Even though radiation therapy is effective in patients with stage IB2 disease, up to 8-10% of patients with bulky disease experienced central disease recurrence. This led investigators to evaluate the use of extrafascial hysterectomy. However, a large randomized study reported by Key and colleagues found no difference in overall survival in patients treated with extrafascial hysterectomy compared with patients who did not receive extrafascial hysterectomy when concurrent chemotherapy was used. In fact, recent studies show that chemoradiation therapy should be considered the standard treatment for majority of patients with stage IB2 and stage IIA disease. The role of surgical debulking of enlarged lymph nodes is not clear, but if nodes are larger than several centimeters, it should be considered and should be done extra-peritoneally to reduce comoplications with radiation therapy is added.

Chemoradiation therapy is the primary treatment for patients with stage IIB-IVA disease. The success of treatment depends on a careful balance between external beam (EBRT) and brachytherapy that optimizes the dose to the tumor and normal tissues and on the overall duration of treatment. Studies have shown that protraction of treatment beyond 7-8 weeks reduces the probability of pelvic disease control.

Radiation therapy is delivered in two parts, including EBRT and brachytherapy. External beam pelvic fields include the cervix and paracervical tissues, including the broad ligaments and uterosacral ligaments as well as nodes at risk, including the obturators, external iliac, internal iliac, common iliac and pre-sacral nodes. Doses of 45-50 Gy are usually delivered in 5 weeks to treat microscopic disease and to shrink the primary tumor.

High-energy photon beams are used to spare superficial tissues and most patients are treated with a four-field technique (anterior, posterior and two lateral fields). Pelvic fields have an upper border at L4/L5 to cover primary-echelon lymph nodes with a margin; however if the patient has positive common iliac nodes, the top border should be the top of L2 and if the patient has positive para-aortic nodes, the top of the field should be T12. Patients with positive nodes should have get a boost after 45 Gy to take the positive nodes to 60-66 Gy.

Brachytherapy is usually delivered using after-loading applicators that are placed in the uterine cavity and vagina. Brachytherapy can be delivered either at a low-dose rate (LDR) (40-60 cGy/hr) or high-dose rate (HDR) (less than 100 cGy/hr). The advantage of HDR brachytherapy is that it can be done entirely on an outpatient basis. Factors including optimizing applicator position, balanced use of external beam therapy and brachytherapy, compact overall treatment duration and delivery of an adequate dose to tumor while respecting normal tissue tolerance limits are critical for success when using either LDR or HDR brachytherapy.

To get optimal recovery of normal tissue, HDR brachytherapy is delivered in 4-6 fractions in the United States. Patients should be examined regularly to determine when to start brachytherapy. Brachytherapy should be considered as soon as the tumor diameter is 4 cm or less, especially when using HDR brachytherapy to keep the overall treatment to time 8 weeks or less.

Dose prescription for brachytherapy presently in the United States is still based on ICRU Report 38 (International Commission on Radiation Units and Measurements, 1985) reference points, including Point A, which represents the para-central dose and lies approximately at the crossing of the ureter and uterine artery. The ultimate goal is to get an 80-85 Gy low dose equivalent to point A, combining doses from external beam and brachytherapy.

During the last decade, image guided adaptive brachytherapy has been used to tailor treatment and hopefully increase local control and decrease long-term side effects. One study from Vienna showed better outcomes with the use of image-based brachytherapy with fewer side effects compared with earlier patients not treated with image-based guidance. However, larger studies are needed to show a clear benefit for image-based brachytherapy.

In 1999, the NCI issued an alert stating that all patients with locally advanced cervical cancer should be treated when possible with concurrent chemotherapy and radiation therapy. This was issued after 5 pivotal trials showed that concurrent (platinum-based) chemotherapy and radiation therapy was better than radiation therapy alone in the treatment of locally advanced cervical cancer. Since that time, a meta-analysis of 18 randomized trials confirmed that chemoradiotherapy is better than radiation therapy alone in the treatment of locally advanced cervical cancer; however, the concurrent chemotherapy does not have to be platinum based and that there may be a benefit for the use of adjuvant chemotherapy as well.

In the United States, the standard treatment for locally advanced cervical carcinoma is weekly cisplatin at 40 mg/m2 with radiation therapy. However, a large randomized trial currently underway is evaluating the use of adjuvant chemotherapy in addition to concurrent chemotherapy and radiation therapy in this group of patients.

4. Complications

A. What complications could arise as a consequence of condition? Are there strategies to lower risk of complications?

Anemia is probably the most common consequence of cervical cancer and should be treated with transfusions. Several studies have shown that patients with hemoglobin lower than 10 have higher local relapses than patients with hemoglobin higher than 10. Also, vaginal packing and emergent start of radiation therapy may reduce active bleeding initially. If there is only minor bleeding, ferric subsulfate solution (Monsel’s solution) at the time of the exam may help reduce the bleeding.

Blockage of ureters (hydronephrosis) due to disease is another common consequence of locally advanced disease. This should be treated either with stents or nephrostomy tubes, especially if renal function is affected. Poor renal function can limit the use of platinum-based chemotherapy during treatment and therefore should be addressed up front.

Pain is another common consequence of locally advanced cervical cancer and its management is crucial for patients’ quality of life. Radiation therapy will help with the pain but it takes time to be effective. Pain medications are useful but having a good symptom management team to help definitely improves care of the patient. Pain medications increase the incidence of constipation, which may already be an issue due to disease, and stool softeners as well as mild laxatives may help manage this problem.

Advanced cancer locally can result in fistulas such as vesico-vaginal and recto-vaginal.

B. What complications could arise as a consequence of the management – chemo, radiation and surgical?

Complications can be broken down to acute complications (complications occurring during treatment) and late complications (complication occurring after treatment).

Acute complications can occur from external beam treatment, brachytherapy and chemotherapy. Common complications from chemotherapy include nausea/vomiting, which can be controlled with anti-nausea medication, and ringing in the ear and hearing loss (controlled with stoppage of the chemotherapy). Most patients will experience at least some diarrhea during external beam irradiation which can be controlled with oral medications and dietary modifications. Less frequently, patients may complain about bladder or urethral irritation, which can be controlled with phenazopyridine hydrochloride or antispasmodics after urinalysis and urine culture has ruled out an urinary tract complication. Complications from brachytherapy are less common but include uterine perforation, vaginal laceration and thromboembolic events.

Late complications from radiation therapy involve the rectum, bladder or small bowel. Overall estimates of the risk of major complications of radiation therapy usually range between 5-15%. Most serious gastrointestinal complications occur with the first 3 years, whereas the average time to onset of major urinary tract complications tend to be somewhat longer than that. The most common serious late complications involve bleeding from the bladder or rectum. The risks of developing hematuria or hematochezia severe enough to require transfusion were 2.6% and 0.7% in 5 years in a large series from M.D. Anderson Cancer Center. The overall risk of developing a gastrointestinal or urinary fistula was 1.7% at 5 years, with an increased risk for patients who underwent adjuvant hysterectomy or pretreatment transperitoneal lymphadenectomy.

The risk of small bowel obstruction is strongly correlated with a number of patient characteristics, including patients size (thinner patients are at a higher risk of complications), history of pelvic infection, smoking history, as well has pelvic radiation doses that are higher than 50 Gy. Patients treated with radiation for cervical carcinoma tend to have varying degrees of atrophy, telangiectasis or scarring of the upper third of the vagina. Mild to moderate apical vaginal ulceration or necrosis occurs in 5-10% of patients treated with cervical cancer. The true incidence of vaginal shortening is unknown; however, severe shortening is more common in postmenopausal patients, patients who are less sexually active and patients with more advanced disease at presentation.

All women treated with definitive radiation therapy to the pelvis undergo menopause unless ovaries have been transposed and are out of the radiated field. Therefore, they will undergo all complications of menopause, including hot flashes, mood swings, decrease libido, vaginal dryness and decreased bone density. Studies have reported a 3-10% incidence of spontaneous bone fractures in the treated field.

C. What other therapies are helpful for reducing complications?

In general, higher energy radiation sources and use of intensity-modulated radiation therapy (IMRT) reduce complications. Also, trying to avoid using radiation after laparotomy is helpful in the prevention of complications. Treatments of complications differ depending on when the complications occur. During treatment complications are usually due to the chemotherapy or external beam radiation therapy. For the nausea/vomiting due to weekly cisplatin, an anti-emetic should be used on a routine basis, as it is better to prevent then wait for the nausea to occur. Ondansetron or its equivalents are good anti-emetics to start with.

Diet modification with reduction in fiber as well as loperomide or diphenoxylate/atrophine help control diarrhea that usually occurs starting the in the 3rd to 4th week of external beam radiation therapy. Phenazopyride hydrochloride or any antispasmodics will help with urinary frequency and burning. Patients who smoke should be strongly encourage to stop to help reduce their risk of complication and disease recurrence, and smoking cessation programs should be recommended to patients.

After treatment, pre-menopausal women should be considered for replacement hormones (a combination of estrogen and progestin) to help with menopausal syndromes as well as to reduce the risk of osteoporosis. Estrogen vaginal cream will help heal the vagina after radiation therapy and will also help with vaginal dryness. All women should take multi-vitamins as well as calcium and vitamin D to help prevent osteoporosis. Vaginal dilators used on a regular basis (at least twice a week) and/or regular sexual intercourse will help reduce the risk of vaginal shortening as well as dyspareunia.

5. Prognosis and outcome

A. What would you tell patient and family about the prognosis?

Cervical carcinoma is a very curable disease if found early and treated correctly. The goal of treatment with a combination of external beam radiation therapy, chemotherapy and brachytherapy is to cure the patient. The cure rate is dependent on FIGO stage, tumor size, nodal involvement, histology, grade, and patient related factors, as well as the quality and length of treatment.

Patients with FIGO stage IB2 disease have 5-year survival rates ranging form 70-90%, depending on the size of the disease. Eifel and colleagues reported 5-year disease-specific survival rates of 90%, 86% and 67% in patients with stage IB tumors with cervical diameters of less than 4 cm, 4-4.9 cm, and 5 cm or more, respectively. The 5-year survival rates of patients with stage IIA disease range from 70-85%, and like survival rates for patients with stage IB2 disease, the survival rates are very dependent on tumor size.

Five-year survival rates of 65-75%, 35-50% and 15-20% have been reported in patients with stage IIB, IIIB and IV tumors respectively, treated with radiation therapy alone. The addition of platinum-containing regimens may further improve local control and survival. However, both local control and distant disease recurrence remain common problems in patients with stage IIIB and IVA disease. Survival rates for patients with positive para-aortic nodes are half those of patients with similar stages of disease without para-aortic lymph node involvement. An increased number of positive nodes and the size of nodes also affect survival.

B. "What if" scenarios

Brachytherapy plays a critical role in the treatment of cervical cancer. Multiple studies have shown that outcomes worsen if brachytherapy is not used. A recent patterns of care study showed a decrease in the use of brachytherapy in the treatment of cervical cancer, particularly in nonacademic centers. Another recent study by Han et al that shows a significant decline in the use of brachytherapy in the treatment of cervical cancer also revealed that patients who were treated with combined external beam and brachytherapy had a significantly better overall survival than those treated with EBRT alone (65% and 50%, respectively).

It is very important that patients with locally advanced cervical cancer be treated with a combination of chemotherapy/EBRT and brachytherapy to achieve the best results, and patients need to be referred to centers that can deliver all three of these treatments expertly.

Fertility preservation is an important consideration in young patients. Onco-fertility counseling should be performed, and these patients should be offered options such as radical trachelectomy for small tumors confined to the cervix or egg, or embryo freezing or ovarian transposition in cases of more advanced tumors.

6. Follow up surveillance and therapy management of recurrences

Patients should be followed every three months after treatment with pap smears for 2 years. It is recommended to get a PET/CT 3-6 months post-treatment. After 2 years, it is recommended that patients be followed every 6 months for additional 3 years, and then annually for the rest of their lives. Pap smears and pelvic exams are recommended with each follow-up visit. Additional imaging is recommended depending on symptoms. Therapy for recurrent disease is discussed in the chapter for treatment of recurrent disease.

7. What is the evidence for specific management and treatment recommendations?

Eifel, PJ, Jhingran, A, Atkinson, HN. “Correlation of smoking history and other patient characteristics with major complications of pelvic radiation therapy for cervical cancer”. J Clin Oncol. vol. 20. 2002. pp. 3651-7. (One of the few studies that shows the long term side effects of radiation therapy, including rates and causes.)

Eifel, PJ, Winter, K, Morris, M. “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. vol. 22. 2004. pp. 872-80. (One of the pivotal chemoradiation trials – this an update of the original trial.)

Vale, C, Tierney, JF, Stewart, LA. “Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials”. J Clin Oncol. vol. 26. 2008. pp. 5802-12. A meta-analysis of all the chemoradiation trials showing that chemoradiation therapy is beneficial in the treatment of locally advanced cervical cancer; however, the benefit is not as high as expected in stage IIIB patients.)

Keys, , HM, Bundy, BN, Stehman, FB. “Cisplatin, radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma”. New Engl J Med. vol. 340. 1999. pp. 1154-61. (Another pivotal article to showing chemoRT was better than radiation therapy alone. Also in this article, adding hysterectomy did not increase survival.)

Potter, R, Georg, P, Dimopoulos , JC. “Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer”. Radiother Oncol. vol. 100. 2011. pp. 116-23. (One of the first articles showing the advantage of image=based brachytherapy.)

Han, K, Milosevic, M, Flyes, A. “Trends in the utilization of brachytherapy in cervical cancer in the United States”. Int J Radiat Oncol Biol Phys. vol. 87. 2013. pp. 111-9. (Recent study that shows a decline in the use of brachytherapy in the treatment of cervical cancer with a decrease in survival in patients that it was not used in.)

Landoni, F, Maneo, A, Colombo, A. “Randomised study of radical surgery versus radiotherapy for stage Ib-IIA cervical cancer”. Lancet. vol. 350. 1997. pp. 535-40. (A pivotal paper for the treatment of patients with stage IB2 cervical carcinoma.)

Grigsby, PW, Siegel, BA, Dehdashti, F. “Lymph node staging by positron emission tomography in patients with carcinoma of the cervix”. J Clin Oncol. vol. 19. 2001. pp. 3745-9. (First paper to really show the benefit for the use of PET in the staging and treatment of cervical carcinoma.)

Fyles, A, Keane, TJ, Barton, M. “The effects of treatment duration in the local control of cervix cancer”. Radiother Oncol. vol. 25. 1992. pp. 273-9. (One of several studies that show that treatment time is so important in the treatment of cervical carcinoma.)

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