Monitoring of the patient with classic Hodgkin lymphoma during and after treatment

INTRODUCTION — Patients with Hodgkin lymphoma (HL, formerly called Hodgkin's disease) are evaluated at the time of initial presentation to determine the stage of the disease, which is then used to determine whether the patient will be treated with radiotherapy, chemotherapy, or both. Patients are then re-evaluated at regular intervals during and after treatment to assess the response and detect possible recurrence. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

The recommended approach to monitoring during and after therapy for HL will be reviewed here. The treatment of patients who develop recurrent disease depends on their initial therapy. These issues are discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

DURING TREATMENT — The patient evaluation after individual treatment cycles consists of a history and physical examination, laboratory studies, and imaging studies.

History — The history should be directed toward the presence or absence of B symptoms (fever, weight loss, and night sweats) or treatment-related toxicity (see "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Clinical presentation'). Performance status should be recorded after each treatment cycle. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

Physical examination — The physical examination should document both the reduction in size of previous sites of lymphadenopathy and the continued absence of involvement of previously unaffected sites. This is particularly important with cyclical chemotherapy, which may be discontinued or changed if the patient fails to show objective evidence of response.

Laboratory studies — Complete blood counts, serum electrolytes, and liver function tests are followed with each cycle of chemotherapy treatment. Therapy should be altered based on these findings.

Radiologic studies — The combination of computed tomography (CT) scans and positron emission tomography (PET) is the current preferred approach to radiologic work-up of patients with HL [1-7]. Checking a PET/CT mid-treatment is controversial, but often done in clinical practice. While it is clear that mid-treatment PET/CT provides prognostic information, there is only limited prospective data to guide patient care based on the results. Additionally, there is controversy regarding the interpretation of PET/CT scans and what constitutes a positive or negative scan in this scenario. The prognostic value of mid-treatment PET/CT is discussed here with a focus on early stage disease. Response adapted therapy for advanced stage HL is discussed separately. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'Response adapted therapy'.)

Studies are in progress to determine whether mid-treatment PET scanning can be used to determine whether or not adjuvant involved-field radiation is needed in individual patients with early stage disease, or to modify the treatment approach in patients who continue to have PET-positive disease after one or more courses of chemotherapy. As examples:

●In the randomized EORTC H10 trial, patients with early stage HL and a positive PET scan after two cycles of chemotherapy received further chemotherapy plus radiation therapy (RT) while those with a negative PET scan were randomly assigned to receive chemotherapy alone versus chemotherapy plus RT [8]. An initial analysis demonstrated higher recurrence rates in patients who were PET negative after two cycles of ABVD and did not receive RT. The trial closed the chemotherapy alone arm due to stopping rules.

●In the UK RAPID trial, 420 patients with early stage non-bulky HL determined by pre-treatment CT scan who achieved a negative PET scan after three cycles of ABVD chemotherapy were randomly assigned to receive 30 Gy involved-field RT or no further therapy [9]. The 145 patients with a positive PET scan received a fourth cycle of ABVD plus involved-field RT. Among those with a negative mid-treatment PET, the addition of RT resulted in a lower rate of disease progression (3.8 versus 9.5 percent; three-year progression-free survival 94.6 versus 90.8 percent) and a higher rate of death without disease progression (2.4 versus 0.9 percent). Further follow-up is needed to evaluate for long-term toxicities and for more mature survival data.

These data suggest that PET scanning can identify patients who are candidates for chemotherapy alone. While disease control with combined therapy is superior compared with chemotherapy alone, this must be weighed against the risks of RT including cardiac disease and secondary malignancies, particularly in young women who are at high risk for the development of breast cancer after chest irradiation. The use of chemotherapy alone for patients with early stage HL is discussed in more detail separately. (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma", section on 'Chemotherapy alone'.)

Although in patients with advanced stage disease PET scanning at the end of treatment is prognostic for frequency of recurrence, its importance in early stage patients who are to receive RT is less clear. Several studies have evaluated the role of PET after completion of treatment:

●A prospective study of 260 patients with newly diagnosed advanced stage HL underwent PET scanning after two cycles of ABVD [6]. Approximately half of these were combined PET/CT scans and half were dedicated PET scans. Treating physicians were blinded to PET results. No treatment change was allowed on the basis of these scans and patients finished chemotherapy with or without RT as initially planned. The two-year progression-free survival was significantly lower for patients with a positive PET scan (13 versus 95 percent).

●A second study of 81 patients examined the predictive value of PET scans performed after the completion of Stanford V chemotherapy but before the initiation of planned RT [10]. Again, some scans were performed with a combined PET/CT scanner and some were performed with a dedicated PET scanner. At a median follow-up of four years, freedom from disease progression was statistically lower in patients who had positive PET scans after chemotherapy but before RT (33 versus 96 percent).

Monitoring for chemotherapy-specific toxicities — Throughout the course of treatment, patients should be monitored periodically for chemotherapy-related toxicities that may affect the treatment course, specifically vinblastine-induced neuropathy and bleomycin-induced pneumonitis. In addition, BEACOPP and particularly escalated BEACOPP are associated with progressive cytopenias due to cumulative myelotoxicity.

Neuropathy — Neuropathy is an uncommon yet potentially serious complication of vinblastine administration. The neuropathy can involve both motor and sensory neurons and often presents with paresthesias in the fingertips and feet, with or without muscle cramps. Constipation is also frequently seen. The diagnosis of vinblastine-associated neuropathy is discussed in more detail separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Other vinca alkaloids'.)

Pneumonitis — Bleomycin therapy is associated with a potentially life-threatening interstitial pulmonary fibrosis (also called fibrosing alveolitis) in up to 10 percent of patients receiving the drug. Symptoms and signs include nonproductive cough, dyspnea, pleuritic or substernal chest pain, fever, tachypnea, auscultatory crackles, lung restriction, and hypoxemia. Although the symptoms and signs usually develop subacutely between one and six months after bleomycin treatment, they may occur while the patient is still receiving therapy.

Details regarding monitoring, diagnosis, and management of bleomycin-induced lung injury is discussed in more detail separately. (See "Bleomycin-induced lung injury".)

AFTER TREATMENT

Overview — One to two months following the completion of planned therapy (or sooner if the outcome is unfavorable), the response should be documented by history, physical examination, and laboratory studies (complete blood count, erythrocyte sedimentation rate, and biochemical profile). Persistent and otherwise unexplained elevation of the erythrocyte sedimentation rate, while not diagnostic of active disease, is an indication for close surveillance [11,12].

Follow-up imaging studies should be obtained one month after finishing chemotherapy in those who do not receive radiation therapy. Among those in whom radiation therapy is also performed, follow-up imaging studies should be obtained three to six months after its completion. The imaging study of choice is a PET/CT scan, which provides information on the size and activity of residual masses and allows the distinction of active disease versus fibrosis; once the PET scan normalizes, only CT scans should be performed. In unusual or highly suspicious lesions (ie, bone lesions), tissue biopsy may be required to establish the presence or absence of active disease. (See 'Radiologic studies' above.)

Imaging studies

PET/CT scan — Positron emission tomography with computed tomography (PET/CT) scan is the examination of choice for detecting disease activity during and right after treatment [13-16]. Compared with CT scan alone, PET/CT scanning is better able to distinguish between active tumor and necrosis or fibrosis in residual masses [13,17-27]. A positive PET scan can be determined by visual assessment and does not require the use of the standardized uptake value (SUV) [28,29].

The negative predictive value of PET, or the ability of a negative scan to exclude persistent disease or future relapse, averages 80 to 90 percent [14,30]. There is a 10 to 20 percent false-negative rate, which is likely due to the inability of imaging techniques to detect microscopic disease.

As an example, of 2126 patients with newly diagnosed advanced stage HL who received BEACOPP-based chemotherapy as part of the GHSG HD15 trial, 739 patients had residual disease measuring 2.5 cm or greater after completion of planned chemotherapy and were eligible for PET scan [31]. The 548 cases that were PET negative (74 percent) had an estimated four-year progression-free survival of 92 percent without radiation therapy. This estimated PFS was independent of the degree of tumor volume shrinkage. In contrast, the 191 cases that were PET positive (26 percent) had an estimated four-year progression-free survival of 86 percent after treatment with radiation therapy. In this subgroup, a relative reduction of tumor volume less than 40 percent was associated with a higher rate of relapse or progression within the first year (23 versus 5 percent). These results suggest that radiation therapy may be avoided in patients with a negative PET scan after BEACOPP-based therapy. They also suggest that patients with poor tumor shrinkage and PET positivity after chemotherapy have a high risk of progression or relapse despite the use of radiation therapy.

The positive predictive value (PPV) of PET scans in response assessment is more variable with an average of 65 percent. Up to 40 percent of patients with a positive PET scan will not relapse. It is therefore imperative that positive PET scans be confirmed by tissue biopsy prior to giving more therapy. Causes of false positive PET scans include post-inflammatory changes after chemotherapy and radiation treatment, rebound thymic hyperplasia, infectious and inflammatory processes, and brown fat [32]. This high frequency of false positive PET scans after treatment raises the question of whether CT scans should be used in place of PET scans once a baseline negative PET scan has been obtained. In our practice, CT scanning is the preferred follow-up imaging study for patients who attain a complete remission.

CT — Computed tomography (CT) is used in the initial staging of HL and is a key component of re-assessing disease status after treatment. CT scans should include all areas of previous disease involvement and new areas of increased activity on PET scan or physical exam. CT is performed with contrast if it is done alone, but without contrast if it is performed as part of a combined PET/CT study.

Since mediastinal nodes are involved in the majority of patients at presentation, chest CT scanning has a significant role in assessing the response to therapy in HL. Following mediastinal irradiation, the reassessment chest CT should be postponed for three to six months; regression of disease may be slow after radiation therapy and, if evaluation is performed too early, a residual mass may still be visible.

Any residual abnormality seen on CT after radiation therapy must be evaluated to distinguish between residual fibrosis and necrosis and active disease [17]. This distinction can be made by serial studies over time since benign disease will remain stable or decrease in size [18,33], while persistent HL will at some time begin to increase in size. An abnormal widening of the mediastinum or architectural distortion of lymphographic studies may persist for many years without therapy and without evidence of recurrent HL [18,33,34].

If there is evidence of worsening disease in the follow-up CT scans, then the PET/CT may be helpful to additional evidence of a potential recurrence.

MRI — Magnetic resonance imaging (MRI) is not usually employed in the follow-up of patients with HL.

Bone marrow biopsy — Bone marrow involvement eventually occurs in approximately 7 percent of patients with HL, although involvement at presentation is exceptionally rare. If the bone marrow was involved at initial diagnosis, a repeat bone marrow biopsy should be performed after treatment to assess response. A bone marrow biopsy should also be performed in the patient with persistently abnormal blood counts.

Tissue biopsy — In unusual or highly suspicious lesions (eg, bone lesions) as detected by PET/CT scan, tissue biopsy is required to establish the presence or absence of active disease [35]. Biopsy must document persistent lymphoma in cases of progressive disease or relapse before proceeding with further salvage therapy.

A positive PET scan in a previously negative site as determined by PET/CT scan may represent active disease or a false positive. In this setting, a CT scan should be performed to confirm the abnormality:

●If a mass is detected by CT scan, recurrent disease is most likely. Most clinicians would obtain a biopsy to help guide further therapy.

●If a mass cannot be found by CT scan, PET/CT scans should be repeated at regular intervals until the PET reverts to normal.

●If the CT scan is most consistent with an inflammatory process and not recurrent malignancy, serial PET/CT scans and/or other modalities may be used to follow the lesion.

RESPONSE CATEGORIES — The International Working Group (IWG) response criteria originally defined clinical and CT-based categories of complete remission, complete remission unconfirmed, partial remission, stable disease, and progressive disease. In 2007, revised IWG response criteria were devised to incorporate PET scan findings [14]. This eliminated the category of complete remission unconfirmed. The following is a summary of these criteria (table 1):

Complete remission — Patients in complete remission (CR) have no clinical evidence of disease or disease-related symptoms. Since HL is typically fluorodeoxyglucose (FDG)-avid, a post-treatment residual mass of any size is permitted as long as it is PET negative. Spleen and liver must be non-palpable and without nodules. If a pre-treatment bone marrow biopsy was positive, an adequate bone marrow biopsy (with a core size of at least 20 mm) from the same site must be cleared of infiltrate; if this is indeterminate by morphology, immunohistochemistry should be negative.

Partial remission — Partial remission (PR) is defined as a decrease by at least 50 percent in the sum of the products of the largest perpendicular diameters (SPD) of up to six of the largest measurable lesions. Since HL is typically FDG-avid, the post-treatment PET should be positive in at least one previously involved site. There should be no increase in the size of other nodes, liver, or spleen and no new areas of disease. Splenic or hepatic nodules must decrease by at least 50 percent in the SPD (or in the greatest transverse diameter for single nodules). Bone marrow biopsy results are not useful in determining PR. However, if the patient otherwise fits the CR criteria but has a positive bone marrow biopsy, the patient is labeled as having a PR.

Stable disease — Stable disease (SD) occurs when treatment fails to attain a CR or PR but does not have progressive disease. Since HL is typically FDG-avid, the post-treatment PET should be positive at prior sites of disease and no new sites should be present on PET or CT.

Progressive disease or relapse after CR — Relapse after CR or progressive disease (PD) is defined as having any new lesion or an increase from nadir by at least 50 percent of previously involved sites. Development of a new lesion is defined by the appearance of any new lesion more than 1.5 cm in long axis. If the long axis diameter is from 1.1 to 1.5 cm, the lesion should only be considered abnormal if its short axis is more than 1.0 cm. PD is also defined as increase of at least 50 percent in the longest diameter of a previously identified node more than 1 cm in short axis or in the SPD of more than one node. Lesions should be PET positive unless they are below a detectable size (ie, <1.5 cm in long axis by CT).

LONG-TERM FOLLOW-UP — Following the completion of therapy and restaging after the documentation of complete response, patients are seen at periodic intervals to assess a possible relapse and for the emergence of long-term toxicities. When planning the post-treatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. There is no role for routine PET or PET/CT imaging in the longitudinal follow-up of asymptomatic patients after response assessment. This is discussed in more detail separately. (See "Approach to the adult survivor of classic Hodgkin lymphoma".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Hodgkin lymphoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Hodgkin lymphoma in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Throughout treatment, patients should be asked about the presence or absence of B symptoms, treatment-related toxicities, and markers of performance status. Tumor measurements should be recorded and complete blood counts, serum electrolytes, and liver function tests are followed with each cycle of chemotherapy treatment. While the combination of CT scans and PET is the current preferred approach to radiologic follow-up of patients with Hodgkin lymphoma (HL), the use of PET/CT mid treatment is controversial. (See 'During treatment' above.)

●One month following the completion of planned therapy (or sooner if the outcome is unfavorable), the response should be documented by history, physical examination, and laboratory studies (complete blood count, erythrocyte sedimentation rate, and biochemical profile). The follow-up imaging studies of choice are PET/CT scans, or CT scans. PET/CT should be obtained one month after finishing chemotherapy (in those who do not receive radiation therapy) or three to six months after completing radiation therapy. (See 'Overview' above.)

●Residual masses on CT or PET/CT require careful consideration as they may represent residual fibrosis and necrosis or active disease. Serial studies over time can help with this distinction since benign disease will remain stable or decrease in size, while persistent HL will at some time begin to increase in size. Biopsy is strongly recommended if there is suspicion of residual disease and the site is accessible. Close monitoring is preferred if major surgical exploration would be required to confirm residual disease, with pathologic confirmation being performed at the first sign of disease progression before salvage treatments are initiated. (See 'CT' above.)

●The revised International Working Group (IWG) response criteria should be used to define complete remission, partial remission, stable disease, progressive disease or relapse (table 1).

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges the late Peter M Mauch, MD, for his previous role as an author for this topic.