Posttreatment Monitoring

INTRODUCTION

Posttreatment monitoring is an important phase of every gynecologic cancer patient’s care. Many patients will continue to have some treatment-related or tumor-related symptoms after treatment is completed; the anxiety caused by these symptoms is lessened if patients know what to expect and are counseled about which symptoms may require acute intervention. Also, close monitoring allows early detection of locoregional recurrences, increasing the likelihood of cure with salvage treatment.

The completion of treatment can be a jarring experience, particularly for patients who have been coming to the clinic daily for radiation treatments and who have developed close, supportive relationships with their caregivers. It is important for patients’ sense of well-being that they feel a sense of continuity between the care provided during treatment and the care provided after treatment. Even when the prognosis is excellent, most patients struggle with the uncertainties attached to a cancer diagnosis.

THE SURVIVORSHIP CARE PLAN

In its 2006 report, From Cancer Patient to Cancer Survivor: Lost in Transition, the Institute of Medicine recommended a series of measures for the quality of care delivered to cancer survivors (Table 9.1).¹ The first measure was “provision of a written posttreatment summary outlining the proposed follow-up plan.” The report also emphasized the importance of communication and coordination between oncologists and primary care providers. A well-articulated survivorship care plan that involves the patient and her providers promotes patient engagement and compliance with posttreatment recommendations and reduces the likelihood of duplicative care.² However, despite these recommendations, surveys suggest that most oncologists and primary care providers do not provide written summaries or even discuss the follow-up care plan with their patients.¹

Every patient should have a clearly defined plan for posttreatment monitoring. Patients and their providers should understand who will be responsible for various aspects of the patient’s care and how monitoring for recurrence (“cancer surveillance”) will be integrated with other aspects of the patient’s overall medical care needs. In the final phases of treatment, every patient should meet with members of her oncology care team to discuss the following questions:

Which provider (gynecologic oncologist, medical oncologist, radiation oncologist, other specialist, or the primary care provider) will be responsible for each aspect of the patient’s care, including posttreatment cancer surveillance, management of treatment-related adverse effects, pain management, management of non-cancerrelated medical problems, and routine cancer screening (e.g., screening for breast and colorectal cancer)?
What will be the frequency of surveillance visits and why?
What methods will be used for cancer surveillance?
When should the patient expect lingering treatmentrelated symptoms to resolve?
What symptoms should cause the patient to contact her provider before scheduled visits?
Assuming the patient does not develop recurrence or adverse effects that require special interventions, how long will she require monitoring by an oncologist, and how much of her cancer surveillance can be shared with her primary care provider?

TABLE 9.1 Potential Survivorship Quality of Care Measures (2006)

Processes of care

Provision of a survivorship care plan, a written posttreatment summary outlining the proposed follow-up plan
Assessment of psychosocial distress, referral to mental health providers
Assessment of employment, insurance, and financial issues, referral to rehabilitation and social work providers
Provision of written information on available community support services

Screening guidelines

Adherence to evidence-based follow-up and surveillance guidelines, where available

Survivorship interventions

Adherence to adjuvant therapy
Assessment and management of pain
When appropriate, referral to enterostomal care
When appropriate, referral for lymphedema management
When appropriate, assessment of sexual function and referral to sexuality counseling
When appropriate, referral to genetic counseling
Recommendation of exercise for fatigue
Smoking cessation counseling, if necessary

Survivor assessments of care

Ratings by survivors of their satisfaction with care, coordination of care, and quality of care

From Hewitt M, Greenfield S, Stovall E. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, DC: National Academies Press; 2006.

At the conclusion of treatment, the patient and her care providers (including her primary care provider) should be given a written summary of the treatment that the patient received and the plan for posttreatment monitoring.

The frequency and nature of follow-up visits should be customized to the patient’s specific problem list and informed by an understanding of the risks of tumor recurrence and treatment-related adverse effects. The following sections of this chapter address these aspects of follow-up care.

MONITORING FOR CANCER RECURRENCE

Early detection of locoregional recurrences that are potentially curable with salvage treatment is one of the most important goals of posttreatment surveillance. The most common types of locoregional recurrence potentially amenable to successful salvage treatment include the following:

Central recurrence after initial definitive surgical treatment. Radiation therapy (RT) or chemoradiation is the usual treatment for isolated central recurrence after definitive surgery unless definitive surgical resection can be accomplished without major organ compromise (CS 12.3, 13.8, 13.9).
Regional nodal recurrence after initial definitive surgical treatment. Isolated nodal recurrences are usually treated with chemoradiation (CS 12.10, 13.6, 13.7).
Nodal recurrence near the margin of RT fields. Depending on the size of the recurrence and its relationship with previous RT fields, marginal nodal recurrences after RT may be treated with RT or surgical resection followed by RT (CS 13.5, 15.3).
Isolated central uterine, cervical, vaginal, or vulvar recurrence near the margin of RT fields (CS 10.8, 12.9). Depending on the size and extent of the recurrence and its relationship with previous RT fields, isolated central recurrences after RT may be treated with radical surgery, radiation, or palliative chemotherapy.
Oligometastasis. Because most patients with distant metastases are incurable, the focus of their treatment is usually palliative (Chapter 16). However, in rare cases, isolated metastases in surgical scars, lungs, or other sites may be amenable to definitive targeted treatments (CS 13.9).

Specific approaches to the treatment of isolated locoregional recurrences are discussed in greater detail in individual disease-site chapters. This section focuses on studies of the time course of locoregional recurrence and recommendations for the monitoring of patients for recurrence after definitive treatment of gynecologic cancers.

How Long Are Patients at Risk for Developing Recurrent Disease?

In all cases of locoregional recurrence, the success of treatment depends on early detection. For this reason, the intensity of surveillance is greatest during the immediate posttreatment period when the risk of recurrence is greatest.

Central Recurrence

For most locally advanced gynecologic cancers treated with definitive RT, the risk of central disease recurrence is greatest during the first posttreatment year and then declines sharply; few recurrences occur after the 3rd year. However, patients who have been treated for human papillomavirus (HPV)-related cancers of the lower genital tract are at risk throughout their lifetime for developing intraepithelial neoplasia or new invasive cancers of the vulva, vagina, or cervix (if the cervix has not been removed).

In a 2006 MD Anderson Cancer Center study of 2,997 patients treated with definitive RT for stages I and II cervical cancer, Eifel et al.³ described the biphasic time course of central recurrences. In that study, the hazard rate peaked at about 8 months after treatment and then declined rapidly to a baseline of <1% per year by the 3rd year (Fig. 9.1a). After the 4th year, there was a low but continuous risk of between 0.2% and 0.5% per year that persisted beyond 30 years of follow-up. Most
of the recurrences occurring more than 3 years after treatment undoubtedly reflected the development of new HPV-related cancers. These late recurrences were the ones most likely to be treated successfully with surgery (usually pelvic exenteration) (Fig. 9.1b). These data suggest that patients who have been cured of locally advanced cervical cancer continue to have a greater risk of developing new preinvasive and invasive cancers of the lower genital tract than does the general population.

FIGURE 9.1 Time course of central disease recurrence (a) and overall survival after central disease recurrence (b) in 2,997 patients treated with definitive RT for stage I or stage II squamous carcinoma of the cervix between 1960 and 2001. All occurrences of invasive squamous carcinoma involving the cervix, paracervix, or vagina were scored as events. For patients with tumors ≥5 cm in diameter, the risk of recurrence was greatest in the first year and then declined rapidly (a). After 3 years (dotted line), the risk of recurrence was approximately constant, at a rate of 0.3% to 0.5% per year. For patients with smaller tumors, the risk of central recurrence averaged about 0.2% per year throughout the follow-up period, with only a small peak in the first 2 years. Patients who had recurrence 3 years or more after the completion of treatment had significantly better overall survival than patients who had recurrence before 3 years (b). The median follow-up duration for patients in this study was 104 months. Most patients did not have concurrent chemotherapy, which would be expected to decrease the central recurrence rate by 30% to 40%. (From Eifel PJ, Jhingran A, Brown J, et al. Time course and outcome of central recurrence after radiation therapy for carcinoma of the cervix. Int J Gynecol Cancer. 2006;16:1106-1111.)

The time course for central recurrence of vaginal or vulvar cancers treated with RT appears to be similar to that for central recurrence of cervical cancers treated with RT.⁴^,⁵

Patients who are treated with radiation for small cancers or with primary surgery for early invasive disease tend to have a constant very low annual risk of recurrence because treatment of the initial lesion is usually successful and most “recurrences” are actually new cancers. This pattern is reflected in the constant low risk of recurrence in patients with small cervical cancers treated with RT (Fig. 9.1a) and patients with early vulvar cancers treated with surgery (Fig. 12.2).

Because patients in the MD Anderson study mentioned above³ were treated between 1960 and 2001, most did not receive concurrent chemotherapy with RT, and none had follow-up positron emission tomography (PET) scans. These 21st-century advances in diagnosis and treatment would be expected to reduce the peak hazard rate and may shorten the mean time to recurrence if central recurrences are detected earlier by PET than by physical examination.

Most vaginal recurrences of endometrial cancer also occur within the first 3 years after hysterectomy. However, vaginal recurrences have been diagnosed as late as 5 to 10 years after hysterectomy, particularly in patients treated for low-grade adenocarcinoma (Fig. 13.3).⁶^,⁷

Nodal Recurrence

Although nodal recurrences are occasionally diagnosed more than 5 years after definitive treatment of gynecologic cancers, such late nodal recurrences are very rare. Of 2,949 patients treated for invasive cervical or vaginal cancers between 1985 and 2006 at MD Anderson, 289 had paraaortic or pelvic wall recurrences without evidence of central disease recurrences. Of these 289 nodal recurrences, 63% were diagnosed within the first year after diagnosis, 84% were diagnosed within 3 years, and 97% were diagnosed within 5 years (unpublished data). Most of these patients did not undergo routine surveillance imaging, and most were symptomatic at the time their nodal recurrences were detected.

The use of modern imaging, particularly PET-computed tomography (PET-CT), for diagnosis and surveillance is likely to alter these statistics. Retrospective studies suggest that regional recurrences are less frequent when RT plans are guided by PET imaging.⁸^,⁹ Evidence also suggests that patients who have routine surveillance imaging are more likely to have nodal recurrences detected at an earlier, more treatable stage than are patients with nodal recurrence diagnosed only after symptoms develop.¹⁰^,¹¹

Nodal recurrences tend to occur in sites of initial disease and at the upper margins of pelvic or extended pelvic RT fields.¹²^,¹³ Factors that are associated with a high risk of regional involvement are discussed in detail in Chapters 10,11,12,13 and 14.

Recommendations for Evaluation for Possible Tumor Recurrence

Both the Society of Gynecologic Oncologists (SGO) and the National Comprehensive Cancer Network (NCCN) have published guidelines for cancer surveillance in patients with gynecologic cancers.¹⁴^,¹⁵^,¹⁶ Their recommendations regarding the frequency of surveillance visits are similar
and reflect the need for closer surveillance during the initial posttreatment period, when the risk of recurrence is highest (Table 9.2).

TABLE 9.2 Suggested Guidelines for Posttreatment Surveillance¹⁴^,¹⁵^,¹⁶

Diagnosis, evaluation		Years after completion of treatment
Diagnosis, evaluation		1	2	3	4-5	>5
Endometrial cancer
Physical examination and symptom review
	Low risk of recurrence	Every 6 mo	Yearly	Yearly	Yearly	Yearly
	Intermediate risk of recurrence	Every 3 mo	Every 6 mo	Every 6 mo	Every 6 mo	Yearly
	High risk of recurrence	Every 3 mo	Every 3 mo	Every 6 mo	Every 6 mo	Yearly
Papanicolaou test		Not indicated
CA-125 measurement		SGO: “insufficient data to support routine use”; NCCN: “optional”
Diagnostic imaging
	No recurrence suspected	SGO: “insufficient data to support routine use”; NCCN: “optional”
	Recurrence suspected	CT or PET ± CA-125
Cervical, vulvar, or vaginal cancer
Physical examination and symptom review
	Low risk of recurrence, treated with surgery only	Every 6 mo	Every 6 mo	Yearly	Yearly	Yearly
	High risk of recurrence, treated with primary or adjuvant RT	Every 3 mo	Every 3 mo	Every 6 mo	Every 6 mo	Yearly
Papanicolaou test		Yearly	Yearly	Yearly	Yearly	Yearly
Diagnostic imaging
	No recurrence suspected	SGO: “insufficient data to support routine use”; NCCN: not recommended for routine surveillance^a
	Recurrence suspected	CT or PET (MRI in selected cases of suspected central recurrence)
^aPer NCCN, “A single PET-CT scan performed at 3-6 months after chemoradiation for locally advanced cervical cancer can be used to suggest early or asymptomatic persistence or recurrence. Other imaging studies (such as chest x-ray, CT scan, MRI, and subsequent PET-CT) may also be used to assess or follow recurrence when clinically indicated but are not recommended for routine surveillance.”
mo, months; SGO, Society of Gynecologic Oncologists; NCCN, National Comprehensive Cancer Network; CT, computed tomography; PET, positron emission tomography; MRI, magnetic resonance imaging; CA-125, cancer antigen-125.
National Comprehensive Cancer Network. Uterine Neoplasms (Version 2.2016). Available at http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed February 23, 2016; National Comprehensive Cancer Network. Cervical Cancer (Version 2.2016). Available at http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed February 23, 2016; Salani R, Backes FJ, Fung MF, et al. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol. 2011;204:466-478.

Physical Examination and Symptom Review

For detection of recurrent disease, both the SGO and NCCN place their greatest emphasis on physical examination and symptom review. For most gynecologic cancers, the hallmark symptoms for recurrence are bleeding, pain, and palpation of a new mass, although metastatic disease can present with a variety of symptoms according to the site of involvement. At the end of treatment and at each follow-up visit, patients should be counseled about symptoms that should prompt patients to schedule an appointment with their oncologist. Follow-up pelvic examinations should include careful inspection of the vulva, vagina, and cervix; bimanual examination; and rectovaginal examination, as discussed in Chapter 4.

Surveillance Imaging

Any patient who has symptoms or clinical findings that suggest possible recurrence should have an appropriately focused diagnostic imaging study, usually CT or PET-CT, although magnetic resonance imaging (MRI) is sometimes particularly valuable for assessment of vaginal or paravaginal abnormalities (Chapter 4).

The indications for imaging of asymptomatic patients are more controversial. Both the SGO and NCCN leave their
recommendations vague, although they agree that routine imaging of every gynecologic cancer patient is inappropriate (Table 9.2).¹⁴^,¹⁵^,¹⁶

Several studies have suggested that patients who have persistent or recurrent cervical cancer are more likely to be cured by salvage treatments if their disease is detected before it becomes symptomatic.¹⁰ These findings led the NCCN to suggest that patients with locoregionally advanced cervical cancer undergo a single PET scan at 3 to 6 months after completion of treatment to allow early detection of potentially treatable recurrences (Table 9.2).¹⁵ Because many insurers do not support more than one follow-up PET scan, the timing of the study is crucial. Ideally, the study should be done when it allows early detection of persistent disease without a high rate of false-positive findings due to post-RT tumor necrosis and inflammation. A modest delay after treatment increases the likelihood that early recurrences near the margins of pelvic RT fields will be detected. However, an overly long delay could miss the optimal window for definitive treatment. Investigators at Washington University, who have done much of the work evaluating the value of PET surveillance, have focused on follow-up PET scans obtained 3 months after RT. Their studies demonstrated that patients who had persistent fluorodeoxyglucose (FDG) uptake in initial sites of involvement were much more likely to have recurrence than were patients who had complete resolution of abnormal FDG uptake.¹⁷ However, in their study, about 30% of patients with persistent FDG uptake failed to have confirmation of progressive disease, and about 20% of patients who had negative findings on PET at 3 months did subsequently develop progressive cervical cancer (Fig. 9.2). We usually recommend performing PET 3 to 5 months after the end of treatment. However, more detailed studies are needed to determine the best timing of this study.

FIGURE 9.2 Relationship between progression-free survival and PET-CT findings 3 months after completion of definitive RT for cervical cancer. Patients who had no residual FDG uptake had significantly better survival than patients who had persistent FDG uptake. All patients who developed new FDG uptake after completion of RT had confirmed progression of their disease. The mean follow-up duration for the 92 patients in this study was 70 months. (Adapted from Schwarz JK, Siegel BA, Dehdashti F, et al. Association of posttherapy positron emission tomography with tumor response and survival in cervical carcinoma. JAMA. 2007;298:2289-2295.)

Neither the SGO nor the NCCN recommends routine imaging in any other setting. However, we believe there are a number of other situations that warrant routine surveillance imaging. The arguments for surveillance imaging of patients with locally advanced cancers involving the vagina are similar to those for follow-up imaging of patients with locally advanced cervical cancer, although MRI may play a more important role in patients with asymptomatic vaginal cancer than in patients with asymptomatic cervical cancer. Patients who have a significant risk of recurrence in unirradiated pelvic or paraaortic nodes are also good candidates for posttreatment imaging. This group includes patients treated with chemotherapy alone for stage IIIC endometrial cancer or with pelvic RT for stage IIIC1 endometrial cancer. These patients are frequently curable if nodal progression is caught early.¹³ On the other hand, there is probably less justification for routine surveillance imaging in patients who have already had full extended-field irradiation, because in-field recurrences can only very rarely be treated successfully. Ultrasound surveillance of groins that may be at risk for nodal recurrence may also be helpful in selected cases (CS 12.10).

Cytologic Screening

Papanicolaou (Pap) screening is no longer recommended for detection of recurrent endometrial cancer. This change followed several reports indicating that fewer than 5% of vaginal recurrences were detected by Pap screening in asymptomatic patients.¹⁸^,¹⁹ For similar reasons, Pap tests are no longer recommended for detection of recurrent cervical or vaginal cancer.²⁰^,²¹ The current recommendation for women who have been treated for HPV-positive cervical or vaginal cancer is for cytologic screening only once a year, in keeping with general cervical cancer screening guidelines. Pap screening should never be performed sooner than 4 months after RT because studies performed before this time are likely to show postradiation cytologic changes that can be misinterpreted as cancer or dysplasia.

As discussed earlier, there is a low but significant rate of locoregional recurrence of gynecologic cancer even after 5 years. By this time, patients are usually being followed by their primary care providers. For this reason, patients and their primary care providers should be reminded about the possibility of late recurrence and the continued need to evaluate any incidence of vaginal bleeding or protracted pelvic pain. Because of the increased risk of second gynecologic cancers, patients who have been treated for an HPV-related cancer should have annual Pap screening for life (Table 9.2).

MONITORING AND MANAGEMENT OF LATE ADVERSE EFFECTS OF TREATMENT

Because many patients with gynecologic cancer are cured, many survive to potentially experience late sequelae of cancer treatments. Most late radiation-related adverse effects occur during the first 3 years after RT; however, in some cases,
symptoms do not begin until many years later, when patients are no longer routinely followed by oncologic specialists. For this reason, it is important to use the first several years of more intensive surveillance to educate patients about the possible late adverse effects of RT and to encourage them to seek specialized care if symptoms develop.

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